@article {pmid39612941,
year = {2024},
author = {Wean, J and Kowalsky, AH and Laker, R and Will, S and Drucker, DJ and Rhodes, CJ and Seeley, RJ},
title = {Specific loss of GIPR signaling in GABAergic neurons enhances GLP-1R agonist-induced body weight loss.},
journal = {Molecular metabolism},
volume = {},
number = {},
pages = {102074},
doi = {10.1016/j.molmet.2024.102074},
pmid = {39612941},
issn = {2212-8778},
abstract = {OBJECTIVES: Dual incretin agonists are among the most effective pharmaceutical treatments for obesity and type 2 diabetes to date. Such therapeutics can target two receptors, such as the glucagon-like peptide-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor in the case of tirzepatide, to improve glycemia and reduce body weight. Regarding body weight effects, GIPR signaling is thought to involve at least two relevant mechanisms: the enhancement of food intake reduction and the attenuation of aversive effects caused by GLP-1R agonists. Although it is known that dual GLP-1R-GIPR agonism produces greater weight loss than GLP-1R agonism alone, the precise mechanism is unknown.

METHODS: To address this question, we used mice lacking GIPR in the whole body, GABAergic neurons, or glutamatergic neurons. These mice were given various combinations of GLP-1R and GIPR agonist drugs with subsequent food intake and conditioned taste aversion measurements.

RESULTS: A GIPR knockout in either the whole body or selectively in inhibitory GABAergic neurons protects against diet-induced obesity, whereas a knockout in excitatory glutamatergic neurons had a negligible effect. Furthermore, we found that GIPR in GABAergic neurons is essential for the enhanced weight loss efficacy of dual incretin agonism, yet, surprisingly, its removal enhances the effect of GLP-1R agonism alone. Finally, GIPR knockout in GABAergic neurons prevents the anti-aversive effects of GIPR agonism.

CONCLUSIONS: Our findings are consistent with GIPR research at large in that both enhancement and removal of GIPR signaling are metabolically beneficial. Notably, however, our findings suggest that future obesity therapies designed to modulate GIPR signaling, whether by agonism or antagonism, would be best targeted towards GABAergic neurons.},
}

@article {pmid39608697,
year = {2024},
author = {Yasuura, N and Inui, T and Yoshizawa, T and Sogawa, N and Sato, Y and Funahashi, M},
title = {Taste preference and conditioned taste aversion of the metallothionein-1/2 null mice.},
journal = {Physiology & behavior},
volume = {},
number = {},
pages = {114757},
doi = {10.1016/j.physbeh.2024.114757},
pmid = {39608697},
issn = {1873-507X},
abstract = {To investigate the effects of metallothionein (MT)-1/2 gene knockout on the taste preference and the conditioned taste aversion (CTA), we performed an experiment comparing the behavior of wild type mice (WT) and MT-1/2 null mice (KO). The taste preference ratio of saccharin solutions (0.1 or 0.2%) was significantly greater in KO mice than WT mice. The preference ratio of salt and bitter solutions was not different between KO mice and WT mice. After feeding with a low zinc diet, the average saccharin preference ratio was not significantly different between WT and KO mice at any concentration of saccharin. Concentrations of zinc in plasma in KO mice was slightly higher than WT mice, but both were within the physiological range. When conditioning for saccharin using intraperitoneal injection of LiCl, a marked CTA was produced in both WT and KO mice. These results suggest that MT may be involved in the regulation of sweet taste preferences and indicate that the brain function that mediates sweet taste-induced CTA acquisition is maintained in KO mice. In addition, it was suggested that MT was not actively involved in the regulation of plasma zinc concentration in either mice fed a normal diet or mice fed a low zinc diet for a week. The relation between the malfunction of MT-1/2 and signal transduction of intracellular zinc remained to be determined.},
}

@article {pmid39492495,
year = {2023},
author = {Agüera, ADR and Cándido, C and Donaire, R and Papini, MR and Torres, C},
title = {Ketamine retards recovery from reward downshift and supports conditioned taste aversion.},
journal = {Pharmacology, biochemistry, and behavior},
volume = {},
number = {},
pages = {173671},
doi = {10.1016/j.pbb.2023.173671},
pmid = {39492495},
issn = {1873-5177},
abstract = {Ketamine is a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist with antidepressant, anxiolytic, and memory effects in clinical and preclinical studies. The present studies investigated the behavioral effects of ketamine in animals exposed to a consummatory successive negative contrast (cSNC) task involving unexpected reward downshift, negative emotion (frustration), and aversive memory. Food-restricted male rats had 5-min access to 32 % sucrose in each of 10 preshift sessions followed by 4 % sucrose in 4 postshift sessions. Unshifted controls had access to 4 % sucrose during all 14 sessions. Ketamine (10 mg/kg, ip) was injected 30 min before sessions 11 and 12 (Experiment 1) or immediately after session 11 (Experiment 3). The results showed that both pre- and postdownshift session injection of ketamine increased consummatory suppression, as Group 32/Ket exhibited lower sucrose intake than Groups 32/Sal, 4/Ket, and 4/Sal. These effects extended beyond the day(s) of injection. Experiments 2 and 4 showed that the same dose, route of administration, and time of injection induced significant conditioned taste aversion to 4 % sucrose, in the absence of reward downshift. These data suggest that ketamine induces an aversive state that may summate with frustration induced by reward downshift in the cSNC task and also support a conditioned taste aversion to 4 % sucrose in the absence of reward downshift. Implications for these and other experiments involving pre- and postsession administration of ketamine are discussed.},
}

@article {pmid39396668,
year = {2024},
author = {Nakajima, S},
title = {Running-based food aversion learning in freely-fed and hydrated rats: Daily monitoring of running-induced nausea by measuring kaolin clay ingestion: Running-based food aversion learning in non-deprived rats.},
journal = {Physiology & behavior},
volume = {},
number = {},
pages = {114715},
doi = {10.1016/j.physbeh.2024.114715},
pmid = {39396668},
issn = {1873-507X},
abstract = {The main objective of this research was to demonstrate food aversion learning in rats with unrestricted access to food and water using a running-based conditioned taste avoidance paradigm. Experiment 1 showed that the target-running paired training group consumed a statistically smaller amount of the target food (tteok rice cakes) compared to the target/running unpaired control group, but the decrease in consumption over days was not fully supported by a statistical test. Experiment 2a improved the methodology by familiarizing rats with tteok before training, which resulted in both a statistically significant group effect and a statistically significant daily decrease in tteok consumption. Experiment 2b demonstrated that tteok aversion could be reacquired after an extinction phase. These experiments indicate that running-based tteok aversion in non-deprived rats is a valid example of Pavlovian conditioning and suggest that wheel running can cause similar effects in unrestricted rats as observed in food- or water-restricted rats. Additionally, daily measurements of kaolin clay ingestion suggested that wheel running induced nausea in the rats of these experiments.},
}

@article {pmid39371183,
year = {2024},
author = {Bearden, DR and Sportiello, K and Mweemba, M and Lungu, F and Mwanza-Kabaghe, S and Birbeck, G},
title = {Adherence, Adverse Events and Viral Control among Children and Adolescents with HIV in Zambia Switched to an Integrase Inhibitor Regimen.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.09.17.24313837},
pmid = {39371183},
abstract = {BACKGROUND: Based on recent World Health Organization recommendations, there has been a large-scale transition in Sub-Saharan Africa to integrase inhibitor (II)-based antiretroviral therapy (ART) regimens.

SETTING: This study was conducted at an urban referral center in Lusaka, Zambia.

METHODS: This study included 297 children and adolescents with HIV (CAWH) on ART for one year prior to enrollment and followed for 1-4 years after enrollment. ART adherence, ART regimen, and viral load were assessed periodically. Structured interviews were conducted with a subset of 95 children to assess adherence barriers and side effects.

RESULTS: Children on protease inhibitor (PI)-based regimens were more likely to report adherence problems than children taking II- or Efavirenz-based regimens (10% vs. 28%, p=0.03) and noted more days with missed doses (median 1 vs. 0, p=0.02). In interviews, the most common reasons given for poor adherence included bad medication taste, not being home when medications were due, and perceived side effects. The PI group was more likely to report that taste was a problem affecting adherence (22% vs. 4%, p=0.05) and headache as an ART side effect (17% vs. 4%, p=0.05). Switching from a PI- to an II-based regimen was associated with improved adherence (72% vs. 92%, p=0.01) and an undetectable viral load (67% vs. 78%).

CONCLUSIONS: Switching CAWH from PI-based to II-based regimens has many advantages including superior side effect profiles, adherence, and viral suppression. PI taste aversion may be a significant contributor to pediatric adherence issues. Palatability should be considered in pediatric HIV drug development.},
}

@article {pmid39368616,
year = {2024},
author = {Graney, PL and Chen, MY and Wood, RI and Wagner, CK},
title = {Developmental 17-OHPC exposure disrupts behavior regulated by the mesocorticolimbic dopaminergic system in rats.},
journal = {Pharmacology, biochemistry, and behavior},
volume = {},
number = {},
pages = {173886},
doi = {10.1016/j.pbb.2024.173886},
pmid = {39368616},
issn = {1873-5177},
abstract = {The synthetic progestin, 17α-hydroxyprogesterone caproate (17-OHPC), is administered to pregnant individuals with the intention of reducing preterm birth. Although there is evidence that 17-OHPC is likely transferred from mother to fetus, there is little information regarding the potential effects of 17-OHPC administration on behavioral and neural development in offspring. Neonatal 17-OHPC exposure disrupts the development of the mesocorticolimbic dopaminergic pathway and associated behaviors in rats. 17-OHPC exposure altered dopaminergic innervation of prelimbic medial prefrontal cortex (mPFC) in neonates and adolescents and altered performance in measures of decision-making, set-shifting, and reversal-learning tasks. The present study tested the effects of developmental 17-OHPC exposure on numerous cognitive behaviors mediated by the mesocorticolimbic dopaminergic system, such as decision-making in a delay discounting task, latent inhibition following conditioned taste aversion (CTA), and spatial memory in the Morris Water Maze (MWM). The present work also aimed to further investigate response omissions in rats exposed to 17-OHPC during development and the potential role of dopamine D2 receptor in altering omissions in a delay discounting task. 17-OHPC exposure rendered rats less sensitive to an Eticlopride-induced increase in omissions in a delay discounting task when compared to controls. Quinpirole flattened the discount curve in both groups but did not significantly affect omissions in 17-OHPC-exposed or control rats. Following CTA, sucrose-pre-exposed 17-OHPC-exposed rats demonstrated decreased latent inhibition when compared to controls. In Morris Water Maze testing, 17-OHPC-exposed rats did not differ from controls after the first day of testing or during probe testing. These results suggest that exposure to 17-OHPC altered aspects of decision-making and latent inhibition in adult male rats, without affecting performance in a measure of spatial learning and memory. Further, the insensitivity of 17-OHPC-exposed males to an Eticlopride-induced increase in omissions suggests a dysfunction in the D2 receptor following exposure to this clinically used synthetic progestin.},
}

@article {pmid39362067,
year = {2024},
author = {Womersley, JS and Obellianne, C and Padula, AE and Lopez, MF and Griffin, WC and Ball, LE and Berto, S and Grant, KA and Townsend, DM and Uys, JD and Mulholland, PJ},
title = {Adaptations in glutathione-based redox protein signaling pathways and alcohol drinking across species.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {180},
number = {},
pages = {117514},
doi = {10.1016/j.biopha.2024.117514},
pmid = {39362067},
issn = {1950-6007},
abstract = {Alcohol use disorder (AUD) is the most prevalent substance use disorder but there is incomplete knowledge of the underlying molecular etiology. Here, we examined the cytosolic proteome from the nucleus accumbens core (NAcC) of ethanol drinking rhesus macaques to identify ethanol-sensitive signaling proteins. The targets were subsequently investigated using bioinformatics, genetic, and pharmacological manipulations in mouse models of ethanol drinking. Of the 1000+ cytosolic proteins identified in our screen, 50 proteins differed significantly between control and ethanol drinking macaques. Gene Ontology analysis of the differentially expressed proteins identified enrichment in pathways regulating metabolic processes and proteasome activity. Because the family of Glutathione S-transferases (GSTs) was enriched in these pathways, validation studies targeted GSTs using bioinformatics and genetically diverse mouse models. Gstp1 and Gstm2 were identified in Quantitative Trait Loci and published gene sets for ethanol-related phenotypes (e.g., ethanol preference, conditioned taste aversion, differential expression), and recombinant inbred strains that inherited the C57BL/6J allele at the Gstp2 interval consumed higher amounts of ethanol than those that inherited the DBA/2J allele. Genetic deletion of Gstp1/2 led to increased ethanol consumption without altering ethanol metabolism or sucrose preference. Administration of the pharmacologic activator of Gstp1/2, carnosic acid, decreased voluntary ethanol drinking. Proteomic analysis of the NAcC cytosolic of heavy drinking macaques that were validated in mouse models indicate a role for glutathione-mediated redox regulation in ethanol-related neurobiology and the potential of pharmacological interventions targeting this system to modify excessive ethanol drinking.},
}

@article {pmid39134007,
year = {2024},
author = {Havton, GC and Tai, ATC and Vasisht, S and Davies, DL and Asatryan, L},
title = {Preclinical Evaluation of Sodium Butyrate's Potential to Reduce Alcohol Consumption: A Dose-Escalation Study in C57BL/6J Mice in Antibiotic-Enhanced Binge-Like Drinking Model.},
journal = {Pharmacology},
volume = {},
number = {},
pages = {1-13},
doi = {10.1159/000540882},
pmid = {39134007},
issn = {1423-0313},
abstract = {INTRODUCTION: In our earlier efforts to establish gut-brain axis during alcohol use disorder (AUD), we have demonstrated that supplementation of C57BL/6J male mice with 8 mg/mL sodium butyrate, a major short-chain fatty acid, in drinking water reduced ethanol intake and neuroinflammatory response in antibiotic (ABX)-enhanced voluntary binge-like alcohol consumption model, drinking in the dark (DID).

METHODS: To further evaluate the preclinical potential of SB, we have set a dose-escalation study in C57BL/6J male mice to test effects of ad libitum 20 mg/mL SB and 50 mg/mL SB and their combinations with ABX in the DID procedure for 4 weeks. Effects of these SB concentrations on ethanol consumption and bodily parameters were determined for the duration of the treatments. At the end of study, blood, liver, and intestinal tissues were collected to study any potential adverse effects ad to measure blood ethanol concentrations.

RESULTS: Increasing SB concentrations in the drinking water caused a loss in the protective effect against ethanol consumption and produced adverse effects on body and liver weights, reduced overall liquid intake. The hypothesis that these effects were due to aversion to SB smell/taste at these high concentrations were further tested in a follow up proof-of-concept study with intragastric gavage administration of SB. The higher gavage dose (320 mg/kg) caused reduction in ethanol consumption without any adverse effects.

CONCLUSION: Overall, these findings added more support for the therapeutic potential of SB in management of AUD, given a proper form of administration.},
}

@article {pmid39137886,
year = {2024},
author = {Ward-Fear, G and Bruny, M and Rangers, TB and Forward, C and Cooksey, I and Shine, R},
title = {Taste aversion training can educate free-ranging crocodiles against toxic invaders.},
journal = {Proceedings. Biological sciences},
volume = {291},
number = {2028},
pages = {20232507},
doi = {10.1098/rspb.2023.2507},
pmid = {39137886},
issn = {1471-2954},
mesh = {Animals ; *Alligators and Crocodiles/physiology ; *Introduced Species ; Taste ; Avoidance Learning ; Predatory Behavior ; Bufo marinus/physiology ; Western Australia ; },
abstract = {Apex predators play critical ecological roles, making their conservation a high priority. In tropical Australia, some populations of freshwater crocodiles (Crocodylus johnstoni) have plummeted by greater than 70% due to lethal ingestion of toxic invasive cane toads (Rhinella marina). Laboratory-based research has identified conditioned taste aversion (CTA) as a way to discourage consumption of toads. To translate those ideas into landscape-scale management, we deployed 2395 baits (toad carcasses with toxin removed and containing a nausea-inducing chemical) across four gorge systems in north-western Australia and monitored bait uptake with remote cameras. Crocodile abundance was quantified with surveys. Free-ranging crocodiles rapidly learned to avoid toad baits but continued to consume control (chicken) baits. Toad invasion at our sites was followed by high rates of crocodile mortality (especially for small individuals) at a control site but not at nearby treatment sites. In areas with high connectivity to other waterbodies, repeated baiting over successive years had continuing positive impacts on crocodile survival. In summary, we succeeded in buffering the often-catastrophic impact of invasive cane toads on apex predators.},
}

Animals
*Alligators and Crocodiles/physiology
*Introduced Species
Taste
Avoidance Learning
Predatory Behavior
Bufo marinus/physiology
Western Australia

@article {pmid39128699,
year = {2024},
author = {Miranda, MI and Alcalá, A},
title = {Histamine H3 receptor activation in the insular cortex during taste memory conditioning decreases appetitive response but accelerates aversive memory extinction under an ad libitum liquid regimen.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2024.08.002},
pmid = {39128699},
issn = {1873-7544},
abstract = {Conditioned taste aversion (CTA) is a robust associative learning; liquid deprivation during this conditioning allows researchers to obtain readable measures of associative learning. Recent research suggests that thirst could be a crucial motivator that modulates conditioning and memory extinction processes, highlighting the importance of the body's internal state during learning. Furthermore, the histaminergic system is one of the major modulatory systems controlling several behavioral and neurobiological functions, such as feeding, water intake, and nociception. Therefore, this research aimed to assess the effect of H3 histaminergic receptor activation in the insular cortex (IC) during CTA. For this, we conditioned adult male Wistar rats under two regimens: water deprivation and water ad libitum. A classical CTA protocol was used for water deprivation. Before CTA acquisition, 10 μM R-α-methylhistamine (RAMH), an H3 receptor agonist, was injected into the IC. Results showed that RAMH injections decreased CTA in water-deprived rats without affecting the significant aversion conditioning in rats that were given water ad libitum. Moreover, RAMH accelerated the process of aversive memory extinction under ad libitum water conditions. According to our findings, the degree of liquid satiety differentially affected taste-aversive memory formation, and H3 histamine receptors were more involved under water deprivation conditions during acquisition. However, these receptors modulated the strength of aversive conditioning by altering the rate of aversive memory extinction in the absence of deprivation. In conclusion, histaminergic activity in the IC may influence taste memory dynamics through different mechanisms depending on the degree of liquid satiety or deprivation during conditioning.},
}

@article {pmid39008013,
year = {2024},
author = {Fuentes-Ramos, M and Barco, Á},
title = {Unveiling Transcriptional and Epigenetic Mechanisms Within Engram Cells: Insights into Memory Formation and Stability.},
journal = {Advances in neurobiology},
volume = {38},
number = {},
pages = {111-129},
pmid = {39008013},
issn = {2190-5215},
mesh = {*Epigenesis, Genetic ; *Memory/physiology ; Humans ; Animals ; *Neurons/metabolism ; Brain/metabolism ; Fear/physiology ; Transcription, Genetic ; },
abstract = {Memory traces for behavioral experiences, such as fear conditioning or taste aversion, are believed to be stored through biophysical and molecular changes in distributed neuronal ensembles across various brain regions. These ensembles are known as engrams, and the cells that constitute them are referred to as engram cells. Recent advancements in techniques for labeling and manipulating neural activity have facilitated the study of engram cells throughout different memory phases, including acquisition, allocation, long-term storage, retrieval, and erasure. In this chapter, we will explore the application of next-generation sequencing methods to engram research, shedding new light on the contribution of transcriptional and epigenetic mechanisms to engram formation and stability.},
}

*Epigenesis, Genetic
*Memory/physiology
Humans
Animals
*Neurons/metabolism
Brain/metabolism
Fear/physiology
Transcription, Genetic

@article {pmid39004230,
year = {2024},
author = {Batabyal, A and Wiley, B and Matsuoka, H and Komatsuzaki, Y and Lukowiak, K},
title = {Sensory input from osphradium is involved in fluoride detection that alters feeding and memory phenotype in Lymnaea stagnalis.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {115148},
doi = {10.1016/j.bbr.2024.115148},
pmid = {39004230},
issn = {1872-7549},
abstract = {Fluoride (F-) exposure in organisms remains a significant concern due to its widespread presence and potential health implications. Investigating its detection and subsequent effects on behaviour in aquatic organisms like Lymnaea stagnalis provides valuable insights. Our study focused on elucidating the sensory pathways involved in F- detection and its impact on feeding and memory formation. We explored two potential detection mechanisms: direct flow across the integument onto neurons; and sensory input to the central nervous system (CNS) via the osphradium-osphradial ganglion-osphradial nerve pathway (snails use this system for olfactory sensation of multiple compounds). Injection of F- into snails did not alter feeding behaviour or central neuronal activity, suggesting that internalization might not be the primary detection mode. In contrast, severing the osphradial nerve abolished F-'s suppressive effects on feeding and memory formation, implicating the osphradial pathway in F- sensing and behavioral changes. This finding supports the idea that osphradial nerve signaling mediates the behavioral effects of F-. Our study underscores the importance of sensory pathways in F- detection and behavioral modulation in L. stagnalis. Understanding these mechanisms could provide critical insights into how organisms respond to and adapt to environmental chemical stressors like F-.},
}

@article {pmid38815558,
year = {2024},
author = {Xu, LH and Ge, JG and Xiao, SF and Lu, QC and Ji, W and Ma, YQ and Song, JY and Zhang, XY and Cai, ML and Li, X and Zhou, X and Jiang, ZL},
title = {ANP alleviates motion sickness potentially through regulating endolymph volume in the inner ear increased by AVP.},
journal = {Neuroendocrinology},
volume = {},
number = {},
pages = {},
doi = {10.1159/000539586},
pmid = {38815558},
issn = {1423-0194},
abstract = {INTRODUCTION: Dimenhydrinate and scopolamine are frequently used drugs, but they cause drowsiness and performance decrement. Therefore, it is crucial to find peripheral targets and develop new drugs without central side effects. This study aims to investigate the anti-motion sickness action and inner ear-related mechanisms of ANP.

METHODS: Endolymph volume in the inner ear was measured with magnetic resonance imaging and expression of AQP2 and p-AQP2 was detected with Western blot analysis and immunofluorescence method.

RESULTS: Both rotational stimulus and intraperitoneal AVP injection induced conditioned taste aversion (CTA) to 0.15% sodium saccharin solution and an increase in the endolymph volume of the inner ear. However, intraperitoneal injection of ANP effectively alleviated the CTA behaviour, and reduced the increase in the endolymph volume after rotational stimulus. Intratympanic injection of ANP also inhibited rotational stimulus-induced CTA behaviour, but anantin peptide, an inhibitor of ANP receptor A (NPR-A), blocked this inhibitory effect of ANP. Both rotational stimulus and intraperitoneal AVP injection increased the expression of AQP2 and p-AQP2 in the inner ear of rats, but these increases were blunted by ANP injection. In in-vitro experiments, ANP addition decreased AVP-induced increases in the expression and phosphorylation of AQP2 in cultured endolymphatic sac epithelial cells.

