The present thesis examined extinction of conditioned fear in the developing rat. In the adult rat, the hippocampus is thought to be important for the context-specificity of extinction. Because the hippocampus is a late-maturing structure, it was hypothesised that context-modulation of extinction may be different across development. The first series of experiments investigated reinstatement of extinguished fear in the developing rat (Chapter 2). The results showed that P24 rats exhibited context-specific reinstatement. On the other hand, P17 rats did not exhibit reinstatement of extinguished fear following a US reminder treatment. The failure to see reinstatement in P17 rats was not due to the reminder treatment being ineffective in these rats because the same treatment alleviated spontaneous forgetting in rat this age. The second series of experiments then examined the renewal effect and GABAergic involvement in extinction in P24 and P17 rats (Chapter 3). It was observed that P24 rats displayed renewal whereas P17 rats did not. Also, pre-test injection of FG7142 recovered extinguished fear in P24 rats but not in P17 rats, even across a range of doses. This failure to see any FG7142 effect on extinction in P17 rats was not due to the lack of responsiveness to this drug in these rats because FG7142 was found to be effective in alleviating spontaneous forgetting in rats this age. The third series of experiments then examined the effect of temporary inactivation of the amygdala on extinction and re-extinction in the developing rat (Chapter 4). It was observed that extinction retention is impaired in both P24 and P17 rats if the amygdala is inactivated during extinction training. Interestingly, when a CS that had been previously extinguished and then re-trained was re-extinguished, re-extinction was amygdala-independent if initial extinction occurred at 24 days of age but amygdala-dependent if initial extinction occurred at 17 days of age. That is, amygdala involvement in re-extinction was dissociated across development. Taken together, these experiments provide strong evidence for fundamental differences in mechanisms underlying fear extinction across development. The implications of the findings were discussed in light of the theoretical and neural models of extinction.

Due to abnormal functioning of the brain’s reward and prediction system patients with schizophrenia spectrum disorders are thought to assign salience to non-relevant objects and events and to form context-inappropriate associations. The brain’s ventral striatum is critical in the formation of associations, and aberrant associations are believed to create delusional content during psychosis. The study wanted to examine the neural response, particularly in the ventral striatum, combined with subjective reports as patients learn associations in an aversive Pavlovian conditioning paradigm. The stimuli were randomized and involved circles of different colors. The conditioned stimuli (CS+) was followed by an unconditioned stimuli (US), consisting of an unpleasant sound, in 50% of events. The unconditioned (CS-) stimuli was followed by a low, not unpleasant sound in 50% of events. The degree of striatal activation was thought to be associated with the severity of patient’s illness. Functional magnetic resonance imaging (fMRI) blood-oxygen-level dependent (BOLD) responses were examined in eleven unmedicated non-institutionalized patients with schizophrenia spectrum disorders and 15 matched healthy controls. No significant within group differences in neural or subjective response to the [CS+ > CS-] contrast were found. No significant associations between severity of illness and degree of striatal activation in response to CS+ or CS- were found. Significant differences in neural activation for the [CS+ > CS-] contrast were found in the ventral striatum, the right inferor frontal gyrus, and the right angular gyrus, with patients exhibiting stronger activation compared to controls. The results and implications are discussed along with suggestions for future research.

