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1.
Psychopharmacology (Berl) ; 241(5): 947-962, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38172238

RESUMO

RATIONALE: The rat cognitive effort task (rCET), a rodent model of cognitive rather than physical effort, requires animals to choose between an easy or hard visuospatial discrimination, with a correct hard choice more highly rewarded. Like in humans, there is stable individual variation in choice behavior. In previous reports, animals were divided into two groups-workers and slackers-based on their mean preference for the harder option. Although these groups differed in their response to pharmacological challenges, the rationale for using this criterion for grouping was not robust. METHODS: We collated experimental data from multiple cohorts of male and female rats performing the rCET and used a model-based framework combining drift diffusion modeling with cluster analysis to identify the decision-making processes underlying variation in choice behavior. RESULTS: We verified that workers and slackers are statistically different groups but also found distinct intra-group profiles. These subgroups exhibited dissociable performance during the attentional phase, linked to distinct decision-making profiles during choice. Reanalysis of previous pharmacology data using this model-based framework showed that serotonergic drug effects were explained by changes in decision boundaries and non-decision times, while scopolamine's effects were driven by changes in decision starting points and rates of evidence accumulation. CONCLUSIONS: Modeling revealed the decision-making processes that are associated with cognitive effort costs, and how these differ across individuals. Reanalysis of drug data provided insight into the mechanisms through which different neurotransmitter systems impact cognitively effortful attention and decision-making processes, with relevance to multiple psychiatric disorders.


Assuntos
Cognição , Tomada de Decisões , Humanos , Ratos , Masculino , Feminino , Animais , Tomada de Decisões/fisiologia , Ratos Long-Evans , Atenção , Recompensa , Simulação por Computador
2.
Hippocampus ; 33(6): 730-744, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36971428

RESUMO

Pyramidal cells in hippocampal area CA2 have synaptic properties that are distinct from the other CA subregions. Notably, this includes a lack of typical long-term potentiation of stratum radiatum synapses. CA2 neurons express high levels of several known and potential regulators of metabotropic glutamate receptor (mGluR)-dependent signaling including Striatal-Enriched Tyrosine Phosphatase (STEP) and several Regulator of G-protein Signaling (RGS) proteins, yet the functions of these proteins in regulating mGluR-dependent synaptic plasticity in CA2 are completely unknown. Thus, the aim of this study was to examine mGluR-dependent synaptic depression and to determine whether STEP and the RGS proteins RGS4 and RGS14 are involved. Using whole cell voltage-clamp recordings from mouse pyramidal cells, we found that mGluR agonist-induced long-term depression (mGluR-LTD) is more pronounced in CA2 compared with that observed in CA1. This mGluR-LTD in CA2 was found to be protein synthesis and STEP dependent, suggesting that CA2 mGluR-LTD shares mechanistic processes with those seen in CA1, but in addition, RGS14, but not RGS4, was essential for mGluR-LTD in CA2. In addition, we found that exogenous application of STEP could rescue mGluR-LTD in RGS14 KO slices. Supporting a role for CA2 synaptic plasticity in social cognition, we found that RGS14 KO mice had impaired social recognition memory as assessed in a social discrimination task. These results highlight possible roles for mGluRs, RGS14, and STEP in CA2-dependent behaviors, perhaps by biasing the dominant form of synaptic plasticity away from LTP and toward LTD in CA2.


Assuntos
Proteínas RGS , Receptores de Glutamato Metabotrópico , Animais , Camundongos , Hipocampo/fisiologia , Potenciação de Longa Duração/fisiologia , Depressão Sináptica de Longo Prazo/fisiologia , Plasticidade Neuronal , Células Piramidais/fisiologia , Receptores de Glutamato Metabotrópico/metabolismo , Proteínas RGS/genética , Proteínas RGS/metabolismo
3.
Psychoneuroendocrinology ; 147: 105953, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36334546

RESUMO

Chronic stress is a known risk factor for the development of major depression (MDD) and is commonly used to induce a depression-like phenotype in rodents. Similar phenotypic effects are also observed in rodents when treated chronically with the stress hormone corticosterone. In this study, we investigated the neuropsychological consequences of chronic corticosterone treatment in male rats using two translational rodent assays of affective bias, the judgement bias task (JBT) and affective bias test (ABT). We also used the reward learning assay (RLA) and sucrose preference test (SPT) to quantify reward-related behaviours. Negative biases in decision-making were observed in the chronic corticosterone-treated group but only when the treatment was given shortly before each behavioural session. The same dose of corticosterone, when given daily after completion of the behavioural session had no effects. Chronic corticosterone treatment did not potentiate negative affective biases in the ABT induced by either an acute pharmacological or stress manipulation but both reward learning and reward sensitivity were blunted. Analysis of the brain tissue from animals receiving chronic corticosterone found reduced hippocampal neurogenesis consistent with previous studies suggesting corticosterone-induced neurotrophic deficits. Taken together, these data suggest chronic corticosterone treatment induces neuropsychological effects related to changes in reward learning, memory and negative biases in decision making, but these decision-making biases depend on whether rewarding outcomes were experienced during the acute effects of the drug. These findings suggest an important interaction between psychological and biological factors resulting in negative biases in decision-making in this model.