CONCLUSION: Therefore, the present study suggests that ANP could alleviate motion sickness through regulating endolymph volume of the inner ear increased by AVP, and this action of ANP is potentially mediated by activating NPR-A and antagonising the increasing effect of AVP on AQP2 expression and phosphorylation.},
}

@article {pmid38660288,
year = {2024},
author = {Rana, H and Panchal, M and Thakkar, V and Gandhi, T and Dholakia, M},
title = {Investigating in-vitro functionality and in-vivo taste assessment of eco-friendly Tadalafil Pastilles.},
journal = {Heliyon},
volume = {10},
number = {8},
pages = {e29543},
pmid = {38660288},
issn = {2405-8440},
abstract = {Tadalafil (TDL) has poor bioavailability due to the less aqueous solubility and bitter taste. Oral solid dosage forms, especially tablets, have a broad market worldwide. Constraints of tablets are a long process, pollution, high processing cost, and requiring more excipient. The research was performed to optimize an eco-friendly immediate-acting pastille of TDL to put forward an alternate formulation to a tablet using advanced data mining tools. Another objective is to assess the taste masking of TDL using the Brief Access Taste Aversion (BATA) model. The amount of PEG-4000, Polyox N-10, and Kyron T-314 were chosen as critical material attributes from failure mode effect analysis. Box-Behnken design (BBD) was utilized to optimize the pastilles and ascertained the significant impact of chosen variables on disintegration time and % CDR at 10 min. The control strategy and optimal region were located using an overlay plot. The pastilles were able to release the drug within 15 min due to faster disintegration. The formulated pastilles were of uniform size, shape, and mechanical strength. The bitter taste of TDL was masked and confirmed by the BATA model. The newer formulation may be helpful in the industry due to its eco-friendly, single-step, and economical process. It unlocks a new direction in the field of oral solid dosage form as an alternative to tablets.},
}

@article {pmid38656972,
year = {2024},
author = {Perez, CI and Luis-Islas, J and Lopez, A and Diaz, X and Molina, O and Arroyo, B and Moreno, MG and Lievana, EG and Fonseca, E and Castañeda-Hernández, G and Gutierrez, R},
title = {Tesofensine, a novel antiobesity drug, silences GABAergic hypothalamic neurons.},
journal = {PloS one},
volume = {19},
number = {4},
pages = {e0300544},
doi = {10.1371/journal.pone.0300544},
pmid = {38656972},
issn = {1932-6203},
mesh = {Animals ; *GABAergic Neurons/drug effects/metabolism ; Rats ; Mice ; *Anti-Obesity Agents/pharmacology ; Male ; *Obesity/drug therapy/metabolism ; Feeding Behavior/drug effects ; Hypothalamic Area, Lateral/drug effects/metabolism ; Hypothalamus/drug effects/metabolism ; Mice, Transgenic ; Weight Loss/drug effects ; Rats, Sprague-Dawley ; *Bridged Bicyclo Compounds, Heterocyclic ; },
abstract = {Obesity is a major global health epidemic that has adverse effects on both the people affected as well as the cost to society. Several anti-obesity drugs that target GLP-1 receptors have recently come to the market. Here, we describe the effects of tesofensine, a novel anti-obesity drug that acts as a triple monoamine neurotransmitter reuptake inhibitor. Using various techniques, we investigated its effects on weight loss and underlying neuronal mechanisms in mice and rats. These include behavioral tasks, DeepLabCut videotaped analysis, electrophysiological ensemble recordings, optogenetic activation, and chemogenetic silencing of GABAergic neurons in the Lateral Hypothalamus (LH). We found that tesofensine induces a greater weight loss in obese rats than lean rats, while differentially modulating the neuronal ensembles and population activity in LH. In Vgat-ChR2 and Vgat-IRES-cre transgenic mice, we found for the first time that tesofensine inhibited a subset of LH GABAergic neurons, reducing their ability to promote feeding behavior, and chemogenetically silencing them enhanced tesofensine's food-suppressing effects. Unlike phentermine, a dopaminergic appetite suppressant, tesofensine causes few, if any, head-weaving stereotypy at therapeutic doses. Most importantly, we found that tesofensine prolonged the weight loss induced by 5-HTP, a serotonin precursor, and blocked the body weight rebound that often occurs after weight loss. Behavioral studies on rats with the tastant sucrose indicated that tesofensine's appetite suppressant effects are independent of taste aversion and do not directly affect the perception of sweetness or palatability of sucrose. In summary, our data provide new insights into the effects of tesofensine on weight loss and the underlying neuronal mechanisms, suggesting that tesofensine may be an effective treatment for obesity and that it may be a valuable adjunct to other appetite suppressants to prevent body weight rebound.},
}

Animals
*GABAergic Neurons/drug effects/metabolism
Rats
Mice
*Anti-Obesity Agents/pharmacology
Male
*Obesity/drug therapy/metabolism
Feeding Behavior/drug effects
Hypothalamic Area, Lateral/drug effects/metabolism
Hypothalamus/drug effects/metabolism
Mice, Transgenic
Weight Loss/drug effects
Rats, Sprague-Dawley
*Bridged Bicyclo Compounds, Heterocyclic

@article {pmid38639079,
year = {2024},
author = {Rivi, V and Batabyal, A and Benatti, C and Sarti, P and Blom, JMC and Tascedda, F and Lukowiak, K},
title = {A translational and multidisciplinary approach to studying the Garcia effect, a higher form of learning with deep evolutionary roots.},
journal = {The Journal of experimental biology},
volume = {227},
number = {8},
pages = {},
doi = {10.1242/jeb.247325},
pmid = {38639079},
issn = {1477-9145},
support = {//Natural Sciences and Engineering Research Council of Canada/ ; //Regione Emilia Romagna/ ; //Università Degli Studi di Modena e Reggio Emila/ ; },
abstract = {Animals, including humans, learn and remember to avoid a novel food when its ingestion is followed, hours later, by sickness - a phenomenon initially identified during World War II as a potential means of pest control. In the 1960s, John Garcia (for whom the effect is now named) demonstrated that this form of conditioned taste aversion had broader implications, showing that it is a rapid but long-lasting taste-specific food aversion with a fundamental role in the evolution of behaviour. From the mid-1970s onward, the principles of the Garcia effect were translated to humans, showing its role in different clinical conditions (e.g. side-effects linked to chemotherapy). However, in the last two decades, the number of studies on the Garcia effect has undergone a considerable decline. Since its discovery in rodents, this form of learning was thought to be exclusive to mammals; however, we recently provided the first demonstration that a Garcia effect can be formed in an invertebrate model organism, the pond snail Lymnaea stagnalis. Thus, in this Commentary, after reviewing the experiments that led to the first characterization of the Garcia effect in rodents, we describe the recent evidence for the Garcia effect in L. stagnalis, which may pave the way for future studies in other invertebrates and mammals. This article aims to inspire future translational and ecological studies that characterize the conserved mechanisms underlying this form of learning with deep evolutionary roots, which can be used to address a range of different biological questions.},
}

@article {pmid38587941,
year = {2024},
author = {Michaud, NL and Bouton, ME},
title = {An analysis of reinstatement after extinction of a conditioned taste aversion.},
journal = {Journal of experimental psychology. Animal learning and cognition},
volume = {50},
number = {2},
pages = {144-160},
doi = {10.1037/xan0000378},
pmid = {38587941},
issn = {2329-8464},
support = {/NH/NIH HHS/United States ; },
abstract = {Taste aversion learning has sometimes been considered a specialized form of learning. In several other conditioning preparations, after a conditioned stimulus (CS) is conditioned and extinguished, reexposure to the unconditioned stimulus (US) by itself can reinstate the extinguished conditioned response. Reinstatement has been widely studied in fear and appetitive Pavlovian conditioning, as well as operant conditioning, but its status in taste aversion learning is more controversial. Six taste-aversion experiments with rats therefore sought to discover conditions that might encourage it there. The results often yielded little to no evidence of reinstatement, and we also found no evidence of concurrent recovery, a related phenomenon in which responding to a CS that has been conditioned and extinguished is restored if a second CS is separately conditioned. However, a key result was that reinstatement occurred when the conditioning procedure involved multiple closely spaced conditioning trials that could have allowed the animal to learn that a US presentation signaled or set the occasion for another trial with a US. Such a mechanism is precluded in many taste aversion experiments because they often use very few conditioning trials. Overall, the results suggest that taste aversion learning is experimentally unique, though not necessarily biologically or evolutionarily unique. (PsycInfo Database Record (c) 2024 APA, all rights reserved).},
}

@article {pmid38562680,
year = {2024},
author = {Taxier, LR and Flanigan, ME and Haun, HL and Kash, TL},
title = {Retrieval of an ethanol-conditioned taste aversion promotes GABAergic plasticity in the insular cortex.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.03.20.585950},
pmid = {38562680},
abstract = {UNLABELLED: Blunted sensitivity to ethanol's aversive effects can increase motivation to consume ethanol; yet, the neurobiological circuits responsible for encoding these aversive properties are not fully understood. Plasticity in cells projecting from the insular cortex (IC) to the basolateral amygdala (BLA) is critical for taste aversion learning and retrieval, suggesting this circuit's potential involvement in modulating the aversive properties of ethanol. Here, we tested the hypothesis that GABAergic activity onto IC-BLA projections would be facilitated following the retrieval of an ethanol-conditioned taste aversion (CTA). Consistent with this hypothesis, frequency of mIPSCs was increased following retrieval of an ethanol-CTA across cell layers in IC-BLA projection neurons. This increase in GABAergic plasticity occurred in both a circuit-specific and learning-dependent manner. Additionally, local inhibitory inputs onto layer 2/3 IC-BLA projection neurons were greater in number and strength following ethanol-CTA. Finally, DREADD-mediated inhibition of IC parvalbumin-expressing cells blunted the retrieval of ethanol-CTA in male, but not female, mice. Collectively, this work implicates a circuit-specific and learning-dependent increase in GABAergic tone following retrieval of an ethanol-CTA, thereby advancing our understanding of how the aversive effects of ethanol are encoded in the brain.

SIGNIFICANCE STATEMENT: Sensitivity to the aversive properties of ethanol contributes to motivation to consume alcohol. However, the plasticity-associated mechanisms through which ethanol's aversive effects are represented within neural circuits are largely unidentified. In the present study, we used whole-cell patch clamp electrophysiology combined with synaptic input mapping to identify alterations in GABAergic plasticity within the insula, and within cells projecting from the insula to the basolateral amygdala. We demonstrate learning and circuit-specific alterations in GABAergic tone following retrieval of an ethanol-conditioned taste aversion, as well as a male-specific role for Parvalbumin-expressing interneurons in modulating the strength of an ethanol-conditioned taste aversion. Combined, these findings provide novel insights into how the aversive properties of ethanol are encoded within brain circuitry.},
}

@article {pmid38492666,
year = {2024},
author = {Trevisonno, J and Venter, C and Pickett-Nairne, K and Bégin, P and Cameron, SB and Chan, ES and Cook, VE and Factor, JM and Groetch, M and Hanna, MA and Jones, DH and Wasserman, RL and Mack, DP},
title = {Food aversion and anxiety represent primary patient barriers to food oral immunotherapy.},
journal = {The journal of allergy and clinical immunology. In practice},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaip.2024.03.014},
pmid = {38492666},
issn = {2213-2201},
abstract = {While oral immunotherapy (OIT) for food allergy is a reasonable treatment option, barriers to this procedure's implementation have not been extensively evaluated from a patient perspective OBJECTIVE: We evaluated the barriers patients face during OIT administration, including anxiety and taste aversion, and evaluated the role of healthcare professionals, especially dietitians METHODS: A survey in Canada and the US involved families currently enrolled in food OIT programmes RESULTS: Of responses from 379 participants, fear of reaction was the most common barrier to OIT initiation, with 45.6% reporting it being a "very significant" barrier with other fears reported. However, taste aversion represented the prominent obstacle to continuation. Taste aversion was associated with slower buildup (p=0.02), and reduction in dose (p=0.002). Taste aversion was a strongly age-dependent barrier for initiation (p<0.001) and continuation (p<0.002), with older children over 6 years of age reporting it as a very significant barrier (p<0.001). Boredom was reported as a concern for specific allergens such as peanut, egg, sesame, and hazelnuts (p<0.05), emphasizing the need for diverse food options. Notably, 59.9% of respondents mixed OIT foods with sweet items. Despite these dietary concerns, dietitians were underutilized, with only 9.5% of respondents having seen a dietitian and the majority finding dietitian support helpful with greater certainty about the exact dose (p<0.001) CONCLUSIONS: Taste aversion and anxiety represent primary patient-related barriers to OIT. Taste aversion was highly age-dependent, with older patients being more affected. Dietitians and psychology support were underutilized, representing a critical target to improve adherence and OIT success.},
}

@article {pmid38471095,
year = {2024},
author = {Osler, AL and Alfredo, KA and Mihelcic, JR},
title = {Chlorine Water Taste Threshold and Acceptability among Indigenous and Non-Indigenous Populations in Rural Panama.},
journal = {Environmental science & technology},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.est.3c05630},
pmid = {38471095},
issn = {1520-5851},
abstract = {Although gains in access to water services over the past two decades have been large, more than two billion people still lack access to safely managed drinking water. This study examines and compares free chlorine taste and acceptability thresholds of rural Indigenous Ngäbe and rural Latino Panamanians to study if taste aversion may be a limiting factor in chlorination of community systems in Panama using the three-alternative forced choice test methodology. This study is the first to establish a best-estimate taste threshold for a rural Indigenous group and the only study in Latin America to report best-estimate taste thresholds using those methods. Median taste thresholds were 0.87 mg/L Cl2 for Indigenous Ngäbe participants (n = 82) and 1.64 mg/L Cl2 for Latino participants (n = 64), higher than both the minimum concentration for biologically safe water (0.2 mg/L) and the recommended concentration range in Panama (0.3-0.8 mg/L). Median acceptability thresholds were established much higher than taste thresholds at 3.45 mg/L Cl2. The results show that the ability to accurately taste chlorine may not be the limiting factor for adoption of safe water initiatives in remote and Indigenous communities.},
}

@article {pmid38383904,
year = {2024},
author = {Ramirez, LA and Przybysz, KR and Pitock, JR and Starr, EM and Yang, H and Glover, EJ},
title = {Attenuated incubation of ethanol-induced conditioned taste aversion in a model of dependence.},
journal = {Psychopharmacology},
volume = {},
number = {},
pages = {},
pmid = {38383904},
issn = {1432-2072},
support = {AA029130/AA/NIAAA NIH HHS/United States ; AA022538/AA/NIAAA NIH HHS/United States ; AA024208/AA/NIAAA NIH HHS/United States ; AA026577/AA/NIAAA NIH HHS/United States ; },
abstract = {RATIONALE: Preclinical studies report attenuated ethanol-induced conditioned taste aversion (CTA) following chronic ethanol exposure, suggesting that tolerance develops to the aversive properties of ethanol. However, these studies are confounded by pre-exposure to the unconditioned stimulus (US; ethanol), which is well known to hinder conditioning.

OBJECTIVES: This study was designed to determine whether chronic ethanol exposure produces tolerance to the aversive properties of ethanol in the absence of a US pre-exposure confound.

METHODS: CTA was performed in adult male and female Long-Evans rats by pairing 0.1% ingested saccharin with an intraperitoneal injection of ethanol (1.5 or 2.0 g/kg) or saline. Rats were then rendered ethanol dependent using chronic intermittent ethanol (CIE) vapor exposure. Controls were exposed to room air (AIR). The effect of chronic ethanol on CTA expression and reconditioning were examined following vapor exposure.

RESULTS: Prior to vapor exposure, both sexes developed CTA to a comparable degree with 2.0 g/kg producing greater CTA than 1.5 g/kg ethanol. Following vapor exposure, AIR controls exhibited an increase in CTA magnitude compared to pre-vapor levels. This effect was largely absent in CIE-exposed rats. Re-conditioning after vapor exposure facilitated increased CTA magnitude to a similar degree in AIR- and CIE-exposed males. In contrast, CTA magnitude was unchanged by re-conditioning in females.

CONCLUSIONS: These data suggest that chronic ethanol does not facilitate tolerance to the aversive properties of ethanol but rather attenuates incubation of ethanol-induced CTA. Loss of CTA incubation suggests that CIE exposure disrupts circuits encoding aversion.},
}

@article {pmid38332437,
year = {2024},
author = {Boakes, RA and Badolato, C and Rehn, S},
title = {Taste aversion learning during successive negative contrast.},
journal = {Learning & behavior},
volume = {},
number = {},
pages = {},
pmid = {38332437},
issn = {1543-4508},
support = {ARC DP17010392//Australian Research Council/ ; },
abstract = {Previous experiments found that acceptance of saccharin by rats was reduced if they had prior experience of sucrose or some other highly palatable solution. This study tested whether such successive negative contrast (SNC) effects involve acquisition of an aversion to the new taste. In three experiments, rats were switched from sucrose exposure in Stage 1 to a less palatable solution containing a new taste in Stage 2. In Experiments 1 and 2, a novel flavor was added to a saccharin solution at the start of Stage 2. In Experiment 1, preference tests revealed a weak aversion to the added vanilla flavor in the Suc-Sacch group, while in Experiment 2 an aversion was found in the Suc-Sacch group to the salty flavor that was used, compared with controls given access either saccharin or water in Stage 1. In Experiment 3, the Suc-Quin group, given quinine solution in Stage 2, displayed a greater aversion to quinine than a Water-Quin control group. These results support the suggestion that taste aversion learning plays a role in the initial suppression of intakes in a qualitative consummatory SNC effect. However, in the light of other evidence, it seems that the unusual persistence of successive negative contrast when rats are switched from sucrose to saccharin is not due to a long-lasting reduction in the value of saccharin.},
}

@article {pmid38303664,
year = {2024},
author = {Przybysz, KR and Ramirez, LA and Pitock, JR and Starr, EM and Yang, H and Glover, EJ},
title = {A translational rodent model of individual differences in sensitivity to the aversive properties of ethanol.},
journal = {Alcohol, clinical & experimental research},
volume = {},
number = {},
pages = {},
doi = {10.1111/acer.15267},
pmid = {38303664},
issn = {2993-7175},
support = {AA022538/AA/NIAAA NIH HHS/United States ; AA024208/AA/NIAAA NIH HHS/United States ; AA026577/AA/NIAAA NIH HHS/United States ; AA029130/AA/NIAAA NIH HHS/United States ; },
abstract = {BACKGROUND: A strong relationship exists between individual sensitivity to the aversive properties of ethanol and risk for alcohol use disorder (AUD). Despite this, our understanding of the neurobiological mechanisms underlying the subjective response to ethanol is limited. A major contributor to this lack of knowledge is the absence of preclinical models that enable exploration of this individual variability such as is possible in studies of humans.

METHODS: Adult male and female Long-Evans rats were trained to associate a novel tastant (saccharin) with acute exposure to either saline or ethanol (1.5 g/kg or 2.0 g/kg i.p.) over three conditioning days using a standard conditioned taste aversion (CTA) procedure. Variability in sensitivity to ethanol-induced CTA was phenotypically characterized using a median split across the populations studied.

RESULTS: When examining group averages, both male and female rats exposed to saccharin paired with either dose of ethanol exhibited lower saccharin intake relative to saline controls indicative of ethanol-induced CTA. Examination of individual data revealed a bimodal distribution of responses uncovering two distinct phenotypes present in both sexes. CTA-sensitive rats exhibited a rapid and progressive reduction in saccharin intake with each successive ethanol pairing. In contrast, saccharin intake was unchanged or maintained after an initial decrease from baseline levels in CTA-resistant rats. While CTA magnitude was similar between male and female CTA-sensitive rats, among CTA-resistant animals females were more resistant to the development of ethanol-induced CTA than males. Phenotypic differences were not driven by differences in baseline saccharin intake.

CONCLUSIONS: These data parallel work in humans by revealing individual differences in sensitivity to the aversive properties of ethanol that emerge immediately after initial exposure to ethanol in both sexes. This model can be used in future studies to investigate the neurobiological mechanisms that confer risk for AUD.},
}

@article {pmid38298775,
year = {2024},
author = {Douton, JE and Carelli, RM},
title = {Unraveling Sex Differences in Affect Processing: Unique Oscillatory Signaling Dynamics in the Infralimbic Cortex and Nucleus Accumbens Shell.},
journal = {Biological psychiatry global open science},
volume = {4},
number = {1},
pages = {354-362},
doi = {10.1016/j.bpsgos.2023.08.011},
pmid = {38298775},
issn = {2667-1743},
abstract = {BACKGROUND: Negative affect is prevalent in psychiatric diseases such as depression and addiction. Projections from the infralimbic cortex (IL) to the nucleus accumbens shell (NAcSh) are causally linked to learned negative affect as 20 Hz optogenetic stimulation of this circuit reduces conditioned taste aversion (CTA) in male but not female rats. However, the prior study did not provide insight into how innate versus learned negative affect are processed in these areas across sex.

METHODS: To address this issue, local field potential activity was simultaneously recorded in the IL and NAcSh in response to intraoral infusion of rewarding (saccharin) and aversive (quinine) tastants and following induction of a CTA in male and female Sprague Dawley rats.

RESULTS: Local field potential oscillatory activity within each brain region to saccharin varied across sex. In males, CTA increased IL resting-state power, which was correlated with the strength of the learned aversion, and reduced beta power and IL-NAcSh coherence. In females, CTA increased gamma power in the NAcSh. Similar effects were observed in males and females after CTA in theta-low gamma phase-amplitude coupling. Finally, while quinine produced similar effects in oscillatory power across sex, females showed differences in phase-amplitude coupling within the NAcSh that may be linked to aversion resistance.