Pesquisas sobre interação entre contingências de treino Pavloviano (PV) e treino operante (OP) têm enfatizado a influência do treino Pavloviano sobre o responder operante, mas não uma interação entre ambos os tipos de condicionamento. Neste trabalho é proposto estudar a interação a partir da combinação dos estímulos de ambas as contingências de treino, de forma que eles atuem simultaneamente como variáveis independentes na produção de um fenômeno comportamental. Para isso, a manipulação da taxa de reforço correlacionada aos estímulos condicional (CS) e discriminativo (SD) e a combinação desses estímulos em procedimentos de discriminação com estímulo composto foram utilizados como estratégias experimentais. No Estudo 1, três experimentos foram realizados com o objetivo de verificar a relação linear entre a taxa de reforço (r) correlacionada aos estímulos e a taxa de resposta (R) em treinos de discriminação com estímulos compostos em ratos. Nos Experimentos 1 (treino PV) e 2 (treino OP), ratos passaram por treino com um estímulo composto AB100% e três estímulos elementais, B50%, C50% e D25%. No Experimento 1 uma solução aquosa de sacarose (SAC) era liberada, como estímulo incondicional (US), em 100% das tentativas de AB100%, em 50% das vezes em B50% e C50% e em 25% das tentativas com D25%, em esquema de tempo variável VT-10s. No Experimento 2 a mesma taxa de SAC correlacionada aos estímulos foi mantida, mas dependeu do responder em esquema variável VI-10 s. Após essa fase, em ambos os experimentos, tentativas de sonda com o estímulo A, em extinção, foi adicionada. As respostas avaliadas foram inserir a cabeça no bebedouro (RIC) no treino PV (Experimento 1) e pressão à barra (RPB) no OP (Experimento 2). No experimento 3, a r na presença do estímulo A100% foi 100% e de B50% e C50% foi 50%. O estímulo avaliado em sonda foi um composto BC. Os resultados dos Experimentos 1 e 2 mostraram que a R da Sonda A foi equivalente à R nos estímulos B50% e C50%, indicando uma relação linear entre r e R (i.e., rA = rAB-rB). No Experimento 3, a R na Sonda BC foi equivalente à R em A100%, indicando somação das taxas de reforço (i.e., rBC = rB + rC). Nos experimentos 4 e 5 (Estudo 2) os treinos PV e OP foram combinados. Ratos passaram por PV e OP na mesma sessão, como o objetivo de verificar a somação da taxa de reforço (i.e., US e Sr) a partir da combinação de CS e SD em condicionamento com estímulo composto. Nas tentativas de OP, RPB em VI-10 s foi seguido por SAC em 100% das vezes nas tentativas com o estímulo A100% e em 50% das vezes em C50%. Nas tentativas de treino PV, o estímulo B50% foi seguido por SAC em 50% das vezes, em VT-10s, com a barra ausente. Após essa fase, os estímulos B50% e um composto BC foram adicionados ao treino por dez sessões, mas apresentados em tentativas de sonda em extinção (Exp. 4); no Experimento 5, foram realizadas sete sessões apenas com a Sonda BC e mais quatro sessões com as Sondas B e BC. Os resultados do experimento 4 indicaram somação entre os estímulos B e C em relação à resposta RIC (R em Sonda BC equivalente à R em A100%), mas não para RPB. No experimento 5, houve ocorrência de somação entre os estímulos B e C em ambos os tipos de treino (R em BC foi equivalente à R em A100%, para ambas as respostas RIC e RPB). Os dados foram discutidos em termos da teoria da estimação da taxa (RET), somação da taxa de reforço envolvendo CS e SD combinados e valor preditivo dos estímulos durante o condicionamento / Researches on Pavlovian-operant training interaction have emphasized the influence of Pavlovian training on the operant responding, but not an interaction between both type of conditioning. In this work, it is proposed to study the interaction through the combination of the stimuli of both training contingencies, so that they act simultaneously as independent variables in the production of a behavioral phenomenon. For this, the manipulation of the reinforcement rate correlated to the conditional (CS) and discriminative (SD) stimuli, and the combination of these stimuli in the procedure of discrimination with compound stimulus were used as experimental strategies. In study1, three previous experiments were carried out with the objective of verifying the linear relationship between the reinforcement rate (r) correlated to stimuli and rate response (R) on compound stimulus discrimination in rats. In Experiments 1 (PV training) and 2 (OP training), rats were trained with a compound stimulus AB100% and three individual stimuli B50%, C50%, and D25%. In PV, the aqueous solution of sucrose (SUC) was delivered as the unconditional stimulus on 100% of trials with AB100%, 50% of times in B50%, and C50% and 25% of trials with D25%, on a variable time schedule VT-10 s. In the OP, the same SAC rate correlated to the stimuli was maintained but depended on the responding on a variable schedule VI-10 s. After this phase, in both experiments, probe trials with the stimulus A, in extinction, was added to each experimental session. The evaluated responses were a head entry (HE) in the PV training and lever pressing (LP) in OP training. In Experiment 3, rats received a similar training to Experiment 2, the stimulus A100% with r of 100% of trials, B50% and C50% with r of 50%. The probe stimulus was a compound BC. The results of Experiments 1 and 2 showed that R of Probe A was equivalent to R in B50% and C50% stimuli, indicating a linear relationship between r and R (i.e., rA = rAB-rB). In Experiment 3 (OP), R in Probe BC was equivalent to R in A100%, indicating summation of the reinforcement rates (i.e., rBC = rB + rC). The Experiments 4 and 5 (Study 2) were carried out with the combination of PV and OP training. Rats were trained in PV and OP procedures in the same session with the objective of verifying summation of reinforcement rates (i.e., US, and Sr) from the combination of CS and SD in conditioning with the compound stimuli. Rats were trained in PV and OP procedures in the same session, with the objective of verifying the summation of the reinforcement rate (i.e., US and Sr) from the combination of CS and SD in compound stimulus conditioning. In OP trials, LP on a VI-10s were followed by SUC on 100% of times in the A100% trials, and 50% of trials with C50%. In PV trials, the stimulus B50% was followed by SUC on 50% of trials on VT-10 s, without the lever. After this phase, B50% stimuli and a BC compound were added in OP contingency for ten sessions, in extinction (Exp 4); in Experiment 5, seven sessions were performed with only the Probe BC and four sessions with Probes BC and B. The results of Experiment 4 indicated evidence for summation in relation to HE (R in BC probe equivalent to R in A100%), but not for LP. In Experiment 5, there was the occurrence of summation in both types of training (R in BC was equivalent to R in A100%, for both HE and LP responses). The data were discussed in terms of Rate Estimation Theory (RET), the summation of the reinforcement rate involving combined CS and SD, and the predictive value of the stimuli during conditioning