Assuntos
Corticosterona , Transtorno Depressivo Maior , Ratos , Masculino , Animais , Corticosterona/farmacologia , Depressão/psicologia , Recompensa , Julgamento
4.
Eur J Neurosci ; 55(9-10): 2955-2970, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-33502040

RESUMO

Studies in human and non-human species suggest that decision-making behaviour can be biased by an affective state, also termed an affective bias. To study these behaviours in non-human species, judgement bias tasks (JBT) have been developed. Animals are trained to associate specific cues (tones) with a positive or negative/less positive outcome. Animals are then presented with intermediate ambiguous cues and affective biases quantified by observing whether animals make more optimistic or more pessimistic choices. Here we use a high versus low reward JBT and test whether pharmacologically distinct compounds, which induce negative biases in learning and memory, have similar effects on decision-making: tetrabenazine (0.0-1.0 mg/kg), retinoic acid (0.0-10.0 mg/kg), and rimonabant (0.0-10.0 mg/kg). We also tested immunomodulatory compounds: interferon-α (0-100 units/kg), lipopolysaccharide (0.0-10.0 µg/kg), and corticosterone (0.0-10.0 mg/kg). We observed no specific effects in the JBT with any acute treatment except corticosterone which induced a negative bias. We have previously observed a similar lack of effect with acute but not chronic psychosocial stress and so next tested decision-making behaviour following chronic interferon-alpha. Animals developed a negative bias which was sustained even after treatment was ended. These data suggest that decision-making behaviour in the task is sensitive to chronic but not acute effects of most pro-depressant drugs or immunomodulators, but the exogenous administration of acute corticosterone induces pessimistic behaviour. This work supports our hypothesis that biases in decision-making develop over a different temporal scale to those seen with learning and memory which may be relevant in the development and perpetuation of mood disorders.


Assuntos
Corticosterona , Agentes de Imunomodulação , Animais , Viés , Corticosterona/farmacologia , Interferon-alfa , Julgamento , Ratos
5.
Curr Opin Behav Sci ; 22: 136-142, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30123817

RESUMO

Loss of interest in rewarding activities is a hallmark of many psychiatric disorders and may be relevant for neurodegenerative disorders and patients suffering from brain injury. There is increasing evidence that deficits in reward-related behaviour are more complex than previously described. The traditional view of anhedonia as 'the inability to experience pleasure' may be too limited to fully encompass the types of reward deficit observed in these patients. Developments in methods to measure different aspects of reward processing in humans and animals are starting to provide insights into the complexity of this behaviour. In this article we consider the rodent models which have traditionally been used to study reward deficits in psychiatric disorders and consider their limitations relative to clinical findings. We then discuss work where methods derived from human neuropsychological tests are providing insights into the complexity of reward-related behaviour. Specifically, we consider tasks which investigate different aspects of reward-related behaviour focusing on learning and memory as well as decision-making and consider what these may mean in terms of how we model reward deficits in rodents.

6.
Eur Neuropsychopharmacol ; 27(12): 1268-1280, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29100819

RESUMO

Major depressive disorder (MDD) is one of the most prevalent psychiatric disorders. Until the recent discovery of the rapid onset antidepressant action of ketamine, pharmacological treatments for MDD were limited to conventional antidepressant drugs with delayed clinical efficacy. Using a judgement bias task, this study has investigated whether the temporal differences observed in patients would be reflected in affective biases and decision making behaviour in rodents. The diffusion model was also used to investigate the underlying decision making processes. Positive biases were induced in this task over timeframes that mirror the rapid versus delayed antidepressant efficacy of the drugs in clinical populations. Diffusion modelling revealed that the antidepressants tested also have different effects on decision making processes, suggesting they may act through different neurobiological substrates. This combination of behaviour and computational modelling may provide a useful approach to further investigate the mechanisms underlying rapid antidepressant effect and assess potential new treatments.