CONCLUSIONS: We revealed sex-specific hedonic processing in the IL and NAcSh and how oscillatory signaling is disrupted in learned negative affect, revealing translationally relevant insight into potential treatment strategies that can help to reduce the deleterious effects of learned negative affect in psychiatric illnesses.},
}

@article {pmid38215678,
year = {2023},
author = {Yoshida, Y and Fujishiro, S and Kawai, R and Kawabata, F},
title = {Characterization of taste sensitivities to amino acids and sugars by conditioned taste aversion learning in chickens.},
journal = {Animal : an international journal of animal bioscience},
volume = {18},
number = {2},
pages = {101050},
doi = {10.1016/j.animal.2023.101050},
pmid = {38215678},
issn = {1751-732X},
abstract = {Taste plays an essential role in regulating the feeding behaviors of animals. The present study aimed to characterize the taste sensory profiles of amino acids and sugars in chickens. To achieve this, we employed a conditioned taste aversion learning method, which is characterized by a specific pairing of gastrointestinal malaise and taste perception. Our findings revealed that chickens were able to learn to avoid L-Val, L-Lys, and L-His through conditioned taste aversion learning, and exhibited a strong aversion to L-Arg. These results suggest that chickens are primarily sensitive to basic amino acids, including L-Lys, which is a crucial limiting amino acid in feeds. Interstingly, this sensitivity to basic amino acids in chickens contrasts with humans, who are mainly sensitive to acidic amino acids as umami taste. Furthermore, despite the absence of a mammalian sweet taste receptor gene in the chicken genome, we demonstrated that chickens learned to avoid glucose, galactose, sucrose, and maltose by conditioned taste aversion learning. Taken together, the present study provides the idea that chickens possess a gustatory perception toward specific amino acids and sugars for the detection of beneficial nutrients in their feeds.},
}

@article {pmid38211776,
year = {2024},
author = {Briones-Vidal, MG and Reyes-García, SE and Escobar, ML},
title = {NEUROTROPHIN-3 INTO THE INSULAR CORTEX STRENGTHENS CONDITIONED TASTE AVERSION MEMORY.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {114857},
doi = {10.1016/j.bbr.2024.114857},
pmid = {38211776},
issn = {1872-7549},
abstract = {Memory consolidation is an essential process of long-term memory formation. Neurotrophins have been suggested as key regulators of activity dependent changes in the synaptic efficacy and morphology, which are considered the downstream mechanisms of memory consolidation. The neurotrophin 3 (NT-3), a member of the neurotrophin family, and its high affinity receptor TrkC, are widely expressed in the insular cortex (IC), a region with a critical role in the consolidation of the conditioned taste aversion (CTA) paradigm, in which an animal associates a novel taste with nausea. Nevertheless, the role of this neurotrophin in the cognitive processes that the IC mediates remains unexamined. To answer whether NT-3 is involved in memory consolidation at the IC, adult male Wistar rats were administered with NT-3 or NT-3 in combination with the Trk receptors inhibitor K252a into the IC, immediately after CTA acquisition under two different conditions: a strong-CTA (0.2M lithium chloride i.p.) or a weak-CTA (0.1M lithium chloride i.p.). Our results show that NT-3 strengthens the memory trace of CTA, transforming a weak conditioning into a strong one, in a Trk-dependent manner. The present evidence suggests that NT-3 has a key role in the consolidation process of an aversive memory in a neocortical region.},
}

@article {pmid38204574,
year = {2023},
author = {Zhang, FX and Xie, XH and Guo, ZX and Wang, HD and Li, H and Wu, KLK and Chan, YS and Li, YQ},
title = {Evaluating proxies for motion sickness in rodent.},
journal = {IBRO neuroscience reports},
volume = {15},
number = {},
pages = {107-115},
pmid = {38204574},
issn = {2667-2421},
abstract = {Motions sickness (MS) occurs when the brain receives conflicting sensory signals from vestibular, visual and proprioceptive systems about a person's ongoing position and/or motion in relation to space. MS is typified by symptoms such as nausea and emesis and implicates complex physiological aspects of sensations and sensorimotor reflexes. Use of animal models has been integral to unraveling the physiological causality of MS. The commonly used rodents (rat and mouse), albeit lacking vomiting reflex, reliably display phenotypic behaviors of pica (eating of non-nutritive substance) and conditioned taste aversion (CTAver) or avoidance (CTAvoi) which utilize neural substrates with pathways that cause gastrointestinal malaise akin to nausea/emesis. As such, rodent pica and CTAver/CTAvoi have been widely used as proxies for nausea/emesis in studies dealing with neural mechanisms of nausea/emesis and MS, as well as for evaluating therapeutics. This review presents the rationale and experimental evidence that support the use of pica and CTAver/CTAvoi as indices for nausea and emesis. Key experimental steps and cautions required when using rodent MS models are also discussed. Finally, future directions are suggested for studying MS with rodent pica and CTAver/CTAvoi models.},
}

@article {pmid38161042,
year = {2023},
author = {Lockwood, DR and Cassell, JA and Smith, JC and Houpt, TA},
title = {Patterns of ingestion of rats during chronic oral administration of lithium chloride.},
journal = {Physiology & behavior},
volume = {},
number = {},
pages = {114454},
doi = {10.1016/j.physbeh.2023.114454},
pmid = {38161042},
issn = {1873-507X},
abstract = {Chronic lithium administration to rodents is used to explore the potential neural mechanisms of mood stabilization, as well as to model the side effects of chronic lithium on multiple organ systems. Oral administration of lithium in the maintenance diet or drinking water is convenient, but lithium can acutely affect intake and it can mediate acquisition of conditioned taste aversions. We compared ad libitum food and fluid intake by male rats with LiCl or NaCl solutions as their sole source of fluid across 20 days, with a commonly used dosage of LiCl (24 mM: 1 g / L LiCl). To quantify the pattern of intake, rats were housed in cages equipped with lickometers to detect licks and infrared photobeams to detect food access with 6-s resolution. To determine if rats formed a CTA to LiCl, they were subsequently tested with access to NaCl. Rats showed an immediate avoidance of the LiCl solution, as seen on the first day of access by an increased latency to initiate drinking and a decreased size of drinking bouts. Rats showed a differential response to LiCl vs. NaCl after as few as 5 licks. Chronic consumption of LiCl solution led to significantly decreased food and fluid intake compared to baseline, with concomitant weight loss. The decreased intake was realized by marked changes in the pattern of drinking and feeding bouts: a decrease in per-lick volume and a decrease in licks per drinking bout, and an increase in feeding bout duration resulting in an overall decrease in eating rate. Conversely, chronic NaCl access led to an increase in drinking bout number and licks/bout. The avoidance of LiCl was likely a combination of toxic effects of ingested LiCl and rapid acquisition of a learned aversion to the taste of LiCl, as shown by an extinguishable generalized aversion to NaCl solution during subsequent NaCl test days. The marked effect of chronic oral LiCl on ingestion may impact the oral dosing of lithium as well as the rat's metabolic status.},
}

@article {pmid38154277,
year = {2023},
author = {Gradowski, L},
title = {From fringe to mainstream: The Garcia effect.},
journal = {Studies in history and philosophy of science},
volume = {103},
number = {},
pages = {114-122},
doi = {10.1016/j.shpsa.2023.12.004},
pmid = {38154277},
issn = {0039-3681},
abstract = {The rejection of research results is sometimes thought to be justified in cases of individuals embracing fringe ideas that depart significantly from prevailing orthodoxy, or in cases of individuals who lack appropriate expertise or credentials. The case of John Garcia exhibits both of these dimensions, and illustrates that such rejection can delay scientific advancements. Garcia's work decisively challenged what was the orthodoxy in psychology in the midcentury: behaviorism. Behaviorist learning theorists suffered from theory-entrenchment insofar as they failed to acknowledge Garcia's anomalous research findings that ran counter to their theoretical expectations. The case study also illustrates that theories on the margins can become embraced as a result of advancements in adjacent research fields. Studying how Garcia's work moved from fringe to mainstream results in lessons for the philosophy of science and epistemology more generally. Only when we see the mechanisms of exclusion at work can we understand how science and other knowledge production systems can inadvertently act counterproductively via gatekeeping practices that filter out unorthodox points of view.},
}

@article {pmid38048984,
year = {2023},
author = {Dornellas, APS and Thiele, TE and Navarro, M},
title = {Chemogenetic inhibition of locus coeruleus to rostromedial tegmental nucleus noradrenergic pathway increases light cycle ethanol drinking in male and female mice and blunts ethanol-induced CTA.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {109809},
doi = {10.1016/j.neuropharm.2023.109809},
pmid = {38048984},
issn = {1873-7064},
abstract = {We recently showed that chemogenetic activation of the locus coeruleus (LC) to the rostromedial tegmental nucleus (RMTg) noradrenergic (NE) pathway significantly blunted binge-like ethanol drinking and induced aversive-like behaviors in mice. The aim of the present study is to determine if silencing this TH + LC → RMTg noradrenergic pathway promotes increased levels of binge-like ethanol intake and reduced ethanol-induced conditioned taste aversion (CTA). To this end, both male and female TH-ires-cre mice on a C57BL/6 J background were cannulated in the RMTg and injected in the LC with rAVV viruses that encode cre-dependent Gi-expressing designer receptor exclusively activated by designer drugs (DREADDs), or its control, to directly control the activity of NE neurons. Inhibition of the LC to RMTg pathway had no effect on the binge-ethanol drinking in a "drinking-in-the-dark" (DID) paradigm. However, when using this paradigm during the light cycle, silencing of this circuit significantly increased ethanol intake without altering sucrose drinking. Moreover, we found that inhibition of this circuit significantly attenuated an ethanol-induced CTA. In addition, when compared to control animals, pairing RMTg-directed Clozapine N-oxide (CNO) with an i.p. injection of 1.5 g/kg ethanol reduced c-Fos activation in the LC, and increased c-Fos expression in the ventral tegmental area (VTA) in Gi-expressing mice. Our data show that inhibition of the TH + LC to the RMTg pathway significantly increased ethanol drinking as well as attenuated ethanol-induced CTA, supporting the involvement of the LC to RMTg noradrenergic circuit as an important protective mechanism against excessive ethanol consumption.},
}

@article {pmid37989122,
year = {2023},
author = {Dong, XC and Xu, DY},
title = {Research progress on the role and mechanism of GDF15 in body weight regulation.},
journal = {Obesity facts},
volume = {},
number = {},
pages = {},
doi = {10.1159/000535089},
pmid = {37989122},
issn = {1662-4033},
abstract = {BACKGROUND: Growth differentiation factor-15 (GDF-15) is a member of the growth differentiation factor subfamily in the transforming growth factor beta superfamily. GDF15 has multiple functions and can regulate biological processes. High levels of GDF15 in the circulation can affect metabolic processes. Studies have shown that GDF15 is associated with changes in body weight.

SUMMARY: This review reviews the current knowledge on the relationship between GDF15 and body weight change, focusing on the role and mechanism of GDF15 in body weight regulation. GDF15 plays an important role in reducing food intake, improving insulin resistance, and breaking down fat, suggesting that GDF15 has an important regulatory effect on body weight. The mechanism by which GDF15 causes reduced food intake may be related to changes in food preference, delayed gastric emptying, and conditioned taste aversion. GDF15 can combat insulin resistance induced by inflammation or protect β-cell from apoptosis. GDF15 probably promote lipolysis through a brain-somatic tissue circuit. Several factors and related signaling pathways are also mentioned that can contribute to the effects of GDF15 on reducing weight.

KEY MESSAGE: GDF15 plays an important role in weight regulation and provides a new direction for the treatment of obesity. Its effects on resisting obesity are of great significance to inhibiting the progression of metabolic diseases. It is expected to become a new target for regulating body weight, improving obesity, and treating metabolic diseases such as diabetes.},
}

@article {pmid37883032,
year = {2023},
author = {Rehn, S and Boakes, RA and Dwyer, DM},
title = {Switching from sucrose to saccharin: Extended successive negative contrast is not maintained by hedonic changes.},
journal = {Journal of experimental psychology. Animal learning and cognition},
volume = {49},
number = {4},
pages = {289-295},
doi = {10.1037/xan0000362},
pmid = {37883032},
issn = {2329-8464},
support = {//Experimental Psychology Society/ ; },
abstract = {Previous experiments found that acceptance of saccharin by rats was reduced if they had prior experience of sucrose or some other highly palatable solution. This reduction in saccharin consumption was particularly extended after a switch from sucrose. On the surface, this seems to correspond to a successive negative contrast (SNC) effect. This term was coined by C. F. Flaherty to describe the situation where consumption of a target solution is reduced by prior experience of a more valuable solution, typically a more concentrated version of the target solution. However, SNC effects are normally transient and assessed relative to a nonshifted control. Here, we confirm that the reduction in consumption seen when shifting from sucrose to saccharin is persistent and is seen relative to the traditional unshifted control. In addition, an analysis of licking microstructure showed that the shift from sucrose to saccharin suppressed the hedonic value of saccharin relative to controls, but this effect was less persistent than consumption suppression. Interestingly, a similar dissociation is observed in extinction of conditioned taste aversion (CTA): suppression of consumption produced by CTA is far more persistent than suppression of hedonic value. The comparison of results across procedures suggests that persistent SNC produced by a qualitative downshift from sucrose to saccharin appears different from quantitative downshifts in the concentration of a single solution, and qualitative downshift effects may involve CTA. (PsycInfo Database Record (c) 2023 APA, all rights reserved).},
}

@article {pmid37882427,
year = {2023},
author = {Expósito, AN and Vázquez-Agredos, A and Menchén, S and Gámiz, F and Gallo, M},
title = {Taste Neophobia, Latent Inhibition of Taste Aversion and Object Recognition Memory in Adolescent Rats.},
journal = {Psicothema},
volume = {35},
number = {4},
pages = {423-431},
doi = {10.7334/psicothema2022.256},
pmid = {37882427},
issn = {1886-144X},
abstract = {BACKGROUND: Adolescence in mammals is a period marked by increased novelty-seeking and enhanced responsiveness to the stressful properties of novel stimuli. Despite the need to taste potentially toxic novel foods during the adolescent growth spurt, there has been little study of taste neophobia and its attenuation.

METHOD: Four experiments were carried out to compare taste neophobia and related memory processes in male and female adolescent (PND28) and adult (PND70) Wistar rats. Experiments 1 and 2 evaluated attenuation of taste neophobia to cider vinegar (3%) and sodium saccharin (0.1%) solutions were evaluated. Additionally, to test the role of memory in neophobia during adolescence, latent inhibition of taste aversion and object recognition memory were assessed in Experiment 3 and Experiment 4, respectively.

RESULTS: Adolescent and adult rats exhibited taste neophobia to the saccharin solution but adolescent rats required more exposure trials than adults to recognize the vinegar solution as safe. Both groups exhibited similar latent inhibition of taste aversion and object recognition memory. No sex effect was significant.

CONCLUSIONS: Contrary to the accepted view associating adolescence with reduced neophobia, adolescent rats exhibited taste neophobia which even increased when sour tastes were encountered.},
}

@article {pmid37818887,
year = {2023},
author = {Chikamoto, N and Fujimoto, K and Nakai, J and Totani, Y and Hatakeyama, D and Ito, E},
title = {Expression Level Changes in Serotonin Transporter are Associated with Food Deprivation in the Pond Snail Lymnaea stagnalis.},
journal = {Zoological science},
volume = {40},
number = {5},
pages = {382-389},
doi = {10.2108/zs230027},
pmid = {37818887},
issn = {0289-0003},
abstract = {In the pond snail Lymnaea stagnalis, serotonin (5-HT) plays an important role in feeding behavior and its associated learning (e.g., conditioned taste aversion: CTA). The 5-HT content in the central nervous system (CNS) fluctuates with changes in the nutritional status, but it is also expected to be influenced by changes in the serotonin transporter (SERT) expression level. In the present study, we identified SERT in Lymnaea and observed its localization in 5-HTergic neurons, including the cerebral giant cells (CGCs) in the cerebral ganglia and the pedal A cluster neurons and right and left pedal dorsal 1 neurons in the pedal ganglia by in situ hybridization. Real-time PCR revealed that the SERT mRNA expression level was lower under severe food deprivation than under mild food deprivation in the whole CNS as well as in a single CGC. These results inversely correlated with previous data that the 5-HT content in the CNS was higher in the severely food-deprived state than in the mildly food-deprived state. Furthermore, in single CGCs, we observed that the 5-HT level was significantly increased in the severely food-deprived state compared with the mildly food-deprived state. Our present findings suggest that changes in the SERT expression level associated with food deprivation may affect 5-HT signaling, probably contributing to learning and memory mechanisms in Lymnaea.},
}

@article {pmid37816597,
year = {2023},
author = {Hurley, SW and Douton, JE and Carelli, RM},
title = {Neuronal Ensembles in the Infralimbic Cortex Dynamically Process Distinct Aspects of Hedonic Value.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1523/JNEUROSCI.0253-23.2023},
pmid = {37816597},
issn = {1529-2401},
abstract = {Hedonic processing is critical for guiding appropriate behavior, and the infralimbic cortex (IL) is a key neural substrate associated with this function in rodents and humans. We used deep brain, in vivo calcium imaging and taste reactivity (TR) in freely behaving male and female Sprague Dawley rats to examine whether the infralimbic cortex is involved in encoding innate versus conditioned hedonic states. In experiment 1, we examined the IL neuronal ensemble responsiveness to intraoral innately rewarding (sucrose) versus aversive (quinine) tastants. Most IL neurons responded to either sucrose only or both sucrose and quinine, with fewer neurons selectively processing quinine. Among neurons that responded to both stimuli, some appear to encode hedonic processing. In experiment 2, we examined how IL neurons process devalued sucrose using conditioned taste aversion (CTA). We found that neurons that responded exclusively to sucrose were disengaged while additional quinine-exclusive neurons were recruited. Moreover, tastant-specific neurons that did not change their neuronal activity after CTA appeared to encode objective hedonic value. However, other neuronal ensembles responded to both tastants and appear to encode distinct aspects of hedonic processing. Specifically, some neurons responded differently to quinine and sucrose and shifted from appetitive-like to aversive-like activity after CTA, thus encoding the subjective hedonic value of the stimulus. Conversely, neurons that responded similarly to both tastants were heightened after CTA. Our findings show dynamic shifts in IL ensembles encoding devalued sucrose and support a role for parallel processing of objective and subjective hedonic value.Significance StatementDisrupted affective processing contributes to psychiatric disorders including depression, substance use disorder, and schizophrenia. We assessed how the infralimbic cortex, a key neural substrate involved in affect generation and affect regulation, processes innate and learned hedonic states using deep brain in vivo calcium imaging in freely behaving rats. We report that unique infralimbic cortex ensembles encode stimulus subjective and objective hedonic value. Further, our findings support similarities and differences in innate versus learned negative affective states. This study provides insight into the neural mechanisms underlying affect generation and help establish a foundation for the development of novel treatment strategies to reduce negative affective states that arise in many psychiatric disorders.},
}

@article {pmid37806503,
year = {2023},
author = {Ranmal, SR and Nhouchi, Z and Keeley, A and Adler, L and Lavarde, M and Pensé-Lhéritier, AM and Tuleu, C},
title = {Taste assessment for Paediatric Drug Development: A Comparison of Bitterness Taste Aversion in Children versus Naïve and Expert Young Adult Assessors.},
journal = {International journal of pharmaceutics},
volume = {},
number = {},
pages = {123494},
doi = {10.1016/j.ijpharm.2023.123494},
pmid = {37806503},
issn = {1873-3476},
abstract = {Medicines for children often taste bitter, presenting a significant challenge to treatment compliance. However, most studies on paediatric drug development rely on adult volunteers for sensory research, and the level of expertise required from these assessors is unclear. This study aimed to address this gap by investigating perceived bitterness aversion to taste strips impregnated with different concentrations of quinine hydrochloride in 439 school-aged children. Expert (n=26) and naïve (n=65) young adult assessors evaluated quinine solutions as well as taste strips, for methodological bridging purposes. All assessors differentiated the aversiveness of the taste strips in a dose dependent manner. Younger children aged 4-8 years had difficulty discriminating higher bitter concentrations, whereas pre-adolescents 9-11 years and naive adults showed better discrimination at the top of the scale. Naive assessors showed similar bitter perception as children. However, the results were slightly different between strips and solution in adults. These findings highlight the key role that adult panels can play in paediatric formulation development. Taste strips show promise as a safe and pragmatic tool for sensory pharmaceutical evaluations, though further studies are warranted to establish the relationship between age and hedonic taste perception using compounds with diverse physicochemical and sensory qualities.},
}

@article {pmid37805008,
year = {2023},
author = {Kobayashi, S and Kajiwara, M and Cui, Y and Sako, T and Sasabe, T and Hayashinaka, E and Wada, Y and Kobayashi, M},
title = {Activation of multiple neuromodulatory systems in alert rats acquiring conditioned taste aversion revealed by positron emission tomography.},
journal = {Brain research},
volume = {},
number = {},
pages = {148617},
doi = {10.1016/j.brainres.2023.148617},
pmid = {37805008},
issn = {1872-6240},
abstract = {Conditioned taste aversion (CTA) is an essential ability for animals to consume food safely and is regulated by neuromodulatory systems including the dopamine, noradrenaline, serotonin, and acetylcholine systems. However, because few studies focused on a comprehensive understanding of whole-brain activities, how these neuromodulators contribute to the process of CTA remains an open issue. [18]F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) can visualize activated regions within the whole brain simultaneously and noninvasively. This study aimed to understand the mechanisms of CTA, especially focusing on the retrieval process after CTA acquisition by FDG-PET imaging. CTA was established in rats who received an intraoral application of saccharin solution (IOAS) on the first day (Day1), a LiCl i.p. injection after an IOAS on Day2, and an IOAS on Day3 (CTA group). The subtraction images of Day3 of the SHAM group, which received a 0.9% NaCl (saline) injection instead of a LiCl on Day2, from those of Day3 of the CTA group revealed increases in FDG signals in multiple brain regions including the substantia nigra, ventral tegmental area, locus coeruleus, dorsal raphe, and nucleus basalis magnocellularis, in addition to the hippocampus and nociception-related regions, including the parabrachial nucleus and solitary nucleus. On the other hand, the visceral pain induced by the LiCl injection increased FDG signals in the primary and secondary somatosensory and insular cortices in addition to the parabrachial nucleus and solitary nucleus. These results suggest that the retrieval process of CTA induces brain regions producing neuromodulators and pain-related brainstem.},
}

@article {pmid37805119,
year = {2023},
author = {Gutiérrez-Vera, B and Reyes-García, SE and Escobar, ML},
title = {Brief environmental enrichment elicits metaplasticity on the insular cortex in vivo and reduces the strength of conditioned taste aversion.},
journal = {Neurobiology of learning and memory},
volume = {},
number = {},
pages = {107840},
doi = {10.1016/j.nlm.2023.107840},
pmid = {37805119},
issn = {1095-9564},
abstract = {Environmental enrichment (EE) is known to improve memory and cognition and modulate the impact of aversive stimuli in animals, promoting the development of resilience to stressful situations. Likewise, it is known that EE can modulate synaptic plasticity as is the case of long-term potentiation (LTP). These findings have been described initially in ex vivo preparations, suggesting that the effects of EE are the result of an early modification of the synaptic excitability and transmission. In this regard, it is known that metaplasticity refers to the persistent modification, by previous activity, in the ability to induce synaptic plasticity. Our previous studies have shown that prior training in conditioned taste aversion (CTA) prevents the subsequent induction of LTP in the projection from the basolateral nucleus of the amygdala (Bla) to the insular cortex (IC) in vivo. In addition, we have shown that CTA extinction allows the induction but not the maintenance of IC-LTP of the Bla-IC pathway. Recently, we also showed that prior exposure to environmental enrichment for three weeks reduces the strength of CTA, restoring the brain-derived neurotrophic factor (BDNF) levels in the IC. The present study aimed to analyze the effects of brief exposure to an enriched environment on the strength of aversive memory, as well as on the in vivo IC-LTP. To do so, adult rats were exposed for seven days to an EE, either before CTA training or LTP induction in the Bla-IC pathway. Our results demonstrate that a seven-day exposure to an enriched environment attenuates the aversive response to a strong CTA and allows the induction but not the maintenance of LTP in the insular cortex. These findings provide evidence that metaplastic regulation in a neocortical region takes part in the mechanisms through which brief exposure to enriched environments attenuates an aversive response.},
}

@article {pmid37774959,
year = {2023},
author = {Lamb, RJ and Schindler, CW and Ginsburg, BC},
title = {Effects of an Ethanol-Paired Conditioned Stimulus on Responding for Ethanol Suppressed by a Conditioned-Taste-Aversion.},
journal = {Alcohol (Fayetteville, N.Y.)},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.alcohol.2023.09.008},
pmid = {37774959},
issn = {1873-6823},
abstract = {Ethanol-Paired Conditioned Stimuli (CS) can increase ethanol responding either in extinction or occurring at low rates late in a session. To examine the generality of CS induced increases in ethanol-responding, we examined if a CS could increase responding suppressed by Conditioned-Taste-Aversion (CTA), which presumably suppresses responding by changing ethanol's valence from positive to negative. Rats were trained to respond for ethanol under a Random Interval (RI) schedule. We then removed the lever and paired Random-Time ethanol deliveries with illumination of a stimulus light (i.e., CS) for ten sessions. Results were compared with a Truly Random Control group, in which the light and ethanol deliveries occurred independently. In a subsequent experiment, rats were treated similarly, except the light served as a discriminative stimulus, as the lever was extended and ethanol deliveries were available under a RI during light presentations. After this training, the lever was returned and rats again responded for ethanol. Subsequently, sessions were followed by LiCl administration. When responding reached low levels, LiCl administration stopped and the light was occasionally illuminated during the session. Responding during the light presentation was compared to responding during the period preceding light presentation. Responding partially recovered across ten sessions and was greater during light presentations than in the period before it in all three groups. Increases were not reliably different between the groups indicating that explanations for these increases such as CS-induced increases in motivation or approach towards the light are unlikely to be correct. The most likely explanation for these light-induced increases is that during sessions in which the light had been presented previously, LiCl had never been presented and thus, the light had come to signal that ethanol was safe to drink.},
}

@article {pmid37759600,
year = {2023},
author = {Nakai, J and Namiki, K and Fujimoto, K and Hatakeyama, D and Ito, E},
title = {FOXO in Lymnaea: Its Probable Involvement in Memory Consolidation.},
journal = {Biology},
volume = {12},
number = {9},
pages = {},
doi = {10.3390/biology12091201},
pmid = {37759600},
issn = {2079-7737},
support = {JPMJSP2128//Japan Science and Technology Agency/ ; none//Waseda University/ ; },
abstract = {Food deprivation activates forkhead box O (FOXO), a transcription factor downstream of insulin receptors. In the pond snail Lymnaea stagnalis, insulin signaling and food deprivation improve memory consolidation following conditioned taste aversion (CTA) learning. We investigated the subcellular localization of FOXO in Lymnaea and changes in its expression levels following food deprivation, CTA learning, and insulin administration. Immunohistochemistry revealed that Lymnaea FOXO (LymFOXO) was located in the central nervous system (CNS) neuronal cytoplasm in food-satiated snails but was mainly in neuronal nuclei in food-deprived snails. Following CTA acquisition, LymFOXO translocated to the nuclei in food-satiated snails and remained in the nuclei in food-deprived snails. Contrary to our expectations, insulin administered to the CNS did not induce LymFOXO translocation into the nuclei in food-satiated snails. Real-time PCR was used to quantify LymFOXO mRNA levels, its target genes, and insulin signaling pathway genes and revealed that LymFOXO mRNA was upregulated in food-deprived snails compared to food-satiated snails. Insulin applied to isolated CNSs from food-satiated snails increased LymFOXO compared to vehicle-treated samples. Food deprivation prepares FOXO to function in the nucleus and enhances CTA learning in snails. Insulin application did not directly affect LymFOXO protein localization. Thus, insulin administration may stimulate pathways other than the LymFOXO cascade.},
}

@article {pmid37745477,
year = {2023},
author = {Ramirez, LA and Przybysz, KR and Pitock, JR and Starr, EM and Yang, H and Glover, EJ},
title = {Attenuated incubation of ethanol-induced conditioned taste aversion in a model of dependence.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2023.09.13.557582},
pmid = {37745477},
abstract = {RATIONALE: Preclinical studies report attenuated ethanol-induced conditioned taste aversion (CTA) following chronic ethanol exposure, suggesting that tolerance develops to the aversive properties of ethanol. However, these studies are confounded by pre-exposure to the unconditioned stimulus (US; ethanol), which is well known to hinder conditioning.