In the field of drug addiction, relapse back to drug seeking and taking is the major unmet clinical need. The rate of relapse back to drug-taking is ~70-80% within a year of drug abstinence. Gaining a better understanding of the prolonged neuronal changes that have taken place during drug addiction may lead to the design of better anti-relapse therapies. It is now widely believed that one component of drug addiction is by aberrant learning and memory processes. To study this, we investigated synaptic changes caused by the development of drug-seeking behaviour in C57BL/6J mice. Mice were treated either with non-contingent morphine or trained to exhibit drug-seeking behaviour following morphine-induced conditioned place preference (CPP) training, hippocampal slices were taken from these animals and synaptic changes examined at the CA3-CA1 synapse using electrophysiological methods. Mice that underwent morphine CPP were demonstrated to exhibit a significant preference for the morphine paired compartment before ex vivo electrophysiological analysis. Using field recordings, both non-contingent morphine and morphine CPP treatments resulted in a reduced ability to undergo stimulus-induced LTP compared to their respective controls. Whole cell patch clamp was then utilised to further investigate these effects. Non-contingent morphine treatment resulted in both pre- and post-synaptic changes with an increased AMPA:NMDA receptor ratio, concurrent increases in cell size, and reductions in the release probability of both glutamate and GABA. Morphine CPP treatment resulted in a more variable increase in AMPA:NMDA receptor ratio (presumably by the same mechanism but in a more specific group of neurones) and GABA release probability was also decreased. There were no detected increases in cell size however, or any detected changes in glutamate release probability. These findings therefore reveal a set of synaptic adaptations in the hippocampus unique to morphine-induced behavioural change, and may provide targets for future intervention in drug addiction.

The attribution of incentive salience to cues that become associated with drugs of abuse is a critical characteristic of individuals who may be vulnerable to drug addiction. Rodents with the propensity to sign track are thought to be vulnerable to drug abuse. The goal of the current work was to investigate whether sign trackers (STs) would acquire cocaine conditioned place preference (CPP) to a discrete cue using an avian species. In Experiment 1, sign and goal trackers (GTs) were first identified using a one third rank order split. Following identification, cocaine-CPP was conducted with a discrete cue in each end chamber. Contrary to previous research, results showed that GTs showed a CPP to the discrete cue but STs did not. Experiment 2 was conducted to determine whether sign and GTs had been misclassified with the rank order split. Experiment 2 compared the rank order method with a t-test method (absolute criterion). Misclassification of both sign and GTs occurred using the rank order split. The findings indicated that use of a more accurate method to identify sign and GTs may have led to different results for Experiment 1. The t-test method may be useful for models that require identification of STs.

Le conditionnement Pavlovien, l'acquisition de réponses vers des stimuli neutres associés à des récompenses, et le conditionnement instrumental, l'expression de comportements pour atteindre des buts, sont au cœur de nos capacités d'apprentissage. Ils sont souvent étudiés séparément malgré les preuves de leur enchevêtrement. Les modèles de conditionnement instrumental reposent sur le formalisme de l'apprentissage par renforcement (RL), alors que les modèles du conditionnement Pavlovien reposent surtout sur des architectures dédiées souvent incompatibles avec ce formalisme, compliquant l'étude de leurs interactions.Notre objectif est de trouver des concepts, qui combinés à des modèles RL puissent offrir une architecture unifiée permettant une telle étude. Nous développons un modèle qui combine un système RL classique, qui apprend une valeur par état, avec un système RL révisé, évaluant les stimuli séparément et biaisant le comportement vers ceux associés aux récompenses. Le modèle explique certaines réponses inadaptées par l'interaction néfaste des systèmes, ainsi que certaines différences inter-individuelles par une simple variation au niveau de la population de la contribution de chaque système dans le comportement global.Il explique une activité inattendue de la dopamine, vis-à-vis de l'hypothèse qu'elle encode un signal d'erreur, par son calcul sur les stimuli et non les états. Il est aussi compatible avec une hypothèse alternative que la dopamine contribue aussi à rendre certains stimuli recherchés pour eux-mêmes. Le modèle présente des propriétés prometteuses pour l'étude du conditionnement Pavlovien,du conditionnement instrumental et de leurs interactions. / Pavlovian conditioning, the acquisition of responses to neutral stimuli previously paired with rewards, and instrumental conditioning, the acquisition of goal-oriented responses, are central to our learning capacities. However, despite some evidences of entanglement, they are mainly studied separately. Reinforcement learning (RL), learning by trials and errors to reach goals, is central to models of instrumental conditioning, while models of Pavlovian conditioning rely on more dedicated and often incompatible architectures. This complicates the study of their interactions. We aim at finding concepts which combined with RL models may provide a unifying architecture to allow such a study. We develop a model that combines a classical RL system, learning values over states, with a revised RL system, learning values over individual stimuli and biasing the behaviour towards reward-related ones. It explains maladaptive behaviours in pigeons by the detrimental interaction of systems, and inter-individual differences in rats by a simple variation at the population level in the contribution of each system to the overall behaviour. It explains unexpected dopaminergic patterns with regard to the dominant hypothesis that dopamine parallels a reward prediction error signal by computing such signal over features rather than states, and makes it compatible with an alternative hypothesis that dopamine also contributes to the acquisition of incentive salience, making reward-related stimuli wanted for themselves. The present model shows promising properties for the investigation of Pavlovian conditioning, instrumental conditioning and their interactions.