Assuntos
Antidepressivos/uso terapêutico , Aprendizagem por Associação/efeitos dos fármacos , Tomada de Decisões/efeitos dos fármacos , Transtorno Depressivo Maior/tratamento farmacológico , Tempo de Reação/efeitos dos fármacos , Estimulação Acústica , Anfetamina/farmacologia , Analgésicos/farmacologia , Animais , Antidepressivos/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Cocaína/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/farmacologia , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Ketamina/farmacologia , Masculino , Modelos Biológicos , Fenciclidina/farmacologia , Ratos , Fatores de Tempo
7.
PLoS One ; 11(3): e0152592, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27023442

RESUMO

Human decision making is modified by emotional state. Rodents exhibit similar biases during interpretation of ambiguous cues that can be altered by affective state manipulations. In this study, the impact of negative affective state on judgement bias in rats was measured using an ambiguous-cue interpretation task. Acute treatment with an anxiogenic drug (FG7142), and chronic restraint stress and social isolation both induced a bias towards more negative interpretation of the ambiguous cue. The diffusion model was fit to behavioural data to allow further analysis of the underlying decision making processes. To uncover the way in which parameters vary together in relation to affective state manipulations, independent component analysis was conducted on rate of information accumulation and distances to decision threshold parameters for control data. Results from this analysis were applied to parameters from negative affective state manipulations. These projected components were compared to control components to reveal the changes in decision making processes that are due to affective state manipulations. Negative affective bias in rodents induced by either FG7142 or chronic stress is due to a combination of more negative interpretation of the ambiguous cue, reduced anticipation of the high reward and increased anticipation of the low reward.


Assuntos
Tomada de Decisões , Julgamento , Modelos Teóricos , Animais , Comportamento Animal , Viés , Difusão , Masculino , Análise de Componente Principal , Ratos , Reprodutibilidade dos Testes , Análise e Desempenho de Tarefas
8.
Br J Pharmacol ; 171(20): 4524-38, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24467454

RESUMO

Major depressive disorder (MDD) affects more than 10% of the population, although our understanding of the underlying aetiology of the disease and how antidepressant drugs act to remediate symptoms is limited. Major obstacles include the lack of availability of good animal models that replicate aspects of the phenotype and tests to assay depression-like behaviour in non-human species. To date, research in rodents has been dominated by two types of assays designed to test for depression-like behaviour: behavioural despair tests, such as the forced swim test, and measures of anhedonia, such as the sucrose preference test. These tests have shown relatively good predictive validity in terms of antidepressant efficacy, but have limited translational validity. Recent developments in clinical research have revealed that cognitive affective biases (CABs) are a key feature of MDD. Through the development of neuropsychological tests to provide objective measures of CAB in humans, we have the opportunity to use 'reverse translation' to develop and evaluate whether similar methods are suitable for research into MDD using animals. The first example of this approach was reported in 2004 where rodents in a putative negative affective state were shown to exhibit pessimistic choices in a judgement bias task. Subsequent work in both judgement bias tests and a novel affective bias task suggest that these types of assay may provide translational methods for studying MDD using animals. This review considers recent work in this area and the pharmacological and translational validity of these new animal models of CABs.


Assuntos
Transtorno Depressivo Maior , Modelos Animais de Doenças , Animais , Viés , Cognição , Transtorno Depressivo Maior/psicologia , Humanos , Aprendizagem
9.
Pharmacol Biochem Behav ; 98(1): 87-93, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21172385

RESUMO

Previous work has indicated that the neuropeptide galanin decreases sensitivity to the rewarding effects of morphine and cocaine, but increases alcohol drinking. The aim of the current study was to examine the role of galanin signaling in nicotine reward by testing the effects of nicotine in mice lacking galanin peptide (GAL-/-) as compared to wild-type (GAL+/+) controls. Using an unbiased, three-chamber conditioned place preference (CPP) paradigm the dose-response function for nicotine CPP was tested in GAL-/- and GAL+/+ mice. Since activation of extracellular signal-related kinase (ERK2) is involved in the rewarding effects of several classes of drugs of abuse, we then measured the level of ERK2 phosphorylation in the nucleus accumbens shell (NACsh) and core (NACco) of GAL-/- and GAL+/+ mice following re-exposure to the CPP chamber previously paired with nicotine as a marker of mesolimbic system activation. Finally, we examined whether acute nicotine administration affects ERK2 activity in GAL-/- and GAL+/+ mice. GAL-/- mice required a higher dose of nicotine to induce a significant CPP compared to GAL+/+ mice. In the conditioning groups showing significant expression of nicotine CPP, only GAL+/+ mice showed ERK2 activation in the NACsh. This suggests that the nicotine CPP observed in GAL+/+ mice resulted in differential recruitment of ERK signaling in the NACsh compared to GAL-/- mice. In addition, no activation of ERK2 was observed following acute nicotine administration in either genotype. These data, along with prior results, suggest that galanin alters sensitivity to drugs of abuse differentially, with morphine, cocaine and amphetamine place preference suppressed, and nicotine and alcohol preference increased, by galanin signaling.


Assuntos
Condicionamento Psicológico/efeitos dos fármacos , Condicionamento Psicológico/fisiologia , Galanina/deficiência , Nicotina/farmacologia , Animais , Cocaína/farmacologia , Galanina/genética , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Congênicos , Camundongos Knockout , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Morfina/farmacologia , Nicotina/administração & dosagem , Nicotina/toxicidade , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Fosforilação , Recompensa , Transdução de Sinais , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia
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