OBJECTIVES: This study was designed to determine whether chronic ethanol exposure produces tolerance to the aversive properties of ethanol in the absence of a US pre-exposure confound.

METHODS: CTA was performed in adult male and female Long-Evans rats by pairing 0.1% ingested saccharin with an intraperitoneal injection of ethanol (1.5 or 2.0 g/kg) or saline. Rats were then rendered ethanol dependent using chronic intermittent ethanol (CIE) vapor exposure. Controls were exposed to room air (AIR). The effect of chronic ethanol on CTA expression and reconditioning were examined following vapor exposure.

RESULTS: Prior to vapor exposure, both sexes developed CTA to a comparable degree with 2.0 g/kg producing greater CTA than 1.5 g/kg ethanol. Following vapor exposure, AIR controls exhibited an increase in CTA magnitude compared to pre-vapor levels. This effect was absent in CIE-exposed rats. These group differences were eliminated upon re-conditioning after vapor exposure.

CONCLUSIONS: These data suggest that chronic ethanol does not facilitate tolerance to the aversive properties of ethanol but rather, attenuates incubation of ethanol-induced CTA. Loss of CTA incubation suggests that CIE exposure disrupts circuits encoding aversion.},
}

@article {pmid37713319,
year = {2023},
author = {Barnhart, WR and Dial, LA and Jordan, AK and Studer-Perez, EI and Kalantzis, MA and Musher-Eizenman, DR},
title = {Higher meal disengagement and meal presentation are uniquely related to psychological distress and lower quality of life in undergraduate students.},
journal = {Journal of American college health : J of ACH},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/07448481.2023.2245912},
pmid = {37713319},
issn = {1940-3208},
abstract = {Objective: Picky eating, which occurs in emerging adulthood and is associated with psychological distress and quality of life, has historically been conceptualized as unidimensional despite research suggesting it is a multifaceted construct. Participants: An undergraduate sample (N = 509; Mage = 19.96). Methods: A cross-sectional survey assessed picky eating facets (food variety, meal disengagement, meal presentation, and taste aversion), disordered eating, anxiety, depression, stress, obsessive compulsive disorder (OCD), and social phobia symptoms, and quality of life. Results: Meal disengagement was uniquely related to higher anxiety, depression, stress, and social phobia symptoms and lower quality of life, whereas meal presentation was uniquely related to higher anxiety, stress, and OCD symptoms, beyond covariates and disordered eating. Food variety and taste aversion were not uniquely related to outcomes. Conclusions: Considering picky eating multidimensionally may yield important insights beyond the broader construct in terms of its relationship with psychological well-being in undergraduates.},
}

@article {pmid37626986,
year = {2023},
author = {Rivi, V and Batabyal, A and Lukowiak, K and Benatti, C and Rigillo, G and Tascedda, F and Blom, JMC},
title = {LPS-Induced Garcia Effect and Its Pharmacological Regulation Mediated by Acetylsalicylic Acid: Behavioral and Transcriptional Evidence.},
journal = {Biology},
volume = {12},
number = {8},
pages = {},
doi = {10.3390/biology12081100},
pmid = {37626986},
issn = {2079-7737},
support = {L.R. N. 20/2002 PROGETTI DI RICERCA SUI METODI ALTERNATIVI ALL'UTILIZZO DI ANIMALI//Regione Emilia Romagna/ ; FAR 2016//Department of Life Sciences - University of Modena and Reggio Emilia/ ; 227993-2019//Natural Sciences and Engineering Research Council of Canada/ ; },
abstract = {Lymnaea stagnalis learns and remembers to avoid certain foods when their ingestion is followed by sickness. This rapid, taste-specific, and long-lasting aversion-known as the Garcia effect-can be formed by exposing snails to a novel taste and 1 h later injecting them with lipopolysaccharide (LPS). However, the exposure of snails to acetylsalicylic acid (ASA) for 1 h before the LPS injection, prevents both the LPS-induced sickness state and the Garcia effect. Here, we investigated novel aspects of this unique form of conditioned taste aversion and its pharmacological regulation. We first explored the transcriptional effects in the snails' central nervous system induced by the injection with LPS (25 mg), the exposure to ASA (900 nM), as well as their combined presentation in untrained snails. Then, we investigated the behavioral and molecular mechanisms underlying the LPS-induced Garcia effect and its pharmacological regulation by ASA. LPS injection, both alone and during the Garcia effect procedure, upregulated the expression levels of immune- and stress-related targets. This upregulation was prevented by pre-exposure to ASA. While LPS alone did not affect the expression levels of neuroplasticity genes, its combination with the conditioning procedure resulted in their significant upregulation and memory formation for the Garcia effect.},
}

@article {pmid37190662,
year = {2023},
author = {Gao, ZY and Huang, CM and Cheng, CN and Huang, AC},
title = {D2 Receptors and Sodium Ion Channel Blockades of the Basolateral Amygdala Attenuate Lithium Chloride-Induced Conditioned Taste Aversion Applying to Cancer Chemotherapy Nausea and Vomiting.},
journal = {Brain sciences},
volume = {13},
number = {4},
pages = {},
pmid = {37190662},
issn = {2076-3425},
support = {NSTC 111-2410-H-431-010//National Science and Technology Council/ ; YSVH110-09//Taipei Veterans General Hospital/ ; },
abstract = {Cancer patients regularly suffer from the behavioral symptoms of chemotherapy-induced nausea and vomiting. Particularly, it is involved in Pavlovian conditioning. Lithium chloride (LiCl) was used as the unconditioned stimulus (US) and contingent with the tastant, for example, a saccharin solution (i.e., the conditioned stimulus; CS), resulted in conditioned taste aversion (CTA) to the CS intake. The present study employed an animal model of LiCl-induced CTA to imitate chemotherapy-induced nausea and vomiting symptoms. Recently, the basolateral amygdala (BLA) was shown to mediate LiCl-induced CTA learning; however, which brain mechanisms of the BLA regulate CTA by LiCl remain unknown. The present study was designed to test this issue, and 4% lidocaine or D2 blocker haloperidol were microinjected into BLA between the 0.1% saccharin solution intake and 0.15M LiCl. The results showed lidocaine microinjections into the BLA could attenuate the LiCl-induced CTA. Microinjections of haloperidol blunted the CTA learning by LiCl. Altogether, BLA via the sodium chloride ion channel and D2 receptors control LiCl-induced conditioned saccharin solution intake suppression. The findings can provide some implications and contributions to cancer chemotherapy-induced nausea and vomiting side effects, and will help to develop novel strategies to prevent the side effects of cancer chemotherapy.},
}

@article {pmid36635250,
year = {2023},
author = {Kolatt Chandran, S and Yiannakas, A and Kayyal, H and Salalha, R and Cruciani, F and Mizrahi, L and Khamaisy, M and Stern, S and Rosenblum, K},
title = {Intrinsic Excitability in Layer IV-VI Anterior Insula to Basolateral Amygdala Projection Neurons Correlates with the Confidence of Taste Valence Encoding.},
journal = {eNeuro},
volume = {10},
number = {1},
pages = {},
pmid = {36635250},
issn = {2373-2822},
mesh = {Mice ; Animals ; *Basolateral Nuclear Complex/physiology ; Amygdala/physiology ; Taste/physiology ; Avoidance Learning/physiology ; Neurons ; },
abstract = {Avoiding potentially harmful, and consuming safe food is crucial for the survival of living organisms. However, the perceived valence of sensory information can change following conflicting experiences. Pleasurability and aversiveness are two crucial parameters defining the perceived valence of a taste and can be impacted by novelty. Importantly, the ability of a given taste to serve as the conditioned stimulus (CS) in conditioned taste aversion (CTA) is dependent on its valence. Activity in anterior insula (aIC) Layer IV-VI pyramidal neurons projecting to the basolateral amygdala (BLA) is correlated with and necessary for CTA learning and retrieval, as well as the expression of neophobia toward novel tastants, but not learning taste familiarity. Yet, the cellular mechanisms underlying the updating of taste valence representation in this specific pathway are poorly understood. Here, using retrograde viral tracing and whole-cell patch-clamp electrophysiology in trained mice, we demonstrate that the intrinsic properties of deep-lying Layer IV-VI, but not superficial Layer I-III aIC-BLA neurons, are differentially modulated by both novelty and valence, reflecting the subjective predictability of taste valence arising from prior experience. These correlative changes in the profile of intrinsic properties of LIV-VI aIC-BLA neurons were detectable following both simple taste experiences, as well as following memory retrieval, extinction learning, and reinstatement.},
}

Mice
Animals
*Basolateral Nuclear Complex/physiology
Amygdala/physiology
Taste/physiology
Avoidance Learning/physiology
Neurons

@article {pmid37406868,
year = {2023},
author = {Nakajima, S and Umemoto, S and Nagaishi, T},
title = {Food avoidance learning based on swimming in laboratory mice (Mus musculus).},
journal = {Behavioural processes},
volume = {},
number = {},
pages = {104910},
doi = {10.1016/j.beproc.2023.104910},
pmid = {37406868},
issn = {1872-8308},
abstract = {Although it is now well documented that laboratory rats learn to avoid the flavored substance consumed immediately before running in activity wheels or swimming in water buckets, research on this activity-based flavor avoidance learning in other species is limited. Recently, running-based flavor avoidance learning has been demonstrated in laboratory mice by employing a method of resistance-to-habituation of neophobic reaction to novel food; mice that repeatedly experience running after encountering a novel food have a prolonged tendency to reject that food compared to control mice without paired running. The present article reports a series of attempts to obtain evidence of flavor avoidance learning based on swimming rather than running using this resistance-to-habituation method. Swimming-based flavor avoidance was clearly demonstrated in a differential conditioning paradigm; however, its demonstration in a simple conditioning paradigm requires a post-training choice test of the target food and another type of food. These results are likely due to the short swimming time (20min) and the formation of weak flavor aversion.},
}

@article {pmid37382606,
year = {2023},
author = {Kagan, D and Hollings, J and Batabyal, A and Lukowiak, K},
title = {Five-minute exposure to a novel appetitive food substance is sufficient time for a microRNA-dependent long-term memory to form.},
journal = {Journal of comparative physiology. A, Neuroethology, sensory, neural, and behavioral physiology},
volume = {},
number = {},
pages = {},
pmid = {37382606},
issn = {1432-1351},
support = {227993-2019//Natural Sciences and Engineering Research Council of Canada/ ; },
abstract = {The Garcia effect is a unique form of conditioned taste aversion which requires that a novel food stimulus be followed sometime later by a sickness state associated with the novel food stimulus. The long-lasting associative memory resulting from the Garcia effect ensures that organisms avoid toxic foods in their environment. Considering its ecological relevance, we sought to investigate whether a brief encounter (5 min) with a novel, appetitive food stimulus can cause a persisting long-term memory (LTM) to form that would in turn block the Garcia effect in Lymnaea stagnalis. Furthermore, we wanted to explore whether that persisting LTM could be modified by the alteration of microRNAs via an injection of poly-L-lysine (PLL), an inhibitor of Dicer-mediated microRNA biogenesis. The Garcia effect procedure involved two observations of feeding behavior in carrot separated by a heat stress (30 °C for 1 h). Exposing snails to carrot for 5 min caused a LTM to form and persist for 1 week, effectively preventing the Garcia effect in snails. In contrast, PLL injection following the 5-min carrot exposure impaired LTM formation, allowing the Garcia effect to occur. These results provide more insight into LTM formation and the Garcia effect, an important survival mechanism.},
}

@article {pmid37352906,
year = {2023},
author = {Su, S and Wei, Z and Huang, H and Yoshizawa, T and Inui, T and Funahashi, M},
title = {Conditioned nausea induced by cisplatin and emetine identified by a taste reactivity test in rats.},
journal = {Physiology & behavior},
volume = {},
number = {},
pages = {114278},
doi = {10.1016/j.physbeh.2023.114278},
pmid = {37352906},
issn = {1873-507X},
abstract = {No prior studies have shown that gaping reactions are produced with the avoidance of conditioned taste caused by cisplatin and emetine. Therefore, we tried to demonstrate it using a taste reactivity test in rats and found the gaping reactions induced when saccharin is readministered after gustatory conditioning that paired saccharin with cisplatin or emetine. Since conditioned gaping reactions indicate the aversion to saccharin taste and conditioned nausea, the present study suggest that the taste aversion is induced by cisplatin and emetine. It was also found that with intraperitoneal injections of emetine alone, gaping almost never occurs.},
}

@article {pmid37333122,
year = {2023},
author = {Przybysz, KR and Ramirez, LA and Pitock, JR and Starr, EM and Yang, H and Glover, EJ},
title = {A translational rodent model of individual differences in sensitivity to the aversive properties of ethanol.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2023.06.08.544209},
pmid = {37333122},
abstract = {BACKGROUND: A strong relationship exists between individual sensitivity to the aversive properties of ethanol and risk for alcohol use disorder (AUD). Despite this, our understanding of the neurobiological mechanisms underlying subjective response to ethanol is relatively poor. A major contributor to this is the absence of preclinical models that enable exploration of this individual variability similar to studies performed in humans.

METHODS: Adult male and female Long-Evans rats were trained to associate a novel tastant (saccharin) with acute exposure to either saline or ethanol (1.5 g/kg or 2.0 g/kg i.p.) over three conditioning days using a standard conditioned taste aversion (CTA) procedure. Variability in sensitivity to ethanol-induced CTA was phenotypically characterized using a median split across the populations studied.

RESULTS: When examining group averages, both male and female rats that had saccharin paired with either dose of ethanol exhibited reduced saccharin intake relative to saline controls of ethanol-induced CTA. Examination of individual data revealed a bimodal distribution of responses uncovering two distinct phenotypes present in both sexes. CTA-sensitive rats exhibited a rapid and progressive reduction in saccharin intake with each successive ethanol pairing. In contrast, saccharin intake was unchanged or maintained after an initial decrease from baseline levels in CTA-resistant rats. While CTA magnitude was similar between male and female CTA-sensitive rats, CTA-resistant females were more resistant to the development of ethanol-induced CTA than their male counterparts. Phenotypic differences were not driven by differences in baseline saccharin intake. CTA sensitivity correlated with behavioral signs of intoxication in only a subset of rats.

CONCLUSIONS: These data parallel work in humans by revealing individual differences in sensitivity to the aversive properties of ethanol that emerge immediately after initial exposure to ethanol in both sexes. This model can be leveraged in future studies to investigate the neurobiological mechanisms that confer risk for AUD.},
}

@article {pmid37306398,
year = {2023},
author = {Cote, JM and Hood, A and Kwon, B and Smith, JC and Houpt, TA},
title = {Behavioral and neural responses to high strength magnetic fields are reduced in otolith mutant mice.},
journal = {American journal of physiology. Regulatory, integrative and comparative physiology},
volume = {},
number = {},
pages = {},
doi = {10.1152/ajpregu.00317.2022},
pmid = {37306398},
issn = {1522-1490},
abstract = {Static high magnetic fields (MFs) interact with the vestibular system of humans and rodents. In rats and mice, exposure to MFs causes perturbations such as head movements, circular locomotion, suppressed rearing, nystagmus, and conditioned taste aversion acquisition. To test the role of otoconia, two mutant mouse models were examined: head-tilt Nox3[het] (het) and tilted Opt1[tlt] (tlt), with mutations respectively in Nox3, encoding the NADPH oxidase 3 enzyme, and Opt1, encoding the opterin1 proton channel, which are normally expressed in the otolith organs, and are critical for otoconia formation. Consequently, both mutants show a near complete loss of otoconia in the utricle and saccule, and are non-responsive to linear acceleration. Mice were exposed to a 14.1 T MF for 30 min. After exposure, locomotor activity, conditioned taste aversion and c-Fos (in het) were assessed. Wild-type mice exposed to the MF showed suppressed rearing, increased latency to rear, locomotor circling, and c-Fos in brainstem nuclei related to vestibular processing (prepositus, spinal vestibular, and supragenual nuclei). Mutant het mice showed no response to the magnet and were similar to sham animals in all assays. Unlike het, tlt mutants exposed to the MF showed significant locomotor circling and suppressed rearing compared to sham controls, although they failed to acquire a taste aversion. The residual responsiveness of tlt vs het mice might reflect a greater semicircular deficit in het mice. These results demonstrate the necessity of the otoconia for the full effect of exposure to high MFs, but also suggest a semicircular contribution.},
}

@article {pmid37113545,
year = {2023},
author = {Yu, YH and Tsai, AC and Ou, CY and Cheng, CN and Chang, FC and Shyu, BC and Huang, ACW},
title = {Optogenetic stimulation in the medial prefrontal cortex modulates stimulus valence from rewarding and aversive to neutral states.},
journal = {Frontiers in psychiatry},
volume = {14},
number = {},
pages = {1119803},
pmid = {37113545},
issn = {1664-0640},
abstract = {INTRODUCTION: Understanding the modulations of the medial prefrontal cortex (mPFC) in the valence of the stimulus from rewarding and aversive status to neutral status is crucial for the development of novel treatments for drug addiction. This study addressed this issue and examined whether optogenetic ChR2 photostimulation in the cingulate, prelimbic, and infralimbic cortices of the mPFC regulated the valence of saccharin solution consumption from the rewarding property, the aversive property induced by morphine's conditioning, and the neutral states via saccharin extinction processes after morphine's conditioning.

METHODS: All rats received virus infection, buried optical fiber, optical stimulation, water deprivation, and saccharin solution consumption phases. In Experiment 1, rats were given ChR2 virus infection into the cingulate cortex (Cg1), prelimbic cortex (PrL), and infralimbic cortex (IL) to influence the rewarding saccharin solution consumption under photostimulation. In Experiment 2, rats were given ChR2 or EYFP virus infection into the Cg1, PrL, and IL to alter the saccharin solution consumption in the morphine-induced aversively conditioned taste aversion (CTA) and the saccharin solution consumption in the neutral state following the extinction process under photostimulation. Later, the immunohistochemical staining with c-Fos protein was performed for the Cg1, IL, PrL, nucleus accumbens core, nucleus accumbens shell, central amygdala, basolateral amygdala, ventral tegmental area, and dentate gyrus.

RESULTS: The results showed that optogenetic PrL stimulation decreased the rewarding valence of saccharin solution consumption and increased the morphine-induced, aversive valence of saccharin solution consumption. PrL stimulation decreased the neutral valence of saccharin solution consumption via the extinction process. Cg1 optogenetic stimulation increased the rewarding valence of saccharin solution consumption and the aversive valence of saccharin solution consumption induced by morphine in conditioning. Optogenetic IL stimulation increased the aversive valence of saccharin solution consumption induced by morphine via conditioning.