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Chez l’espèce humaine comme pour de nombreuses autres espèces animales, lorsque des stimuli environnementaux précèdent de façon régulière la présentation d’événements importants pour un individu, ces stimuli vont acquérir sous certaines conditions la capacité à évoquer des comportements dits d’anticipation. Cette capacité est considérée par de nombreux auteurs comme ayant une haute valeur adaptative, favorisant le contact avec des événements appétitifs et permettant l’évitement d’événements aversifs. Ces dernières décennies, deschercheurs ont initié un rapprochement entre le phénomène d’anticipation et le conditionnement Pavlovien. Ce rapprochement repose à la fois sur une similarité dans les caractéristiques des événements mis en jeux mais surtout sur de nombreux effets et phénomènes semblables, amenant ces auteurs à considérer que les comportements ditsd’anticipation, d’une façon générale, reposeraient sur le processus Pavlovien. Leconditionnement Pavlovien offre une littérature extrêmement riche dont l’une des principalesquestions de recherche concerne le problème des conditions à l’apparition du processus.Parmi les hypothèses existantes, l’Hypothèse de l’Information est sans aucun doute l’une desplus importantes par son influence. Selon cette hypothèse, un apprentissage associatifPavlovien n’aura lieu que lorsqu’un événement important sera présenté de façon inattendu à un sujet, et l’apprentissage, ou les associations apprises, ne porteront que sur des stimuli prédictifs de l’événement important (i.e. permettant son anticipation). A travers deux expériences appliquant une procédure de conditionnement rétrograde à une procédure de renforcement conditionné, nous avons cherché à tester les propositions faites par cette hypothèse. Nos résultats vont directement à l’encontre de ces propositions et vont au contraire dans le sens de deux autres propositions théoriques faites sur le conditionnement Pavlovien,illustrées par le modèle SOP et l’Hypothèse du Codage Temporel. Ces deux propositions sont testées au sein d’une troisième et dernière expérience, dont les implications pour ces modèles comme pour la conceptualisation du conditionnement Pavlovien et de l’anticipation de façon générale sont discutées. / In human and non-human animals, environmental stimuli that reliably accompany the presentation of significant events are able after repeated exposures of eliciting anticipatory behaviors. Many authors underlined the adaptive value of anticipatory responses, and suggested a connection with Pavlovian conditioning. Linking anticipatory behaviors to Pavlovian conditioning is supported by the similarity in procedure (i.e. a pairing between a neutral stimulus with a significant event), but also on the common effects and phenomena, and the authors assume that Pavlovian conditioning is the process underlying the anticipation of events. This assumption is at the heart of the Information Hypothesis, and more generally of a functional and predictive perspective of Pavlovian conditioning. According to the Information Hypothesis, Pavlovian conditioning only occurs when an unexpected significant event is presented, and learning (i.e. the formation of association) would be about stimuli that allow the anticipation of the significant event. Using a backward conditioning procedure in a conditioned reinforcement preparation, we tested the assumptions made by the Information Hypothesis. The results found argue against the Information Hypothesis and, in contrast, support the assumption made by two others types of leaning models, illustrated by the Temporal Coding Hypothesis and the SOP model. The Temporal Coding Hypothesis and SOP are tested in a third experiment. Implications for Pavlovian conditioning models and anticipatory behaviors in general are discussed.

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Dysfunktionale Lernvorgänge (wie z.B. Pawlowsche Konditionierung) können bei Patienten mit Alkoholabhängigkeit das Rückfallrisiko erhöhen, was innerhalb der vorliegenden Arbeit mittels drei Studien untersucht wurde.