CONCLUSION: Altogether, optogenetic stimulation in the subareas of the mPFC modulated the reward, aversion, and neutral valences of the stimulus and altered neuronal activity in the mPFC, amygdala, nucleus accumbens, and hippocampus. Notably, the change of valence was temporary alternation during light-on related to the light-off periods. However, the findings may provide insights in the development of novel treatments for addictive symptoms.},
}

@article {pmid36906931,
year = {2023},
author = {Chen, A and Wang, R and Kang, Y and Liu, J and Wu, J and Zhang, Y and Zhang, Y and Shao, L},
title = {Tongue-brain-transported ZnO NPs induced abnormal taste perception.},
journal = {Advanced healthcare materials},
volume = {},
number = {},
pages = {e2203316},
doi = {10.1002/adhm.202203316},
pmid = {36906931},
issn = {2192-2659},
abstract = {Nanoparticles (NPs) can be transported to the brain, especially the nerve, because of their small size and high biological activity. Our previous studies confirmed that zinc oxide (ZnO) NPs could enter the brain through the tongue-brain pathway, but it is unclear whether they would further affect synaptic transmission and brain perception. In this study, we found that tongue-brain-transported ZnO NPs could cause a decrease in taste sensitivity and taste aversion learning ability, indicating abnormal taste perception. Moreover, the release of miniature excitatory postsynaptic currents, the frequency of action potential release and the expression of c-fos were decreased, suggesting that the synaptic transmission was reduced. To further explore the mechanism, we carried out protein chip detection of inflammatory factors and found that neuroinflammation occurs. Importantly, we found that neuroinflammation originated from neurons. The JAK-STAT signaling pathway was activated, which inhibited the Neurexin1-PSD95-Neurologigin1 pathway and c-fos expression. Blocking the activation of the JAK-STAT pathway prevented neuroinflammation and the reduction in Neurexin1-PSD95-Neurologigin1. These results indicate that ZnO NPs could be transported by the tongue-brain pathway and lead to abnormal taste perception by neuroinflammation-induced deficits in synaptic transmission. Our study reveals the influence of ZnO NPs on neuronal function and provides a novel mechanism. This article is protected by copyright. All rights reserved.},
}

@article {pmid36898644,
year = {2023},
author = {Miranda, MI and Alcalá, A and Vera-Rivera, G and Rangel-Hernández, JA},
title = {Differential effects of thirst and satiety on conditioned taste aversion acquisition, retrieval, and memory extinction.},
journal = {Physiology & behavior},
volume = {},
number = {},
pages = {114143},
doi = {10.1016/j.physbeh.2023.114143},
pmid = {36898644},
issn = {1873-507X},
abstract = {Thirst is an essential motivational component that could modulate the strength of conditioning; pioneer studies show that the rats' sexual dimorphism observed in the rate of aversive memory extinction of conditioned taste aversion (CTA) is affected by the state of fluid deprivation. On the other hand, previous evidence suggests that fluid intake volume and temporal context before and during conditioning may influence CTA. Furthermore, although CTA has been demonstrated using various types of stimuli, neural processing and homeostatic regulation of water and nutritional balance may differ depending on the stimulus used and the conditioning stages. Therefore, this study explored the effects of state motivated by thirst and satiation, using saccharin, as a non-caloric sweet stimulus, during CTA and the aversive memory extinction process under similar contextual and temporal conditions. First, we implemented an ad libitum water protocol in male and female adult rats to evaluate saccharin aversive memory formation; we compared this with a traditional CTA with liquid deprivation in the same context and temporal consumption conditions. Furthermore, we evaluated whether liquid satiety affects the acquisition or the aversive memory retrieval differentially. Our results show that the ad libitum liquid regimen allows reliable quantifications of basal water consumption, monitored every hour for more than five days. We observed a reliable CTA, where the magnitude of aversive memory and its extinction is significantly higher in both male and female rats; the strong CTA observed is substantially due to the satiety state during taste aversion memory retrieval. Our data show that although liquid deprivation does not affect CTA acquisition, it does induce weakness in the magnitude of aversive retrieval expression and fast aversive memory extinction, similarly in male and females. Overall, the results indicate that the need to satiate the demand for liquids during retrieval prevails over the conditioned aversion learned, suggesting, that thirst is a source of temporary variables dominating the aversive responses during CTA retrieval.},
}

@article {pmid36898496,
year = {2023},
author = {Arthurs, J and Pauli, J and Palmiter, RD},
title = {Activation of parabrachial tachykinin 1 neurons counteracts some behaviors mediated by parabrachial CGRP neurons.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2023.03.003},
pmid = {36898496},
issn = {1873-7544},
abstract = {Many threats activate parabrachial neurons expressing calcitonin gene-related peptide (CGRP[PBN]) which transmit alarm signals to forebrain regions. Most CGRP[PBN] neurons also express tachykinin 1 (Tac1), but there are also Tac1-expressing neurons in the PBN that do not express CGRP (Tac1+;CGRP- neurons). Chemogenetic or optogenetic activation of all Tac1[PBN] neurons in mice elicited many physiological/behavioral responses resembling the activation of CGRP[PBN] neurons, e.g., anorexia, jumping on a hot plate, avoidance of photostimulation; however, two key responses opposed activation of CGRP[PBN] neurons. Activating Tac1[PBN] neurons did not produce conditioned taste aversion and it elicited dynamic escape behaviors rather than freezing. Activating Tac1+;CGRP- neurons, using an intersectional genetic targeting approach, resembles activating all Tac1[PBN] neurons. These results reveal that activation of Tac1+;CGRP- neurons can suppress some functions attributed to the CGRP[PBN] neurons, which provides a mechanism to bias behavioral responses to threats.},
}

@article {pmid36856894,
year = {2023},
author = {Muñiz Moreno, J and Loy, I},
title = {Taste aversion learning in the snail Cornu aspersum.},
journal = {Animal cognition},
volume = {},
number = {},
pages = {},
pmid = {36856894},
issn = {1435-9456},
abstract = {The present study was conducted to provide evidence of conditioned taste aversion learning (CTA) in the snail Cornu aspersum, using quinidine as the aversive stimulus in a procedure of Pavlovian Conditioning of Tentacle Lowering. Subjects were split into two groups: paired and unpaired. During the devaluation phase, subjects from the "paired group" received the US followed by the quinidine exposure, while subjects from the "unpaired group" received the quinidine and, 30 min later, the US. Subjects which had received the US paired with the quinidine showed a decrease of the conditioned response (CR), in contrast to subjects which had received the quinidine and the US unpaired. These results provide a useful CTA procedure in terrestrial snails. The implication of the results for learning and the physiological correlates is discussed.},
}

@article {pmid36762112,
year = {2023},
author = {Ou, CY and Yu, YH and Wu, CW and Kozłowska, A and Shyu, BC and Huang, ACW},
title = {Neuronal activity of the medial prefrontal cortex, nucleus accumbens, and basolateral amygdala in conditioned taste aversion and conditioned place preference induced by different doses of morphine administrations in rats.},
journal = {Frontiers in pharmacology},
volume = {14},
number = {},
pages = {1062169},
pmid = {36762112},
issn = {1663-9812},
abstract = {To re-examine the paradoxical effect hypothesis of abused drugs, the present study concerned whether different doses of morphine disparately affect neuronal activity and associations among the subareas of the medial prefrontal cortex (mPFC: cingulate cortex 1-Cg1, prelimbic cortex-PrL, infralimbic cortex-IL), the subregions of the nucleus accumbens (NAc; both core and shell), and the basolateral amygdala (BLA) following conditioned taste aversion (CTA) and conditioned place preference (CPP). All rats were given a 0.1% saccharin solution for 15-min, and they were intraperitoneally injected with saline or 20, 30, or 40 mg/kg morphine to form the aversive CTA learning. Later, half of the rats were tested for CPP (including the CTA and then CPP tests) for 30-min. Finally, the immunohistochemical staining with c-Fos was conducted after the behavioral test. After the CTA test, c-Fos (%) in the Cg1 and PrL (but not the IL) was more in 20-40 mg/kg of the morphine groups; c-Fos (%) in the NAc core, NAc shell, and BLA was more in the 30-40 mg/kg morphine group. After the CPP test, the Cg1, PrL, IL, and BLA showed more c-Fos (%) in 20 mg/kg morphine; the NAc core showed fewer in c-Fos (%) in the 30-40 mg/kg morphine groups. The mPFC subregions (e.g., Cg1, PrL, and IL), NAc subareas (e.g., NAc core and NAc shell), and BLA were involved in the different doses of morphine injections. The correlation analysis showed that a positive correlation was observed between PrL and IL with NAc core with low doses of morphine and with NAc shell with increasing doses of morphine after the CTA test. After the CPP, an association between PrL and NAc core and NAc shell at low doses and between IL and BLA and NAc shell with increasing doses of morphine. Therefore, different neural substrates and the neural connectivity are observed following different doses of morphine and after the CTA and CPP tests. The present data extend the paradoxical effect hypothesis of abused drugs.},
}

@article {pmid36571995,
year = {2022},
author = {Yuan, Y and Yan, Z and Lao, Q and Jiang, N and Wu, S and Lu, Q and Han, J and Zhao, S},
title = {Discovery of a potent and long-acting Xenopus GLP-1-based GLP-1/glucagon/Y2 receptor triple agonist.},
journal = {European journal of medicinal chemistry},
volume = {247},
number = {},
pages = {115036},
doi = {10.1016/j.ejmech.2022.115036},
pmid = {36571995},
issn = {1768-3254},
abstract = {The combination of incretin-based therapies and PYY analogue has shown great potential for the treatment of type 2 diabetes (T2DM) and obesity. In this study we developed the first example of a unimolecular triple agonist peptide to simultaneously target GLP-1, glucagon and Y2 receptors, aiming for superior weight loss and better glycemic control. The strategy for constructing such a unimolecular triple agonist peptide is the conjugation of the GLP-1R/GCGR dual-agonistic moiety and PYY moiety via maleimide-thiol specific reaction. A novel triple agonist peptide, 3b, was identified via stepwise structure optimization, long-acting modification and in vitro receptor screens. Peptide 3b exhibited potent and balanced GCGR and GLP-1R activities as well as potent and highly selective Y2R activity. Peptide 3b potently reduced food intake without triggering nausea associated behavior in kaolin consumption and conditioned taste aversion assays. In diet induced obesity (DIO) mice, a lower dose of 3b achieved significantly better effects on lipid metabolism, body weight, and glycemic control than higher dose of GLP-1R mono-agonist, GLP-1R/GCGR dual agonist and GLP-1R/Y2R dual agonist counterparts. Collectively, these data support the therapeutic potential of our GLP-1R/GCGR/Y2R triple agonist 3b as a novel anti-obesity and anti-diabetic agent. Targeting GLP-1R, GCGR and Y2R with unimolecular triple agonist peptide offers a route to develop new obesity and T2DM treatments.},
}

@article {pmid36563678,
year = {2022},
author = {Lavi, A and Sehgal, M and de Sousa, AF and Ter-Mkrtchyan, D and Sisan, F and Luchetti, A and Okabe, A and Bear, C and Silva, AJ},
title = {Local memory allocation recruits memory ensembles across brain regions.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2022.11.018},
pmid = {36563678},
issn = {1097-4199},
abstract = {Memories are thought to be stored in ensembles of neurons across multiple brain regions. However, whether and how these ensembles are coordinated at the time of learning remains largely unknown. Here, we combined CREB-mediated memory allocation with transsynaptic retrograde tracing to demonstrate that the allocation of aversive memories to a group of neurons in one brain region directly affects the allocation of interconnected neurons in upstream brain regions in a behavioral- and brain region-specific manner in mice. Our analysis suggests that this cross-regional recruitment of presynaptic neurons is initiated by downstream memory neurons through a retrograde mechanism. Together with statistical modeling, our results indicate that in addition to the anterograde flow of information between brain regions, the establishment of interconnected, brain-wide memory traces relies on a retrograde mechanism that coordinates memory ensembles at the time of learning.},
}

@article {pmid36548243,
year = {2022},
author = {Gore-Langton, JK and Varlinskaya, EI and Werner, DF and , },
title = {Ethanol-induced conditioned taste aversion and associated neural activation in male rats: Impact of age and adolescent intermittent ethanol exposure.},
journal = {PloS one},
volume = {17},
number = {12},
pages = {e0279507},
doi = {10.1371/journal.pone.0279507},
pmid = {36548243},
issn = {1932-6203},
abstract = {Individuals that initiate alcohol use at younger ages and binge drink during adolescence are more susceptible to developing alcohol use disorder. Adolescents are relatively insensitive to the aversive effects of alcohol and tend to consume significantly more alcohol per occasion than adults, an effect that is conserved in rodent models. Adolescent typical insensitivity to the aversive effects of alcohol may promote greater alcohol intake by attenuating internal cues that curb its consumption. Attenuated sensitivity to the aversive effects of alcohol is also retained into adulthood following protracted abstinence from adolescent intermittent ethanol (AIE) exposure. Despite these effects, much remains unknown regarding the neural contributors. In the present study, we used a conditioned taste aversion (CTA) paradigm to investigate neuronal activation in late-developing forebrain structures of male adolescents and adult cFos-LacZ transgenic rats as well as in AIE adults following consumption of 0.9% sodium chloride previously paired with an intraperitoneal injection of 0, 1.5 or 2.5 g/kg of ethanol. Adults that were non-manipulated or received water exposure during adolescence showed CTA to both ethanol doses, whereas adolescents displayed CTA only to the 2.5 g/kg ethanol dose. Adults who experienced AIE did not show CTA. Adults displayed increased neuronal activation indexed via number of β-galactosidase positive (β-gal+) cells in the prefrontal and insular cortex that was absent in adolescents, whereas adolescents but not adults had a reduced number of β-gal+ cells in the central amygdala. Adults also displayed greater cortical-insular functional connectivity than adolescents as well as insular-amygdalar and prefrontal cortex-accumbens core functional connectivity. Like adolescents, adults previously exposed to AIE displayed reduced prefrontal-insular cortex and prefrontal-accumbal core functional connectivity. Taken together, these results suggest that attenuated sensitivity to the aversive effects of ethanol is related to a loss of an insular-prefrontal cortex-accumbens core circuit.},
}

@article {pmid36509179,
year = {2022},
author = {Kikuchi, E and Inui, T and Su, S and Sato, Y and Funahashi, M},
title = {Chemogenetic inhibition of the bed nucleus of the stria terminalis suppresses the intake of a preferable and learned aversive sweet taste solution in male mice.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {114253},
doi = {10.1016/j.bbr.2022.114253},
pmid = {36509179},
issn = {1872-7549},
abstract = {Conditioned taste aversion (CTA) is established by pairing a taste solution as a conditioned stimulus (CS) with visceral malaise as an unconditioned stimulus (US). CTA decreases the taste palatability of a CS. The bed nucleus of the stria terminalis (BNST) receives taste inputs from the brainstem. However, the involvement of the BNST in CTA remains unclear. Thus, this study examined the effects of chemogenetic inhibition of the BNST neurons on CS intake after CTA acquisition. An adeno-associated virus was microinjected into the BNST of male C57/BL6 mice to induce the inhibitory designer receptor hM4Di. The mice received a pairing of 0.2% saccharin solution (CS) with 0.3M lithium chloride (2% BW, intraperitoneal). After conditioning, the administration of clozapine-N-oxide (CNO, 1mg/kg) significantly enhanced the suppression of CS intake on the retrieval of CTA compared with its intake following saline administration (p < 0.01). We further assessed the effect of BNST neuron inhibition on the intake of water and taste solutions (saccharin, sucralose, sodium chloride, monosodium glutamate, quinine hydrochloride, and citric acid) using naïve (not learned CTA) mice. CNO administration significantly decreased the intake of saccharin and sucralose (p < 0.05). Our results indicate that BNST neurons mediate sweet taste and regulate sweet intake, regardless of whether sweets should be ingested or rejected. BNST neurons may be inhibited in the retrieval of CTA, thereby suppressing CS intake.},
}

@article {pmid36508476,
year = {2022},
author = {Hatakeyama, D and Chikamoto, N and Fujimoto, K and Kitahashi, T and Ito, E},
title = {Comparison between relative and absolute quantitative real-time PCR applied to single-cell analyses: Transcriptional levels in a key neuron for long-term memory in the pond snail.},
journal = {PloS one},
volume = {17},
number = {12},
pages = {e0279017},
doi = {10.1371/journal.pone.0279017},
pmid = {36508476},
issn = {1932-6203},
abstract = {Quantitative real-time PCR (qPCR) is a powerful method for measuring nucleic acid levels and quantifying mRNA levels, even in single cells. In the present study, we compared the results of single-cell qPCR obtained by different quantification methods (relative and absolute) and different reverse transcription methods. In the experiments, we focused on the cerebral giant cell (CGC), a key neuron required for the acquisition of conditioned taste aversion in the pond snail Lymnaea stagnalis, and examined changes in the mRNA levels of 3 memory-related genes, cAMP-response element binding proteins (LymCREB1 and LymCREB2) and CREB-binding protein (LymCBP), during memory formation. The results obtained by relative quantification showed similar patterns for the 3 genes. For absolute quantification, reverse transcription was performed using 2 different methods: a mixture of oligo d(T) primers and random primers (RT method 1); and gene-specific primers (RT method 2). These methods yielded different results and did not show consistent changes related to conditioning. The mRNA levels in the samples prepared by RT method 2 were up to 3.3 times higher than those in samples prepared by RT method 1. These results suggest that for qPCR of single neurons, the efficacy and validity do not differ between relative and absolute quantification methods, but the reverse transcription step critically influences the results of mRNA quantification.},
}

@article {pmid36444166,
year = {2022},
author = {Al-Kuraishy, HM and Al-Gareeb, AI and Alexiou, A and Papadakis, M and Nadwa, EH and Albogami, SM and Alorabi, M and Saad, HM and Batiha, GE},
title = {Metformin and growth differentiation factor 15 (GDF15) in type 2 diabetes mellitus: A hidden treasure.},
journal = {Journal of diabetes},
volume = {},
number = {},
pages = {},
doi = {10.1111/1753-0407.13334},
pmid = {36444166},
issn = {1753-0407},
abstract = {Type 2 diabetes mellitus (T2DM) is a chronic endocrine disorder due to the reduction of insulin sensitivity and relative deficiency of insulin secretion. Growth differentiation factor 15 (GDF15) belongs to the transforming growth factor beta (TGF-β) superfamily and was initially identified as macrophage inhibitory cytokine-1 (MIC-1). GDF15 is considered a cytokine with an anti-inflammatory effect and increases insulin sensitivity, reduces body weight, and improves clinical outcomes in diabetic patients. GDF15 acts through stimulation of glial-derived neurotrophic factor (GDNF) family receptor α-like (GFRAL), which is highly expressed in the brain stem to induce taste aversion. Metformin belongs to the group of biguanides that are derived from the plant Galega officinalis. It is interesting to note that metformin is an insulin-sensitizing agent used as a first-line therapy for T2DM that has been shown to increase the circulating level of GDF15. Thus, the present review aims to determine the critical association of the GDF15 biomarker in T2DM and how metformin agents affect it. This review illustrates that metformin activates GDF15 expression, which reduces appetite and leads to weight loss in both diabetic and nondiabetic patients. However, the present review cannot give a conclusion in this regard. Therefore, experimental, preclinical, and clinical studies are warranted to confirm the potential role of GDF15 in T2DM patients.},
}

@article {pmid36439968,
year = {2022},
author = {Panayi, MC and Killcross, S},
title = {Outcome devaluation by specific satiety disrupts sensory-specific Pavlovian-to-instrumental transfer.},
journal = {Frontiers in behavioral neuroscience},
volume = {16},
number = {},
pages = {983480},
pmid = {36439968},
issn = {1662-5153},
abstract = {Reward predictive cues can selectively motivate instrumental behaviors that predict the same rewarding outcomes, an effect known as specific Pavlovian-to-instrumental transfer (PIT). This selective effect is thought to be mediated by a representation of the sensory specific properties of an outcome, that has become associated with both the Pavlovian cue and the instrumental response during initial learning. Specific satiety is a common method of outcome devaluation that reduces an outcome's value but might also lead to the habituation of the outcome's sensory properties. Previous research has demonstrated that specific PIT is insensitive to changes in specific outcome value following taste aversion devaluation, as well as general satiety manipulations, and therefore specific satiety should not disrupt specific PIT by reducing outcome value. The present rodent experiments used a specific satiety devaluation procedure immediately prior to a specific PIT test to show that habituation of these outcome specific sensory representations can disrupt its efficacy as a stimulus and abolish the specific PIT effect. Experiment 1 employed a two-lever choice test to show that a non-devalued stimulus supports specific PIT, whereas a devalued stimulus abolished the specific PIT effect. Experiment 2 replicated this procedure while controlling for response competition by using a single-lever test to confirm that a devalued stimulus abolishes the specific PIT effect. These findings demonstrate that specific satiety can disrupt the ability of an outcome specific representation to support specific PIT. Given previous findings that specific PIT is insensitive to changes in outcome value by general satiety and taste aversion devaluation, this suggests that specific satiety devaluation might disrupt the use of sensory specific outcome representations to guide behavior via a mechanism that is independent of the outcome's current value.},
}

@article {pmid36382058,
year = {2022},
author = {Yoshida, Y and Tanaka, R and Fujishiro, S and Nishimura, S and Tabata, S and Kawabata, F},
title = {Conditioned Taste Aversion to L-Amino Acid Taste Stimuli and Oral Transcriptional Changes to Type 1 Taste Receptors T1R1 and T1R3 on Chronic Exposure to L-Alanine Solution in Chickens.},
journal = {The journal of poultry science},
volume = {59},
number = {4},
pages = {348-356},
pmid = {36382058},
issn = {1349-0486},
abstract = {Elucidating taste sensing systems in chickens is an important step toward understanding poultry nutrition. Amino acid taste receptors, type 1 taste receptors 1 and 3 (T1R1 and T1R3, respectively), are expressed in chicken taste cells, and chicken T1R1/T1R3 is activated by L-alanine (L-Ala) and L-serine (L-Ser), but not by L-proline (L-Pro). However, it is not clear whether chickens have a gustatory perception of L-amino acids. Here, we found that chickens conditioned to avoid either L-Ala, L-Ser, or L-Pro solutions could successfully learn to avoid the corresponding L-amino acid solution in the conditioned taste aversion (CTA) test. Because CTA is a well-established learning paradigm generated specifically by pairing gustatory perception and gastrointestinal malaise, the present study suggests that chickens can sense L-amino acids by gustatory perception. In addition, we found that the expression of the T1R1 and T1R3 genes was significantly downregulated in response to chronic exposure to L-Ala solution, but not to acute oral stimulation. Taken together, the present study suggests that chickens have a gustatory perception of L-amino acids, and the expression of T1R1/T1R3 mRNAs in the oral cavity can be regulated by L-amino acid intake. Since chickens can detect L-Pro solutions, additional amino acid receptors, other than T1R1/T1R3, may be involved in L-amino acid taste detection in chickens.},
}

@article {pmid36368526,
year = {2022},
author = {Reich, N and Hölscher, C},
title = {Beyond appetite: Acylated ghrelin as a learning, memory and fear behavior-modulating hormone.},
journal = {Neuroscience and biobehavioral reviews},
volume = {143},
number = {},
pages = {104952},
doi = {10.1016/j.neubiorev.2022.104952},
pmid = {36368526},
issn = {1873-7528},
mesh = {Humans ; *Ghrelin/metabolism ; *Memory/physiology ; Appetite ; Fear/physiology ; Amygdala/physiology ; Hippocampus/physiology ; },
abstract = {Although often referred to as a hunger hormone, recent evidence highlights a neuroprotective function of acylated ghrelin (AG) and a substantial role in the regulation of declarative and aversive memories as well as fear behavior. As such, in this review, we i) evaluate what specific stages and forms of memory, as well as which respective brain areas are affected by acylated ghrelin, ii) illustrate the plasticity-associated signaling pathways of AG in the hippocampus, also involving memory resolution-enhancing neurogenesis, iii) elucidate how the peptide modulates neurotransmitter systems (glutamate, γ-aminobutyric acid, dopamine, serotonin), iV) clarify the role of AG in conditioned taste aversion, novelty learning and the formation of spatial, recognition, auditory fear, contextual fear and passive avoidance memories in the hippocampus and amygdala as well as V) solve the mystery behind AG, its impact on the 5-HT system, the recently established link to post-traumatic stress disorder and the either fear-suppressing or fear-potentiating effects under neutral and acutely stressed conditions or chronic stress, respectively.},
}

Humans
*Ghrelin/metabolism
*Memory/physiology
Appetite
Fear/physiology
Amygdala/physiology
Hippocampus/physiology

@article {pmid36261035,
year = {2022},
author = {Staszko, SM and Boughter, JD and Fletcher, ML},
title = {The impact of familiarity on cortical taste coding.},
journal = {Current biology : CB},
volume = {32},
number = {22},
pages = {4914-4924.e4},
pmid = {36261035},
issn = {1879-0445},
support = {R01 DC016833/DC/NIDCD NIH HHS/United States ; },
mesh = {Mice ; Animals ; *Cerebral Cortex/physiology ; *Taste/physiology ; Taste Perception/physiology ; Neurons/physiology ; Recognition, Psychology ; },
abstract = {The role of the gustatory region of the insular cortex in mediating associative taste learning, such as conditioned taste aversion, has been well studied. However, while associative learning plays a role in some taste behaviors, such as avoiding toxins, animals often encounter taste stimuli in their natural environment without explicit consequences. This type of inconsequential experience with sensory stimuli has been studied in other sensory systems, generally with the finding that neuronal responses habituate with repeated sensory exposure. This study sought to determine the effect of taste familiarity on population taste coding in the mouse gustatory cortex (GC). Using microendoscope calcium imaging, we studied the taste responses of visually identifiable neurons over 5 days of taste experience, during which animals could freely choose to consume taste stimuli. We found that the number of active cells in the insular cortex, as well as the number of cells characterized as taste-responsive, significantly decreased as animals became familiar with taste stimuli. Moreover, the magnitude of taste-evoked excited responses increased while inhibited responses decreased with experience. By tracking individual neurons over time, we identified a subpopulation of stable neurons present on all days of the taste familiarity paradigm and further characterized their taste coding properties. The population-level response across these stable cells was distinct for each taste quality when taste stimuli were novel, but population responses for readily consumed stimuli became more correlated as the stimuli became familiar. Overall, these results highlight the effects of familiarity on both taste-specific and non-taste responses in the gustatory cortex.},
}

Mice
Animals
*Cerebral Cortex/physiology
*Taste/physiology
Taste Perception/physiology
Neurons/physiology
Recognition, Psychology

@article {pmid36248606,
year = {2022},
author = {López, M and Dwyer, DM and Gasalla, P and Jove, C and Begega, A},
title = {Characterizing Hedonic Responses to Flavors Paired with Internal Pain and Nausea through the Taste Reactivity Test in Rats.},
journal = {Bio-protocol},
volume = {12},
number = {18},
pages = {},
pmid = {36248606},
issn = {2331-8325},
abstract = {Feeding behavior is a complex experience that involves not only sensory (i.e., visual, odor, taste, or texture) but also affective or emotional aspects (i.e., pleasure, palatability, or hedonic value) of foods. As such, behavioral tests that assess the hedonic impact of foods are necessary to fully understand the factors involved in ingestive behavior. In this protocol, we use the taste reactivity (TR) test to characterize the hedonic responses of rats to flavors paired with either lithium chloride-induced nausea or internal pain produced by hypertonic NaCl, two treatments that reduce voluntary consumption. This application of the TR test demonstrates how emetic and non-emetic (somatic pain in particular) treatments produce dissociable patterns of hedonic reactions to fluids: only emetic treatments result in the production of aversive orofacial responses, reflecting conditioned nausea, whereas somatic pain produces immobility, reflecting conditioned fear. Other methods, such as the microstructural analysis of licking behavior, do not reliably distinguish conditioned nausea and fear, a key advantage of the more selective TR procedure. This protocol also contains guidance for adaptation to other species and designs.},
}

@article {pmid36190750,
year = {2022},
author = {Buabang, EK and Boddez, Y and Wolf, OT and Moors, A},
title = {The role of goal-directed and habitual processes in food consumption under stress after outcome devaluation with taste aversion.},
journal = {Behavioral neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1037/bne0000439},
pmid = {36190750},
issn = {1939-0084},
abstract = {People are more likely to engage in various suboptimal behaviors such as overeating, addictive behaviors, and short-sighted financial decision-making when they are under stress. Traditional dual-process models propose that stress can impair the ability to engage in goal-directed behavior so that people have to rely on habitual behavior. Support for this idea comes from a study by Schwabe and Wolf (2010), in which stressed participants continued to perform a learned instrumental behavior leading to a liquid after the liquid was devalued with a satiation procedure. Based on these findings, suboptimal behavior under stress is often seen as habitual. In the present study, we conducted a conceptual replication of the study by Schwabe and Wolf (2010). Instead of using a satiation procedure to achieve the outcome devaluation, we devalued outcomes through taste aversion. We did not replicate the pattern of findings by Schwabe and Wolf (2010). Our results indicate instead that stressed participants were sensitive to outcome values when the outcomes became truly aversive and hence that their behavior was goal-directed. This suggests either that (a) habitual processes are subject to boundary conditions or (b) the processes responsible for the findings of Schwabe and Wolf (2010) were never habitual to begin with. This may have far-reaching implications for explaining suboptimal behavior under stress in general. (PsycInfo Database Record (c) 2022 APA, all rights reserved).},
}

@article {pmid36183862,
year = {2022},
author = {Bishnoi, IR and Cloutier, CJ and Tyson, CD and Matic, VM and Kavaliers, M and Ossenkopp, KP},
title = {Infection, learning, and memory: Focus on immune activation and aversive conditioning.},
journal = {Neuroscience and biobehavioral reviews},
volume = {142},
number = {},
pages = {104898},
doi = {10.1016/j.neubiorev.2022.104898},
pmid = {36183862},
issn = {1873-7528},
mesh = {Animals ; *Lipopolysaccharides/pharmacology ; *Avoidance Learning ; Lithium Chloride/pharmacology ; Behavior, Animal/physiology ; Conditioning, Psychological/physiology ; Taste ; },
abstract = {Here we review the effects of immune activation primarily via lipopolysaccharide (LPS), a cell wall component of Gram-negative bacteria, on hippocampal and non-hippocampal-dependent learning and memory. Rodent studies have found that LPS alters both the acquisition and consolidation of aversive learning and memory, such as those evoking evolutionarily adaptive responses like fear and disgust. The inhibitory effects of LPS on the acquisition and consolidation of contextual fear memory are discussed. LPS-induced alterations in the acquisition of taste and place-related conditioned disgust memory within bottle preference tasks and taste reactivity tests (taste-related), in addition to conditioned context avoidance tasks and the anticipatory nausea paradigm (place-related), are highlighted. Further, conditioned disgust memory consolidation may also be influenced by LPS-induced effects. Growing evidence suggests a central role of immune activation, especially pro-inflammatory cytokine activity, in eliciting the effects described here. Understanding how infection-induced immune activation alters learning and memory is increasingly important as bacterial and viral infections are found to present a risk of learning and memory impairment.},
}

Animals
*Lipopolysaccharides/pharmacology
*Avoidance Learning
Lithium Chloride/pharmacology
Behavior, Animal/physiology
Conditioning, Psychological/physiology
Taste

@article {pmid36056214,
year = {2022},
author = {Liu, J and Wu, R and Johnson, B and Zhang, Y and Zhu, Q and Li, JX},
title = {Selective TAAR1 agonists induce conditioned taste aversion.},
journal = {Psychopharmacology},
volume = {239},
number = {10},
pages = {3345-3353},
pmid = {36056214},
issn = {1432-2072},
support = {R01DA034806/DA/NIDA NIH HHS/United States ; R21DA040777/DA/NIDA NIH HHS/United States ; R01DA034806/DA/NIDA NIH HHS/United States ; R21DA040777/DA/NIDA NIH HHS/United States ; },
mesh = {Animals ; *Antipsychotic Agents/chemistry/pharmacology ; Aversive Agents/chemistry/pharmacology ; Humans ; Mammals ; Oxazoles ; Phenethylamines/pharmacology ; Rats ; *Receptors, G-Protein-Coupled/agonists ; Saccharin/pharmacology ; Sodium Chloride ; Taste/drug effects ; *Taste Perception/drug effects ; },
abstract = {RATIONALE: Trace amine-associated receptor 1 (TAAR1) is the best-studied receptor of trace amines, a group of biogenic amines expressed at a relatively low level in the mammalian brain. Growing evidence suggests that TAAR1 plays a critical role in various neuropsychiatric disorders. Given that selective TAAR1 agonists were shown to produce pro-cognition and antipsychotic-like effects as well as to suppress drug use and relapse, they have been proposed to be novel treatments for mental disorders such as schizophrenia and addiction. However, the aversive effects of selective TAAR1 agonists remain largely unknown.

OBJECTIVES: Here, we evaluated whether the selective TAAR1 full agonist RO5166017 and partial agonist RO5263397 could induce conditioned taste aversion (CTA).

RESULTS: We found that RO5166017 and RO5263397 produced significant aversions to both saccharin and NaCl taste novelty. Furthermore, RO5166017 produced CTA to saccharin in TAAR1 heterozygous knockout (taar1[±]) and wild-type rats but not in TAAR1 homozygous knockout rats (taar1[-/-]), suggesting that TAAR1 was sufficient for the taste aversive stimulus property of RO5166017.

CONCLUSIONS: Taken together, our data indicate that selective TAAR1 agonists could produce strong CTA. Our study urges careful evaluations of the aversive effects of TAAR1 agonists before translating them to clinical use for the treatment of mental disorders.},
}

Animals
*Antipsychotic Agents/chemistry/pharmacology
Aversive Agents/chemistry/pharmacology
Humans
Mammals
Oxazoles
Phenethylamines/pharmacology
Rats
*Receptors, G-Protein-Coupled/agonists
Saccharin/pharmacology
Sodium Chloride
Taste/drug effects
*Taste Perception/drug effects

@article {pmid35944659,
year = {2022},
author = {Niedringhaus, M and West, EA},
title = {Prelimbic cortex neural encoding dynamically tracks expected outcome value.},
journal = {Physiology & behavior},
volume = {256},
number = {},
pages = {113938},
doi = {10.1016/j.physbeh.2022.113938},
pmid = {35944659},
issn = {1873-507X},
support = {R00 DA042934/DA/NIDA NIH HHS/United States ; },
mesh = {Animals ; Cerebral Cortex ; *Conditioning, Classical ; Cues ; Extinction, Psychological ; Rats ; *Reward ; },
abstract = {Animals must modify their behavior based on updated expected outcomes in a changing environment. Prelimbic cortex (PrL) neural encoding during learning predicts, and is necessary for, appropriately altering behavior based on a new expected outcome value following devaluation. We aimed to determine how PrL neural activity encodes reward predictive cues after the expected outcome value of those cues is decreased following conditioned taste aversion. In one post-devaluation session, rats were tested under extinction to determine their ability to alter their behavior to the expected outcome values (i.e., extinction test). In a second post-devaluation session, rats were tested with the newly devalued outcome delivered so that the rats experienced the updated outcome value within the session (i.e., re-exposure test). We found that PrL neural encoding of the cue associated with the devalued reward predicted the ability of rats to suppress behavior in the extinction test session, but not in the re-exposure test session. While all rats were able to successfully devalue the outcome during conditioned taste aversion, a subset of rats continued to consume the devalued outcome in the re-exposure test session. We found differential patterns of PrL neural encoding in the population of rats that did not avoid the devalued outcome during the re-exposure test compared to the rats that successfully avoided the devalued outcome. Our findings suggest that PrL neural encoding dynamically tracks expected outcome values, and differential neural encoding in the PrL to reward predictive cues following expected outcome value changes may contribute to distinct behavioral phenotypes.},
}

Animals
Cerebral Cortex
*Conditioning, Classical
Cues
Extinction, Psychological
Rats
*Reward

@article {pmid35931277,
year = {2022},
author = {Ascencio Gutierrez, V and Carrillo, AA and Boersma, GJ and Tamashiro, KLK and Moran, TH and Iñiguez, SD and Treesukosol, Y},
title = {Effect of early-life stress or fluoxetine exposure on later-life conditioned taste aversion learning in Sprague-Dawley rats.},
journal = {Neuroscience letters},
volume = {787},
number = {},
pages = {136818},
doi = {10.1016/j.neulet.2022.136818},
pmid = {35931277},
issn = {1872-7972},
support = {R16 GM145552/GM/NIGMS NIH HHS/United States ; SC2 GM109811/GM/NIGMS NIH HHS/United States ; },
mesh = {*Adverse Childhood Experiences ; Animals ; Avoidance Learning ; Body Weight ; *Fluoxetine/pharmacology ; Lithium Chloride/pharmacology ; Male ; Rats ; Rats, Sprague-Dawley ; Saccharin ; Taste ; },
abstract = {In rodents, early-life exposure to environmental stress or antidepressant medication treatment has been shown to induce similar long-term consequences on memory- and depression-related behavior in adulthood. To expand on this line of work, we evaluated how juvenile exposure to chronic variable stress (CVS) or the selective serotonin reuptake inhibitor fluoxetine (FLX) influences conditioned taste aversion (CTA) learning in adulthood. To do this, in Experiment 1, we examined how adolescent CVS alone (postnatal day [PND] 35-48), or with prenatal stress (PNS) history (PNS + CVS), influenced the acquisition and extinction of CTA in adult male Sprague Dawley rats. Specifically, at PND70+ (adulthood), rats were presented with 0.15 % saccharin followed by an intraperitoneal (i.p.) injection of lithium chloride (LiCl) to induce visceral malaise. A total of four saccharin (conditioned stimulus) and LiCl (unconditioned stimulus) pairings occurred across the CTA acquisition phase. Next, saccharin was presented without aversive consequences, and intake was measured across consecutive days of the extinction phase. No differences in body weight gain across the experimental days, rate of CTA acquisition, or extinction of CTA, were observed among the experimental groups (control, n = 7; CVS, n = 12; PNS + CVS, n = 9). In Experiment 2, we evaluated if early-life FLX exposure alters CTA learning in adulthood. Specifically, adolescent stress naïve male and female rats received FLX (0 or 20 mg/kg/i.p) once daily for 15 consecutive days (PND35-49). During antidepressant exposure, FLX decreased body weight gain in both male (n = 7) and female rats (n = 7), when compared to respective controls (male control, n = 8; female control, n = 8). However, juvenile FLX exposure decreased body weight-gain in adult male, but not female, rats. Lastly, adolescent FLX history had no effect on CTA acquisition or extinction in adulthood (PND70), in neither male nor female rats. Together, the data indicate that juvenile FLX exposure results in a long-term decrease of body weight-gain in a male-specific manner. Yet, independent of sex, neither early-life stress nor FLX exposure alters CTA learning in adulthood.},
}

*Adverse Childhood Experiences
Animals
Avoidance Learning
Body Weight
*Fluoxetine/pharmacology
Lithium Chloride/pharmacology
Male
Rats
Rats, Sprague-Dawley
Saccharin
Taste

@article {pmid35918017,
year = {2022},
author = {Tachibana, T and Nakatani, A and Khan, S and Makino, R and Cline, MA},
title = {Effect of lithium chloride on food intake, cloacal temperature, voluntary activity, and crop-emptying rate in chicks.},
journal = {Comparative biochemistry and physiology. Part A, Molecular & integrative physiology},
volume = {273},
number = {},
pages = {111284},
doi = {10.1016/j.cbpa.2022.111284},
pmid = {35918017},
issn = {1531-4332},
mesh = {Animals ; Anorexia ; *Chickens/physiology ; Eating ; Lipopolysaccharides/pharmacology ; Lithium/pharmacology ; *Lithium Chloride/pharmacology ; Mammals ; Taste ; Temperature ; Zymosan/pharmacology ; },
abstract = {Infections frequently accompany with non-specific symptoms such as anorexia and hyperthermia. In addition, there may be unpleasant sensations such as visceral discomfort during infection. Lipopolysaccharide (LPS), a Gram-negative bacteria cell wall component, is known to induce the unpleasant sensation of conditioned taste aversion in mammals. However, the relationship between unpleasant sensations and changes in behavior and physiological conditions has not been investigated extensively in birds. Lithium chloride (LiCl) is a compound that induces unpleasant sensations, including visceral discomfort, although its effects on behavior and physiological conditions have also not been investigated extensively in birds. Thus, the present study was aimed to investigate the effect of an intraperitoneal (IP) injection of LiCl on conditioned visual aversion, food intake, cloacal temperature, voluntary activity, crop-emptying rate, and blood constituents in chicks (Gallus gallus). We also examined the effect of IP injections of LPS and zymosan, a cell wall component of fungus, on conditioned visual aversion formation. First, IP injection of LiCl was confirmed to induce conditioned visual aversion in chicks. An IP injection of LiCl significantly decreased food intake, voluntary activity, and crop-emptying rate but did not affect the temperature. In addition, the injection of LiCl significantly increased plasma corticosterone concentration, indicating that LiCl serves as a stressor in chicks. Finally, IP injections of LPS and zymosan were found to induce conditioned visual aversion in chicks. Collectively, these results suggest that LiCl induces conditioned aversion, anorexia, hypoactivity, and inhibition of crop-emptying in chicks. In addition, LPS and zymosan would induce unpleasant sensations in chicks.},
}

Animals
Anorexia
*Chickens/physiology
Eating
Lipopolysaccharides/pharmacology
Lithium/pharmacology
*Lithium Chloride/pharmacology
Mammals
Taste
Temperature
Zymosan/pharmacology

@article {pmid35913117,
year = {2022},
author = {Bai, L and Sivakumar, N and Yu, S and Mesgarzadeh, S and Ding, T and Ly, T and Corpuz, TV and Grove, JCR and Jarvie, BC and Knight, ZA},
title = {Enteroendocrine cell types that drive food reward and aversion.},
journal = {eLife},
volume = {11},
number = {},
pages = {},
pmid = {35913117},
issn = {2050-084X},
support = {RF1 NS116626/NS/NINDS NIH HHS/United States ; R01 DK106399/DK/NIDDK NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; },
mesh = {Animals ; Cholecystokinin/metabolism ; *Enteroendocrine Cells/metabolism ; *Food ; Food Preferences ; Mice ; Reward ; Taste ; },
abstract = {Animals must learn through experience which foods are nutritious and should be consumed, and which are toxic and should be avoided. Enteroendocrine cells (EECs) are the principal chemosensors in the GI tract, but investigation of their role in behavior has been limited by the difficulty of selectively targeting these cells in vivo. Here, we describe an intersectional genetic approach for manipulating EEC subtypes in behaving mice. We show that multiple EEC subtypes inhibit food intake but have different effects on learning. Conditioned flavor preference is driven by release of cholecystokinin whereas conditioned taste aversion is mediated by serotonin and substance P. These positive and negative valence signals are transmitted by vagal and spinal afferents, respectively. These findings establish a cellular basis for how chemosensing in the gut drives learning about food.},
}

Animals
Cholecystokinin/metabolism
*Enteroendocrine Cells/metabolism
*Food
Food Preferences
Mice
Reward
Taste

@article {pmid35878079,
year = {2022},
author = {Sánchez, J and Dwyer, DM and Honey, RC and de Brugada, I},
title = {Perceptual learning after rapidly alternating exposure to taste compounds: Assessment with different indices of generalization.},
journal = {Journal of experimental psychology. Animal learning and cognition},
volume = {48},
number = {3},
pages = {169-178},
doi = {10.1037/xan0000333},
pmid = {35878079},
issn = {2329-8464},
support = {/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Animals ; Association Learning/physiology ; Conditioning, Classical ; *Discrimination Learning ; Generalization, Psychological ; Humans ; Learning ; Male ; Rats ; *Taste/physiology ; },
abstract = {Exposure to two similar stimuli (AX and BX; e.g., two tastes) reduces the extent to which a conditioned response later established to BX generalizes to AX. This example of perceptual learning is more evident when AX and BX are exposed in an alternating manner (AX, BX, AX, BX,…) than when AX and BX occur in separate blocks (e.g., AX, AX,…BX, BX,…). We examined in male rats (N = 126) the impact of rapid alternation to AX and BX on generalization of a taste aversion from BX to AX. Experiment 1 showed that such alternating presentations (with 5-min intervals between AX and BX) reduced generalization relative to blocked exposure; but only as assessed by consumption levels and not by lick cluster size (an index of hedonic reactions). Experiment 1 also showed that the nature of exposure did not affect how A influenced performance to a novel conditioned taste, Y. Experiment 2 replicated the pattern of results involving the different influences of rapidly alternating and blocked exposure on generalization from BX to AX, and showed that this effect was only evident when rats received access to water during the 5-min intervals between AX and BX. These results reinforce parallels between perceptual learning effects in rats and humans, both at empirical and theoretical levels. (PsycInfo Database Record (c) 2022 APA, all rights reserved).},
}

Animals
Association Learning/physiology
Conditioning, Classical
*Discrimination Learning
Generalization, Psychological
Humans
Learning
Male
Rats
*Taste/physiology

@article {pmid35864815,
year = {2022},
author = {Shanmugamprema, D and Muthuswamy, K and Ponnusamy, V and Subramanian, G and Velusamy, T and Krishnan, V and Subramaniam, S},
title = {CD36 and GPR120 mediated orogustatory perception of dietary lipids and its physiological implication in the pygmy mouse Mus booduga.},
journal = {Journal of animal physiology and animal nutrition},
volume = {106},
number = {6},
pages = {1408-1419},
doi = {10.1111/jpn.13755},
pmid = {35864815},
issn = {1439-0396},
mesh = {Mice ; Animals ; *Taste Buds/metabolism ; Dietary Fats/metabolism ; CD36 Antigens/genetics/metabolism ; Taste Perception/genetics ; Taste ; Linoleic Acid/metabolism ; Receptors, G-Protein-Coupled/metabolism ; },
abstract = {Fat taste perception has long been concerned in the regulation of dietary fat intake. Substantial experimental evidence defends fat as a sixth taste modality, but its allied peripheral mechanisms are not yet well established. The present study aimed to analyse the diet-induced changes in fat taste perception and its associated physiological variations in Mus booduga. Four groups of animals were used for the present study and were fed any one of the following diet; normal diet (10% fat), low-fat diet (4% fat), high-fat diet (36% fat), or high-fat diet (HFD) (36% fat) + rapeseed oil (HFRDO) (14%) for 9 weeks. The animals were then subjected to metabolic tolerance, fat preference, and conditioned taste aversion studies. Diet-induced alterations in the expression of genes associated with lipogenesis, inflammation, and fat taste (CD36 and GPR120) were analysed. Capacitative calcium signalling induced by both linoleic acid and grifolic acid in taste bud cells (TBCs) was also analysed. In result, both the HFD and HFDRO groups revealed deterioration in glucose homoeostasis and displayed decreased preference scores for fatty acids, which are associated with lower CD36 expression and increased GPR120 expression in TBCs. Furthermore, change in [Ca[2+] ]i induced by LA was also compromised in CD36 positive TBCs along with elevated systemic inflammatory and lipidemic responses in both these obese groups. Overall, for the first time, our results support that chronic HFD feeding alters the CD36 and GPR120 mediated fat taste perception in M. booduga.},
}

Mice
Animals
*Taste Buds/metabolism
Dietary Fats/metabolism
CD36 Antigens/genetics/metabolism
Taste Perception/genetics
Taste
Linoleic Acid/metabolism
Receptors, G-Protein-Coupled/metabolism

@article {pmid35784020,
year = {2022},
author = {Aiyer, A and Bunuba Rangers, and Bell, T and Shine, R and Somaweera, R and Bruny, M and Ward-Fear, G},
title = {Taking the bait: Developing a bait delivery system to target free-ranging crocodiles and varanid lizards with a novel conservation strategy.},
journal = {Ecology and evolution},
volume = {12},
number = {6},
pages = {e8933},
pmid = {35784020},
issn = {2045-7758},
abstract = {In tropical Australia, conditioned taste aversion (CTA) can buffer vulnerable native predators from the invasion of a toxic prey species (cane toads, Rhinella marina). Thus, we need to develop methods to deploy aversion-inducing baits in the field, in ways that maximize uptake by vulnerable species (but not other taxa). We constructed and field-tested baiting devices, in situ with wild animals. Apparatus were set next to waterbodies and baited concurrently at multiple locations (over water, water's edge, and on the bank). Baits were checked and replaced twice daily during the trial; remote cameras recorded visitation by native predators. Bait longevity was compared at sun-exposed and shaded locations over 12 h. The strength required to remove baits from apparatus was measured in varanids and crocodiles. The device promoted high rates of bait uptake by freshwater crocodiles (47% baits consumed), varanid lizards (19% baits consumed), and non-target taxa (34% baits consumed). Targeting specific predators can be achieved by manipulating bait location and time of deployment, as well as the force required to dislodge the bait. Crocodiles were best targeted with over-water baits, whereas varanid lizards preferred baits located at the edges of waterbodies. When testing bait longevity in ambient conditions, during the daytime baits desiccated fully within 12 h, and faster in the sun than in the shade. Based on studies using captive animals, the "pulling force" strength of reptilian predators scaled with body size and was greater in crocodiles than in varanid lizards. We present the first conservation baiting protocol designed specifically for reptiles. Our results demonstrate the feasibility of widespread and taxon-specific deployment of aversion-inducing baits to buffer the impacts of invasive cane toads, and our methods are applicable (with modification) to other research and management programs globally.},
}

@article {pmid35762652,
year = {2022},
author = {Sun, H and Li, J and Yan, J and Sun, B and Wei, X and Song, L and Yan, J},
title = {Decreased taste sensitivity to sucrose in dopamine D3 receptor mutant mice.},
journal = {Chemical senses},
volume = {47},
number = {},
pages = {},
doi = {10.1093/chemse/bjac014},
pmid = {35762652},
issn = {1464-3553},
mesh = {Animals ; *Dysgeusia/genetics ; Mice ; RNA, Messenger/genetics ; *Receptors, Dopamine D3/genetics ; Sucrose/pharmacology ; *Taste/physiology ; *Taste Buds/metabolism ; },
abstract = {Dopamine plays a key role in food rewards and sweet-taste stimulation. We examined the basis for behavioral responses to sweet taste in dopamine D3 receptor-deficient (D3-/-) mice by determining whether the absence of D3 receptors affects the sensitivity to dilute sucrose solutions. In experiment 1, we measured the intensity generalization threshold of conditioned taste aversion (CTA) to a 0.2 M sucrose solution. Results showed that the generalization thresholds were 0.025-0.05 M in D3-/- mice and 0.0025-0.005 M in wild-type (WT) mice. In experiment 2, we found that D3-/- and WT mice had similar capabilities to form and extinguish CTAs. Since the intensity generalization threshold is mainly due to a combination of sweet-taste sensitivity and the robust nature of CTA formation, the results showed that taste sensitivity to sucrose in D3-/- mice was lower than that in WT mice. In experiment 3, to test whether the peripheral sensory signaling may also be affected by the disruption of the dopamine D3 receptors, the mRNA expression levels of sweet-taste-related proteins in taste buds of D3-/- mice were determined. The T1R1 and BDNF mRNA expression levels in D3-/- mice were higher than the controls, whereas T1R2, T1R3, α-gustducin, and TRPM5 mRNA were similar. These findings suggest that disruption of dopamine D3 receptor-mediated signaling decreases the sweet-taste sensitivity and alters the mRNA expression levels of some taste-related molecules.},
}

Animals
*Dysgeusia/genetics
Mice
RNA, Messenger/genetics
*Receptors, Dopamine D3/genetics
Sucrose/pharmacology
*Taste/physiology
*Taste Buds/metabolism

@article {pmid35697908,
year = {2022},
author = {Lyu, H and Mizunami, M},
title = {Conditioned taste aversion in the cricket Gryllus bimaculatus.},
journal = {Scientific reports},
volume = {12},
number = {1},
pages = {9751},
pmid = {35697908},
issn = {2045-2322},
mesh = {Animals ; Avoidance Learning ; *Conditioning, Classical ; Lithium Chloride/pharmacology ; Mammals ; Sucrose/pharmacology ; *Taste ; },
abstract = {Conditioned taste aversion (CTA) is a form of classical conditioning in which animals associate the taste of a food with illness caused by toxin contained in the food. CTA in mammals is achieved with a long interval of up to several hours between food ingestion and illness induced by LiCl injection. Insects also exhibit CTA, but not much is known about its features. We investigated whether the cricket Gryllus bimaculatus exhibits CTA when ingestion of a sugar solution is followed by LiCl injection. Crickets that ingested sucrose solution 5-10 min before LiCl injection exhibited reduction of sucrose consumption tested 24 or 48 h after injection compared to that tested 24 h before injection. In contrast, crickets that ingested sucrose solution 5-10 min after LiCl injection or 1 h or 8 h before or after injection did not exhibit reduction of sucrose consumption, indicating that reduction of sucrose consumption by CTA training is pairing-specific. We conclude that CTA in crickets is similar to that in mammals in that one-trial pairing is sufficient to achieve memory retention for days, but it differs in that it is achieved with a relatively short interval (< 1 h) between food ingestion and toxin injection.},
}

Animals
Avoidance Learning
*Conditioning, Classical
Lithium Chloride/pharmacology
Mammals
Sucrose/pharmacology
*Taste

@article {pmid35679998,
year = {2022},
author = {Reyes-García, SE and Gutiérrez-Vera, B and Escobar, ML},
title = {Calcineurin requirement for in vivo insular cortex LTD and CTA-extinction.},
journal = {Neurobiology of learning and memory},
volume = {193},
number = {},
pages = {107647},
doi = {10.1016/j.nlm.2022.107647},
pmid = {35679998},
issn = {1095-9564},
mesh = {Animals ; *Avoidance Learning/physiology ; *Calcineurin/metabolism ; Cerebral Cortex/physiology ; Insular Cortex ; Male ; Rats ; Rats, Wistar ; Taste/physiology ; },
abstract = {Currently, it is widely accepted that memory extinction involves the formation of a new associative memory rather than unlearning of the information previously acquired. Nonetheless, the cellular and molecular mechanisms underlying this process are still unclear. In this regard, it has been suggested that while kinases modulate conditioning and LTP, phosphatases are relevant for extinction and LTD. In particular, the protein phosphatase calcineurin (CaN) has been involved in the extinction of some behavioral tasks along with LTD. Indeed, studies of our research group have demonstrated that induction of LTD in the basolateral nucleus of the amygdala (Bla) to the insular cortex (IC) pathway facilitates the extinction of conditioned taste aversion (CTA), while the induction of LTP in this pathway slows it down. In addition, we have shown that the extinction of CTA elicits an increase of CaN. The aim of the present study was to evaluate the participation of calcineurin in the extinction of CTA and in the expression of in vivo LTD in the Bla-IC pathway. For this purpose, we chemically inhibited calcineurin in the IC of adult male Wistar rats, either during CTA-extinction or thirty minutes after LTD induction in the Bla-IC pathway. Our results show that calcineurin inhibition slows down the CTA-extinction and blocks the maintenance of LTD. Furthermore, we show that CaN levels increase after LTD induction. These findings support the idea that calcineurin is a key molecular actor for both CTA extinction and LTD expression in the IC, a highly relevant neocortical area for the processing of aversively motivated learning tasks, suggesting that both processes are associated at a molecular level.},
}

Animals
*Avoidance Learning/physiology
*Calcineurin/metabolism
Cerebral Cortex/physiology
Insular Cortex
Male
Rats
Rats, Wistar
Taste/physiology

@article {pmid35644274,
year = {2022},
author = {Gutiérrez-Vera, B and Rivera-Olvera, A and Escobar, ML},
title = {Environmental enrichment attenuates conditioned taste aversion through the restoration of BDNF levels in the insular cortex.},
journal = {Behavioural brain research},
volume = {430},
number = {},
pages = {113947},
doi = {10.1016/j.bbr.2022.113947},
pmid = {35644274},
issn = {1872-7549},
mesh = {Animals ; Avoidance Learning ; Brain-Derived Neurotrophic Factor/*metabolism ; Cerebral Cortex/physiology ; Insular Cortex ; Rats ; Rats, Wistar ; *Taste ; },
abstract = {It has been shown that exposure to an enriched environment (EE) can modulate the physiological impact of aversive stimuli in animals, promoting adaptive attitudes, as well as the development of resilience to stressful situations. These changes are known to be related to increased levels of some trophic factors, such as brain-derived neurotrophic factor (BDNF), which has been considered a regulatory protein for synaptic plasticity in the adult brain. Our previous studies have demonstrated that in the insular cortex (IC), a brain region of the temporal lobe implicated in the acquisition, consolidation, and retention of conditioned taste aversion (CTA) task, BDNF can reverse the CTA memory deficit caused by a protein synthesis inhibitor. Likewise, our research group have also shown that BDNF is required for the maintenance of CTA long-term memory. Here we evaluate the effects of the exposure to an enriched environment on the CTA memory strength, using a weak and strong version of this paradigm. The exposure to an EE for 21 days was able to attenuate the strong-CTA response through the restoration of BDNF levels in the IC of adult rats. These results provide evidence that environmental enrichment is capable of reducing the strength of an aversive memory trace, restoring the BDNF levels in a neocortical region of the adult brain.},
}

Animals
Avoidance Learning
Brain-Derived Neurotrophic Factor/*metabolism
Cerebral Cortex/physiology
Insular Cortex
Rats
Rats, Wistar
*Taste

@article {pmid35641228,
year = {2022},
author = {Jung, AH and King, CT and Blonde, GD and King, M and Griggs, C and Hashimoto, K and Spector, AC and Schier, LA},
title = {A Subregion of Insular Cortex Is Required for Rapid Taste-Visceral Integration and Consequent Conditioned Taste Aversion and Avoidance Expression in Rats.},
journal = {eNeuro},
volume = {9},
number = {4},
pages = {},
pmid = {35641228},
issn = {2373-2822},
support = {R01 DC009821/DC/NIDCD NIH HHS/United States ; },
mesh = {Animals ; *Avoidance Learning/physiology ; Cerebral Cortex/physiology ; Conditioning, Classical/physiology ; Insular Cortex ; Lithium Chloride/pharmacology ; Rats ; Sucrose ; *Taste/physiology ; },
abstract = {Postingestive signals are important for shaping appetitive and consummatory responses, but the brain mechanisms required to assimilate interoceptive events with those at the frontlines of ingestion (taste-guided) are poorly understood. Here, we investigated whether an insular cortex (IC) region, which receives viscerosensory input, including gustatory, is required to modify taste-elicited consummatory reactions in response to a real-time interoceptive change using a serial taste reactivity (TR) test where the rats' oromotor and somatic reactions to intraoral (IO) infusions of sucrose were periodically assessed over 45 min following lithium chloride (LiCl) administration. Results showed that neurally-intact rats shifted from an ingestive repertoire to an aversive one as LiCl took effect. Overall, this hedonic shift was delayed in rats with bilateral neurotoxic IC lesions. Rats with greater neuronal loss in posterior gustatory IC displayed fewer aversive reactions to sucrose following this initial LiCl injection. We further assessed whether the failure to integrate interoceptive feedback with ongoing taste-guided behavior impaired acquisition and/or expression of conditioned aversion and/or avoidance in these same rats. Although, as a group, LiCl-injected rats with IC lesions subsequently avoided the sugar in a 48-h two-bottle test, their preference for sucrose was significantly greater than that of the LiCl-injected neurally-intact rats. Overall lesion size, as well as proportion of the posterior gustatory and/or anterior visceral IC were each associated with impaired avoidance. These findings reveal new roles for the posterior gustatory and anterior visceral ICs in multisensory integrative function.},
}

Animals
*Avoidance Learning/physiology
Cerebral Cortex/physiology
Conditioning, Classical/physiology
Insular Cortex
Lithium Chloride/pharmacology
Rats
Sucrose
*Taste/physiology

@article {pmid35558436,
year = {2022},
author = {Nakai, J and Chikamoto, N and Fujimoto, K and Totani, Y and Hatakeyama, D and Dyakonova, VE and Ito, E},
title = {Insulin and Memory in Invertebrates.},
journal = {Frontiers in behavioral neuroscience},
volume = {16},
number = {},
pages = {882932},
pmid = {35558436},
issn = {1662-5153},
abstract = {Insulin and insulin-like peptides (ILP) help to maintain glucose homeostasis, whereas insulin-like growth factor (IGF) promotes the growth and differentiation of cells in both vertebrates and invertebrates. It is sometimes difficult to distinguish between ILP and IGF in invertebrates, however, because in some cases ILP has the same function as IGF. In the present review, therefore, we refer to these peptides as ILP/IGF signaling (IIS) in invertebrates, and discuss the role of IIS in memory formation after classical conditioning in invertebrates. In the arthropod Drosophila melanogaster, IIS is involved in aversive olfactory memory, and in the nematode Caenorhabditis elegans, IIS controls appetitive/aversive response to NaCl depending on the duration of starvation. In the mollusk Lymnaea stagnalis, IIS has a critical role in conditioned taste aversion. Insulin in mammals is also known to play an important role in cognitive function, and many studies in humans have focused on insulin as a potential treatment for Alzheimer's disease. Although analyses of tissue and cellular levels have progressed in mammals, the molecular mechanisms, such as transcriptional and translational levels, of IIS function in cognition have been far advanced in studies using invertebrates. We anticipate that the present review will help to pave the way for studying the effects of insulin, ILPs, and IGFs in cognitive function across phyla.},
}

@article {pmid35501556,
year = {2022},
author = {Bouton, ME and Michaud, NL},
title = {Partial reinforcement effects on acquisition and extinction of a conditioned taste aversion.},
journal = {Learning & behavior},
volume = {50},
number = {3},
pages = {360-371},
pmid = {35501556},
issn = {1543-4508},
support = {R01 DA033123/DA/NIDA NIH HHS/United States ; },
mesh = {Animals ; *Avoidance Learning ; Conditioning, Classical ; *Extinction, Psychological ; Humans ; Hylobates ; Lithium Chloride/pharmacology ; Rats ; Reinforcement, Psychology ; },
abstract = {Four experiments with rat subjects asked whether a partial reinforcement extinction effect (PREE) occurs in taste aversion learning. The question has received little attention in the literature, and to our knowledge no taste aversion experiment has previously demonstrated a PREE. In each of the present experiments, experimental groups received a taste mixed in drinking water for 20 min; such taste exposures were sometimes paired with a lithium chloride (LiCl) injection and sometimes not. Control groups received only taste-LiCl pairings. There was evidence that each reinforced and non-reinforced trial produced increments and decrements in aversion strength (respectively), and trials mattered more than accumulated time during the conditioned stimulus and during the background (as emphasized in time-accumulation models like those of Gallistel and Gibbon, Psychological Review, 107, 289-344, 2000, and Gibbon and Balsam, Autoshaping and conditioning theory, Academic Press, New York, pp. 219-235, 1981). In addition, a partial reinforcement extinction effect was observed when there was a relatively large number of conditioning trials. The results extend our understanding of extinction in taste aversion learning and provide more evidence that aversion learning might follow rules that are qualitatively similar to those of other forms of learning.},
}

Animals
*Avoidance Learning
Conditioning, Classical
*Extinction, Psychological
Humans
Hylobates
Lithium Chloride/pharmacology
Rats
Reinforcement, Psychology

@article {pmid35500755,
year = {2022},
author = {Haines, KM and Czachowski, CL},
title = {Evaluating habit formation across pairs of female and male selectively bred alcohol-preferring and non-preferring rats.},
journal = {Alcohol (Fayetteville, N.Y.)},
volume = {102},
number = {},
pages = {11-22},
doi = {10.1016/j.alcohol.2022.04.003},
pmid = {35500755},
issn = {1873-6823},
support = {P60 AA007611/AA/NIAAA NIH HHS/United States ; },
mesh = {Alcohol Drinking/genetics ; *Alcoholism/genetics ; Animals ; Conditioning, Classical ; *Ethanol ; Female ; Habits ; Male ; Rats ; },
abstract = {Some individuals with alcohol use disorder (AUD) continue to drink because they have developed a habit where they do not consider the consequences of their actions. Genetically selected lines of alcohol-preferring and non-preferring rats allow for exploration of how specific endophenotypes, such as tendency to form habits, may be risk factors that interact with a genetic predisposition of AUD. While high alcohol drinking (HAD) and alcohol-preferring (P) rats were selectively bred to consume high amounts of freely available ethanol, they exhibit differences in alcohol-seeking behaviors as well as impulsive behaviors, and may represent different behavioral models of AUD. The goal of the current study was to compare the tendency to develop habitual behaviors across female and male HAD1, HAD2, and P rats and their respective alcohol non-preferring counterparts. Alcohol-naïve rats were trained on a variable interval schedule using a non-ethanol reinforcer and were then tested in two extinction sessions, one prior to a reinforcer devaluation (conditioned taste aversion) procedure and one after. There were no differences in total lever presses between P and alcohol non-preferring (NP) rats, but there were differences between HAD and low-alcohol drinking (LAD) rats. All six strains decreased lever pressing after reinforcer devaluation. However, P and NP females did not increase latency to first lever press after devaluation, suggesting some inclination toward habitual behavior that was not apparent in either the HAD or LAD lines. Selective breeding for alcohol preference does not seem to influence the tendency to form habits, whereas background strain and sex may have an influence on this behavior.},
}

Alcohol Drinking/genetics
*Alcoholism/genetics
Animals
Conditioning, Classical
*Ethanol
Female
Habits
Male
Rats

@article {pmid35496768,
year = {2022},
author = {Riley, AL and Manke, HN and Huang, S},
title = {Impact of the Aversive Effects of Drugs on Their Use and Abuse.},
journal = {Behavioural neurology},
volume = {2022},
number = {},
pages = {8634176},
pmid = {35496768},
issn = {1875-8584},
mesh = {Humans ; *Reward ; *Substance-Related Disorders/psychology ; Taste ; },
abstract = {Drug use and abuse are complex issues in that the basis of each may involve different determinants and consequences, and the transition from one to the other may be equally multifaceted. A recent model of the addiction cycle (as proposed by Koob and his colleagues) illustrates how drug-taking patterns transition from impulsive (acute use) to compulsive (chronic use) as a function of various neuroadaptations leading to the downregulation of DA systems, upregulation of stress systems, and the dysregulation of the prefrontal/orbitofrontal cortex. Although the nature of reinforcement in the initiation and mediation of these effects may differ (positive vs. negative), the role of reinforcement in drug intake (acute and chronic) is well characterized. However, drugs of abuse have other stimulus properties that may be important in their use and abuse. One such property is their aversive effects that limit drug intake instead of initiating and maintaining it. Evidence of such effects comes from both clinical and preclinical populations. In support of this position, the present review describes the aversive effects of drugs (assessed primarily in conditioned taste aversion learning), the fact that they occur concurrently with reward as assessed in combined taste aversion/place preference designs, the role of aversive effects in drug-taking (in balance with their rewarding effects), the dissociation of these affective properties in that they can be affected in different ways by the same manipulations, and the impact of various parametric, experiential, and subject factors on the aversive effects of drugs and the consequent impact of these factors on their use and abuse potential.},
}

Humans
*Reward
*Substance-Related Disorders/psychology
Taste

@article {pmid35456614,
year = {2022},
author = {Lopalco, A and Manni, A and Keeley, A and Haider, S and Li, W and Lopedota, A and Altomare, CD and Denora, N and Tuleu, C},
title = {In Vivo Investigation of (2-Hydroxypropyl)-β-cyclodextrin-Based Formulation of Spironolactone in Aqueous Solution for Paediatric Use.},
journal = {Pharmaceutics},
volume = {14},
number = {4},
pages = {},
pmid = {35456614},
issn = {1999-4923},
abstract = {Spironolactone (SPL), a potent anti-aldosterone steroidal drug used to treat several diseases in paediatric patients (e.g., hypertension, primary aldosteronism, Bartter's syndrome, and congestive heart failure), is not available in child-friendly dosage forms, and spironolactone liquids have been reported to be unpalatable. Aiming to enhance SPL solubility in aqueous solution and overcome palatability, herein, the effects of (2-hydroxypropyl)-β-cyclodextrin (HP-β-CyD) were thoroughly investigated on solubilisation in water and on masking the unpleasant taste of SPL in vivo. Although the complexation of SPL with HP-β-CyD was demonstrated through phase solubility studies, Job's plot, NMR and computational docking studies, our in vivo tests did not show significant effects on taste aversion. Our findings, on the one hand, suggest that the formation of an inclusion complex of SPL with HP-β-CyD itself is not necessarily a good indicator for an acceptable degree of palatability, whereas, on the other hand, they constitute the basis for investigating other cyclodextrin-based formulations of the poorly water-soluble steroidal drug, including solid dosage forms, such as spray-dried powders and orodispersible tablets.},
}

@article {pmid35409269,
year = {2022},
author = {Berríos-Cárcamo, P and Quezada, M and Santapau, D and Morales, P and Olivares, B and Ponce, C and Ávila, A and De Gregorio, C and Ezquer, M and Quintanilla, ME and Herrera-Marschitz, M and Israel, Y and Ezquer, F},
title = {A Novel Morphine Drinking Model of Opioid Dependence in Rats.},
journal = {International journal of molecular sciences},
volume = {23},
number = {7},
pages = {},
pmid = {35409269},
issn = {1422-0067},
mesh = {Animals ; Disease Models, Animal ; Morphine/pharmacology ; *Morphine Dependence ; *Opioid-Related Disorders/drug therapy ; Quinine/pharmacology/therapeutic use ; Rats ; Taste ; Water ; },
abstract = {An animal model of voluntary oral morphine consumption would allow for a pre-clinical evaluation of new treatments aimed at reducing opioid intake in humans. However, the main limitation of oral morphine consumption in rodents is its bitter taste, which is strongly aversive. Taste aversion is often overcome by the use of adulterants, such as sweeteners, to conceal morphine taste or bitterants in the alternative bottle to equalize aversion. However, the adulterants' presence is the cause for consumption choice and, upon removal, the preference for morphine is not preserved. Thus, current animal models are not suitable to study treatments aimed at reducing consumption elicited by morphine itself. Since taste preference is a learned behavior, just-weaned rats were trained to accept a bitter taste, adding the bitterant quinine to their drinking water for one week. The latter was followed by allowing the choice of quinine or morphine (0.15 mg/mL) solutions for two weeks. Then, quinine was removed, and the preference for morphine against water was evaluated. Using this paradigm, we show that rats highly preferred the consumption of morphine over water, reaching a voluntary morphine intake of 15 mg/kg/day. Morphine consumption led to significant analgesia and hyperlocomotion, and to a marked deprivation syndrome following the administration of the opioid antagonist naloxone. Voluntary morphine consumption was also shown to generate brain oxidative stress and neuroinflammation, signs associated with opioid dependence development. We present a robust two-bottle choice animal model of oral morphine self-administration for the evaluation of therapeutic interventions for the treatment of morphine dependence.},
}

Animals
Disease Models, Animal
Morphine/pharmacology
*Morphine Dependence
*Opioid-Related Disorders/drug therapy
Quinine/pharmacology/therapeutic use
Rats
Taste
Water

@article {pmid35360496,
year = {2022},
author = {Gil-Lievana, E and Ramírez-Mejía, G and Urrego-Morales, O and Luis-Islas, J and Gutierrez, R and Bermúdez-Rattoni, F},
title = {Photostimulation of Ventral Tegmental Area-Insular Cortex Dopaminergic Inputs Enhances the Salience to Consolidate Aversive Taste Recognition Memory via D1-Like Receptors.},
journal = {Frontiers in cellular neuroscience},
volume = {16},
number = {},
pages = {823220},
pmid = {35360496},
issn = {1662-5102},
abstract = {Taste memory involves storing information through plasticity changes in the neural network of taste, including the insular cortex (IC) and ventral tegmental area (VTA), a critical provider of dopamine. Although a VTA-IC dopaminergic pathway has been demonstrated, its role to consolidate taste recognition memory remains poorly understood. We found that photostimulation of dopaminergic neurons in the VTA or VTA-IC dopaminergic terminals of TH-Cre mice improves the salience to consolidate a subthreshold novel taste stimulus regardless of its hedonic value, without altering their taste palatability. Importantly, the inhibition of the D1-like receptor into the IC impairs the salience to facilitate consolidation of an aversive taste recognition memory. Finally, our results showed that VTA photostimulation improves the salience to consolidate a conditioned taste aversion memory through the D1-like receptor into the IC. It is concluded that the dopamine activity from the VTA into IC is required to increase the salience enabling the consolidation of a taste recognition memory. Notably, the D1-like receptor activity into the IC is required to consolidate both innate and learned aversive taste memories but not appetitive taste memory.},
}

@article {pmid35318075,
year = {2022},
author = {Salguero, A and Marengo, L and Portillo-Salido, E and Ruiz-Leyva, L and Cendán, CM and Morón, I and Marcos Pautassi, R},
title = {Administration of the sigma-1 receptor agonist PRE-084 at emerging adulthood, but not at early adolescence, attenuated ethanol-induced conditioned taste aversion in female rats.},
journal = {Neuroscience letters},
volume = {778},
number = {},
pages = {136585},
doi = {10.1016/j.neulet.2022.136585},
pmid = {35318075},
issn = {1872-7972},
mesh = {Alcohol Drinking ; Animals ; Avoidance Learning ; *Ethanol/pharmacology ; Female ; Morpholines ; Rats ; Rats, Wistar ; Receptors, sigma ; *Taste ; },
abstract = {Ethanol-induced conditioned taste aversion (CTA) is greater in late adolescence or young adulthood than in early adolescence. The role of the sigma receptor system in this age-related difference has not been extensively explored, particularly in female rats. This study assessed the effects of the activation of sigma-1 receptors (S1-R), via the selective S1-R agonist PRE-084, on ethanol-induced CTA at early or at terminal adolescence/emerging adulthood (28 or 56 days-old at the beginning of the procedures, respectively) in female Wistar rats. The modulation of binge-like ethanol intake by PRE-084 was assessed at terminal adolescence. S1-R activation at the acquisition of ethanol-induced CTA attenuated such learning at terminal but not at early adolescence. PRE-084 did not significantly affect ethanol binge drinking in the terminal adolescents. These results highlight the role of S1-R in ethanol-induced CTA and suggest that differential functionality of this transmitter system may underlie age-specific sensitivities to the aversive effects of ethanol.},
}

Alcohol Drinking
Animals
Avoidance Learning
*Ethanol/pharmacology
Female
Morpholines
Rats
Rats, Wistar
Receptors, sigma
*Taste

@article {pmid35295904,
year = {2022},
author = {Ramos, R and Wu, CH and Turrigiano, GG},
title = {Strong Aversive Conditioning Triggers a Long-Lasting Generalized Aversion.},
journal = {Frontiers in cellular neuroscience},
volume = {16},
number = {},
pages = {854315},
pmid = {35295904},
issn = {1662-5102},
abstract = {Generalization is an adaptive mnemonic process in which an animal can leverage past learning experiences to navigate future scenarios, but overgeneralization is a hallmark feature of anxiety disorders. Therefore, understanding the synaptic plasticity mechanisms that govern memory generalization and its persistence is an important goal. Here, we demonstrate that strong CTA conditioning results in a long-lasting generalized aversion that persists for at least 2 weeks. Using brain slice electrophysiology and activity-dependent labeling of the conditioning-active neuronal ensemble within the gustatory cortex, we find that strong CTA conditioning induces a long-lasting increase in synaptic strengths that occurs uniformly across superficial and deep layers of GC. Repeated exposure to salt, the generalized tastant, causes a rapid attenuation of the generalized aversion that correlates with a reversal of the CTA-induced increases in synaptic strength. Unlike the uniform strengthening that happens across layers, reversal of the generalized aversion results in a more pronounced depression of synaptic strengths in superficial layers. Finally, the generalized aversion and its reversal do not impact the acquisition and maintenance of the aversion to the conditioned tastant (saccharin). The strong correlation between the generalized aversion and synaptic strengthening, and the reversal of both in superficial layers by repeated salt exposure, strongly suggests that the synaptic changes in superficial layers contribute to the formation and reversal of the generalized aversion. In contrast, the persistence of synaptic strengthening in deep layers correlates with the persistence of CTA. Taken together, our data suggest that layer-specific synaptic plasticity mechanisms separately govern the persistence and generalization of CTA memory.},
}

@article {pmid35256559,
year = {2022},
author = {Pham, H and Seeley, SL and D'Souza, MS},
title = {Pharmacological activation of kappa opioid receptors in the nucleus accumbens core and ventral tegmental area increases the aversive effects of nicotine.},
journal = {Behavioural pharmacology},
volume = {33},
number = {4},
pages = {266-281},
doi = {10.1097/FBP.0000000000000675},
pmid = {35256559},
issn = {1473-5849},
mesh = {3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer/pharmacology ; Animals ; Nicotine/pharmacology ; Nucleus Accumbens/metabolism ; Rats ; Rats, Wistar ; Receptors, Opioid, kappa/metabolism ; *Tobacco Use Disorder ; *Ventral Tegmental Area ; },
abstract = {Aversive effects of nicotine play an important role in the development of nicotine dependence. However, neural substrates and/or brain regions that play a role in the aversive effects of nicotine have not been fully identified. Previous work done in our laboratory showed that systemic administration of kappa opioid receptors (KORs) agonist ±U50488 increased the aversive effects of nicotine. In this study, we assessed the effects of KOR activation in specific brain regions, namely, the nucleus accumbens (NAcc) core and ventral tegmental area (VTA) on the aversive effects of nicotine using the conditioned taste aversion model. Separate groups of Wistar rats were implanted with cannulae above either the NAcc core or the VTA. KOR agonist (±U50488) was bilaterally infused in the NAcc core (0, 0.3, and 3 ug/0.5 ul/side) or VTA (0, 0.3, 1.5, and 3 ug/0.5 ul/side) prior to receiving nicotine (0.4 mg/kg, base; s.c.) during conditioning. Bilateral infusion of the KOR agonist (3 ug/0.5 ul/side) in the NAcc core or the VTA increased the aversive effects of nicotine compared with respective saline controls. Together, these results suggest that pharmacological activation of the KORs in the NAcc core and VTA dose dependently modulate the aversive effects of nicotine. Because aversive effects of nicotine determine susceptibility to development of nicotine dependence, we can conclude that KOR activity in the NAcc and VTA after administration of nicotine may determine susceptibility to the development of nicotine dependence.},
}

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer/pharmacology
Animals
Nicotine/pharmacology
Nucleus Accumbens/metabolism
Rats
Rats, Wistar
Receptors, Opioid, kappa/metabolism
*Tobacco Use Disorder
*Ventral Tegmental Area

@article {pmid35255434,
year = {2022},
author = {Han, F and Xu, F and Zhu, Q and Sun, P and Zhou, Y and Yu, M},
title = {Virus-mediated GHS-R1a expression in the basolateral amygdala blocks extinction of conditioned taste aversion memory in rats.},
journal = {Biochemical and biophysical research communications},
volume = {602},
number = {},
pages = {57-62},
doi = {10.1016/j.bbrc.2022.02.105},
pmid = {35255434},
issn = {1090-2104},
mesh = {Animals ; *Avoidance Learning ; *Basolateral Nuclear Complex/metabolism ; Feeding Behavior ; Ghrelin/pharmacology ; Rats ; *Receptors, Ghrelin/metabolism ; Taste/physiology ; },
abstract = {Ghrelin is an orexigenic gastric hormone that promotes feeding behaviors and regulating energy homeostasis in both humans and rodents. Our previous studies have shown that ghrelin, when locally infused into the basolateral amygdala (BLA), blocks both acquisition and extinction of conditioned taste aversion (CTA) memory in rats. In this study, we further investigated the effect of virus-mediated overexpression of ghrelin receptor growth hormone secretagogue receptor 1a (GHS-R1a) in BLA pyramidal neurons on CTA memory processes. We found that upregulation of GHS-R1a expression in BLA pyramidal neurons repressed CTA extinction while it had no effect on CTA acquisition. In addition, we reported that local infusion of the endogenous GHS-R1a antagonist, liver-expressed antimicrobial peptide 2 (LEAP2), in the BLA abolished the inhibitory effect of increased GHS-R1a on CTA memory extinction. Those findings provide new supportive evidence that ghrelin/GHS-R1a signaling in the BLA circuit shapes emotional memory processes.},
}

Animals
*Avoidance Learning
*Basolateral Nuclear Complex/metabolism
Feeding Behavior
Ghrelin/pharmacology
Rats
*Receptors, Ghrelin/metabolism
Taste/physiology

@article {pmid35169271,
year = {2022},
author = {Yu, M and Zhu, QQ and Niu, ML and Li, N and Ren, BQ and Yu, TB and Zhou, ZS and Guo, JD and Zhou, Y},
title = {Ghrelin infusion into the basolateral amygdala suppresses CTA memory formation in rats via the PI3K/Akt/mTOR and PLC/PKC signaling pathways.},
journal = {Acta pharmacologica Sinica},
volume = {43},
number = {9},
pages = {2242-2252},
pmid = {35169271},
issn = {1745-7254},
mesh = {Amygdala/physiology ; Animals ; Avoidance Learning ; *Basolateral Nuclear Complex/physiology ; Feeding Behavior ; Ghrelin/pharmacology/physiology ; Glycogen Synthase Kinase 3/pharmacology ; Humans ; Mice ; Phosphatidylinositol 3-Kinases ; Proto-Oncogene Proteins c-akt ; Rats ; Signal Transduction ; TOR Serine-Threonine Kinases ; Type C Phospholipases/metabolism ; },
abstract = {Ghrelin is a circulating orexigenic hormone that promotes feeding behavior and regulates metabolism in humans and rodents. We previously reported that local infusion of ghrelin into the basolateral amygdala (BLA) blocked memory acquisition for conditioned taste aversion (CTA) by activating growth hormone secretagogue receptor 1a. In this study, we further explored the underlying mechanism and signaling pathways mediating ghrelin modulation of CTA memory in rats. Pharmacological agents targeting distinct signaling pathways were infused into the BLA during conditioning. We showed that preadministration of the PI3K inhibitor LY294002 abolished the repressive effect of ghrelin on CTA memory. Moreover, LY294002 pretreatment prevented ghrelin from inhibiting Arc and zif268 mRNA expression in the BLA triggered by CTA memory retrieval. Preadministration of rapamycin eliminated the repressive effect of ghrelin, while Gsk3 inhibitors failed to mimic ghrelin's effect. In addition, PLC and PKC inhibitors microinfused in the BLA blocked ghrelin's repression of CTA acquisition. These results demonstrate that ghrelin signaling in the BLA shapes CTA memory via the PI3K/Akt/mTOR and PLC/PKC pathways. We conducted in vivo multichannel recordings from mouse BLA neurons and found that microinjection of ghrelin (20 µM) suppressed intrinsic excitability. By means of whole-cell recordings from rat brain slices, we showed that bath application of ghrelin (200 nM) had no effect on basal synaptic transmission or synaptic plasticity of BLA pyramidal neurons. Together, this study reveals the mechanism underlying ghrelin-induced interference with CTA memory acquisition in rats, i.e., suppression of intrinsic excitability of BLA principal neurons via the PI3K/Akt/mTOR and PLC/PKC pathways.},
}

Amygdala/physiology
Animals
Avoidance Learning
*Basolateral Nuclear Complex/physiology
Feeding Behavior
Ghrelin/pharmacology/physiology
Glycogen Synthase Kinase 3/pharmacology
Humans
Mice
Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins c-akt
Rats
Signal Transduction
TOR Serine-Threonine Kinases
Type C Phospholipases/metabolism

@article {pmid35156560,
year = {2022},
author = {Totani, Y and Nakai, J and Hatakeyama, D and Dyakonova, VE and Lukowiak, K and Ito, E},
title = {CNS serotonin content mediating food deprivation-enhanced learning is regulated by hemolymph tryptophan concentration and autophagic flux in the pond snail.},
journal = {Nutritional neuroscience},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/1028415X.2022.2033045},
pmid = {35156560},
issn = {1476-8305},
abstract = {Nutritional status affects cognitive function in many types of organisms. In the pond snail Lymnaea stagnalis, 1 day of food deprivation enhances taste aversion learning ability by decreasing the serotonin (5-hydroxytryptamin; 5-HT) content in the central nervous system (CNS). On the other hand, after 5 days of food deprivation, learning ability and the CNS 5-HT concentration return to basal levels. How food deprivation leads to alterations of 5-HT levels in the CNS, however, is unknown. Here, we measured the concentration of the 5-HT precursor tryptophan in the hemolymph and CNS, and demonstrated that the CNS tryptophan concentration was higher in 5-day food-deprived snails than in non-food-deprived or 1-day food-deprived snails, whereas the hemolymph tryptophan concentration was not affected by the duration of food deprivation. This finding suggests the existence of a mediator of the CNS tryptophan concentration independent of food deprivation. To identify the mediator, we investigated autophagic flux in the CNS under different food deprivation conditions. We found that autophagic flux was significantly upregulated by inhibition of the tropomyosin receptor kinase (Trk)-Akt-mechanistic target of rapamycin complex 1 (MTORC1) pathway in the CNS of 5-day food-deprived snails. Moreover, when autophagy was inhibited, the CNS 5-HT content was significantly downregulated in 5-day food-deprived snails. Our results suggest that the hemolymph tryptophan concentration and autophagic flux in the CNS cooperatively regulate learning ability affected by different durations of food deprivation. This mechanism may underlie the selection of behaviors appropriate for animal survival depending on the degree of nutrition.},
}

@article {pmid35091058,
year = {2022},
author = {Boccia, L and Borner, T and Ghidewon, MY and Kulka, P and Piffaretti, C and Doebley, SA and De Jonghe, BC and Grill, HJ and Lutz, TA and Le Foll, C},
title = {Hypophagia induced by salmon calcitonin, but not by amylin, is partially driven by malaise and is mediated by CGRP neurons.},
journal = {Molecular metabolism},
volume = {58},
number = {},
pages = {101444},
pmid = {35091058},
issn = {2212-8778},
support = {R01 DK021397/DK/NIDDK NIH HHS/United States ; R01 DK112812/DK/NIDDK NIH HHS/United States ; R56 DK021397/DK/NIDDK NIH HHS/United States ; },
mesh = {Animals ; Anorexia/chemically induced ; *Appetite Depressants/adverse effects/metabolism ; Calcitonin ; Calcitonin Gene-Related Peptide/metabolism ; *Islet Amyloid Polypeptide/metabolism ; Mice ; Nausea/metabolism ; Neurons/metabolism ; Rats ; Vomiting ; },
abstract = {OBJECTIVE: The behavioral mechanisms and the neuronal pathways mediated by amylin and its long-acting analog sCT (salmon calcitonin) are not fully understood and it is unclear to what extent sCT and amylin engage overlapping or distinct neuronal subpopulations to reduce food intake. We here hypothesize that amylin and sCT recruit different neuronal population to mediate their anorectic effects.

METHODS: Viral approaches were used to inhibit calcitonin gene-related peptide (CGRP) lateral parabrachial nucleus (LPBN) neurons and assess their role in amylin's and sCT's ability to decrease food intake in mice. In addition, to test the involvement of LPBN CGRP neuropeptidergic signaling in the mediation of amylin and sCT's effects, a LPBN site-specific knockdown was performed in rats. To deeper investigate whether the greater anorectic effect of sCT compared to amylin is due do the recruitment of additional neuronal pathways related to malaise multiple and distinct animal models tested whether amylin and sCT induce conditioned avoidance, nausea, emesis, and conditioned affective taste aversion.

RESULTS: Our results indicate that permanent or transient inhibition of CGRP neurons in LPBN blunts sCT-, but not amylin-induced anorexia and neuronal activation. Importantly, sCT but not amylin induces behaviors indicative of malaise including conditioned affective aversion, nausea, emesis, and conditioned avoidance; the latter mediated by CGRP[LPBN] neurons.

CONCLUSIONS: Together, the present study highlights that although amylin and sCT comparably decrease food intake, sCT is distinctive from amylin in the activation of anorectic neuronal pathways associated with malaise.},
}

Animals
Anorexia/chemically induced
*Appetite Depressants/adverse effects/metabolism
Calcitonin
Calcitonin Gene-Related Peptide/metabolism
*Islet Amyloid Polypeptide/metabolism
Mice
Nausea/metabolism
Neurons/metabolism
Rats
Vomiting

@article {pmid35049318,
year = {2022},
author = {Flores, VL and Tanner, B and Katz, DB and Lin, JY},
title = {Cortical taste processing evolves through benign taste exposures.},
journal = {Behavioral neuroscience},
volume = {136},
number = {2},
pages = {182-194},
pmid = {35049318},
issn = {1939-0084},
support = {R21 DC016706/DC/NIDCD NIH HHS/United States ; F31 DC015931/DC/NIDCD NIH HHS/United States ; R01 DC006666/DC/NIDCD NIH HHS/United States ; R01 DC007703/DC/NIDCD NIH HHS/United States ; },
mesh = {Animals ; Learning/physiology ; Neurons/physiology ; Rats ; Rats, Long-Evans ; *Taste/physiology ; *Taste Perception/physiology ; },
abstract = {Experience impacts learning and perception. Familiarity with stimuli that later become the conditioned stimulus (CS) in a learning paradigm, for instance, reduces the strength of that learning-a fact well documented in studies of conditioned taste aversion (CTA; De la Casa & Lubow, 1995; Lubow, 1973; Lubow & Moore, 1959). Recently, we have demonstrated that even experience with "incidental" (i.e., non-CS) stimuli influences CTA learning: Long Evans rats pre-exposed to salty and/or sour tastes later learn unusually strong aversions to novel sucrose (Flores et al., 2016), and exhibit enhanced sucrose-responsiveness after learning in gustatory cortex (GC; Flores et al., 2018). These findings suggest that incidental taste exposure (TE) may change spiking responses that have been shown to underlie the processing of tastes in GC. Here, we test this hypothesis, evaluating whether GC neuron spiking responses change across 3 days of taste exposure. Our results demonstrate that the discriminability of GC ensemble taste responses increases with this familiarization. Analysis of single-neuron responses recorded across multiple sessions reveals that taste exposure not only enriches identity and palatability information in taste-evoked activity but also enhances the discriminability of even novel tastes. These findings demonstrate that "mere" familiarization with incidental episodes of tasting changes the neural spiking responses of taste processing and provides specific insight into how such TE may impact later learning. (PsycInfo Database Record (c) 2022 APA, all rights reserved).},
}

Animals
Learning/physiology
Neurons/physiology
Rats
Rats, Long-Evans
*Taste/physiology
*Taste Perception/physiology

@article {pmid35011797,
year = {2021},
author = {Head, MA and McColl, LK and Klockars, A and Levine, AS and Olszewski, PK},
title = {Acute Hypophagia and Changes in c-Fos Immunoreactivity in Adolescent Rats Treated with Low Doses of Oxytocin and Naltrexone.},
journal = {Journal of clinical medicine},
volume = {11},
number = {1},
pages = {},
pmid = {35011797},
issn = {2077-0383},
abstract = {A recent case report has shown that an adjunctive oxytocin + naltrexone (OT + NTX) treatment promoted more robust hypophagia and body weight reduction than OT alone in an adolescent male with hypothalamic obesity after craniopharyngioma resection. Thus far, there has been no basic research in adolescent laboratory animals that would examine whether the benefit of OT + NTX on appetite extends onto adolescent individuals without surgically induced overeating. Thus, here we examined whether low doses of combined OT + NTX acutely affect post-deprivation intake of energy-dense, standard chow; intake of energy-dense and palatable high-fat high-sugar (HFHS) diet; or calorie-dilute, palaTable 10% sucrose solution without deprivation in adolescent male rats. We assessed whether OT + NTX decreases water intake after water deprivation or produces a conditioned taste aversion (CTA). Finally, by using c-Fos immunoreactivity, we determined changes in activity of feeding-related brain areas after OT + NTX. We found that individual subthreshold doses of OT and NTX decreased feeding induced by energy and by palatability. Significant c-Fos changes were noted in the arcuate and dorsomedial hypothalamic nuclei. The hypophagic doses of OT + NTX did not suppress water intake in thirsty rats and did not cause a CTA, which suggests that feeding reduction is not a secondary effect of gastrointestinal discomfort or changes in thirst processing. We conclude that OT + NTX is an effective drug combination to reduce appetite in adolescent male rats.},
}

@article {pmid34916257,
year = {2022},
author = {Arieli, E and Younis, N and Moran, A},
title = {Distinct Progressions of Neuronal Activity Changes Underlie the Formation and Consolidation of a Gustatory Associative Memory.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {42},
number = {5},
pages = {909-921},
pmid = {34916257},
issn = {1529-2401},
mesh = {Animals ; Association Learning ; Female ; Male ; *Memory Consolidation ; Neurons/*physiology ; Rats ; Rats, Long-Evans ; Sensorimotor Cortex/cytology/*physiology ; *Taste Perception ; },
abstract = {Acquiring new memories is a multistage process. Numerous studies have convincingly demonstrated that initially acquired memories are labile and are stabilized only by later consolidation processes. These multiple phases of memory formation are known to involve modification of both cellular excitability and synaptic connectivity, which in turn change neuronal activity at both the single neuron and ensemble levels. However, the specific mapping between the known phases of memory and the changes in neuronal activity at different organizational levels-the single-neuron, population representations, and ensemble-state dynamics-remains unknown. Here we address this issue in the context of conditioned taste aversion learning by continuously tracking gustatory cortex neuronal taste responses in alert male and female rats during the 24 h following a taste-malaise pairing. We found that the progression of activity changes depends on the neuronal organizational level: whereas the population response changed continuously, the population mean response amplitude and the number of taste-responsive neurons only increased during the acquisition and consolidation phases. In addition, the known quickening of the ensemble-state dynamics associated with the faster rejection of harmful foods appeared only after consolidation. Overall, these results demonstrate how complex dynamics in the different representational levels of cortical activity underlie the formation and stabilization of memory within the cortex.SIGNIFICANCE STATEMENT Memory formation is a multiphased process; early acquired memories are labile and consolidate to their stable forms over hours and days. The progression of memory is assumed to be supported by changes in neuronal activity, but the mapping between memory phases and neuronal activity changes remains elusive. Here we tracked cortical neuronal activity over 24 h as rats acquired and consolidated a taste-malaise association memory, and found specific differences between the progression at the single-neuron and populations levels. These results demonstrate how balanced changes on the single-neuron level lead to changes in the network-level representation and dynamics required for the stabilization of memories.},
}

Animals
Association Learning
Female
Male
*Memory Consolidation
Neurons/*physiology
Rats
Rats, Long-Evans
Sensorimotor Cortex/cytology/*physiology
*Taste Perception

@article {pmid34907488,
year = {2021},
author = {Boniatti, J and Tappin, MRR and da S Teixeira, RG and de A V Gandos, T and Rios, LPS and Ferreira, IAM and Oliveira, KC and Calil-Elias, S and Santana, AKM and da Fonseca, LB and Shimizu, FM and Carr, O and Oliveira, ON and Dantas, FML and Amendoeira, FC and Viçosa, AL},
title = {In Vivo and In Vitro Taste Assessment of Artesunate-Mefloquine, Praziquantel, and Benznidazole Drugs for Neglected Tropical Diseases and Pediatric Patients.},
journal = {AAPS PharmSciTech},
volume = {23},
number = {1},
pages = {22},
pmid = {34907488},
issn = {1530-9932},
mesh = {Animals ; Artesunate ; Child ; Humans ; *Mefloquine ; Nitroimidazoles ; *Praziquantel ; Rats ; Tablets ; Taste ; },
abstract = {The assessment of drug taste is crucial for pediatric treatments so that formulations can be developed to enhance their effectiveness. In this study, in vivo and in vitro methods were applied to evaluate the taste of tablets of three drugs administered to children without taste-masking excipients to treat tropical diseases, namely artesunate-mefloquine (ASMQ), praziquantel (PZQ), and benznidazole (BNZ). In the first method, a model of rat palatability was adapted with recirculation to ensure sample dispersion, and the data were analyzed using ANOVA (single factor, 95%). The taste assessment results (in vivo) indicated an aversion to the three medicines, denoted by the animals retracting themselves to the bottom of the box after the first contact with the drugs. For the placebo samples, the animals behaved normally, indicating that taste perception was acceptable. The second method was based on the in vitro analysis of capacitance data from a homemade impedimetric electronic tongue. Consistent with the in vivo taste assessment results, the data points obtained with PZQ, ASMQ, and BNZ were far away from those of their placebos in a map built with the multidimensional projection technique referred to as Interactive Document Mapping (IDMAP). A combined analysis of the results with the two methods allowed us to confirm the bitterness of the three drugs, also pointing to electronic tongues as a promising tool to replace in vivo palatability tests.},
}

Animals
Artesunate
Child
Humans
*Mefloquine
Nitroimidazoles
*Praziquantel
Rats
Tablets
Taste