Fear memories, here defined as learned associations between a stimulus and a physiological fear reaction, are formed through fear conditioning. In animals, fear memories, present in the lateral amygdala, undergo reconsolidation after recall. Moreover, this reconsolidation process can be disrupted both pharmacologically and behaviourally, resulting in a reduced fear response to the stimulus. This thesis examines the attenuation of fear memories by disrupting reconsolidation in humans, using measures of both the central and peripheral nervous system activity. Serotonergic and dopaminergic genes have previously been tied to both fear conditioning and anxiety disorders, where fear conditioning mechanisms are important. In order to evaluate the possible role of fear memory reconsolidation mechanims in the effect on fear and anxiety by these genes, this thesis also compare the reconsolidation disruption effect between different serotonergic and dopaminergic genotypes. Study I examined the attentuation of fear memories by disrupting reconsolidation in humans using reacquisition as a measure of the return of fear. Moreover, study I investigated the impact of differences in serotonergic and dopaminergic alleles on this process. Study II examined the attentuation of fear memories by disrupting reconsolidation in humans using reinstatement as a measure of the return of fear. Study II also investigated the impact of differences in serotonergic and dopaminergic alleles on the process of fear memory reconsolidation. Study III used psychophysiology and fMRI to localize the functional neural activity mediating the fear memory reconsolidation disruption effect. In summary, this thesis provides evidence that fear memories are attenuated by reconsolidation disruption in humans and that serotonergic and dopaminergic alleles influence this process. Moreover, this thesis support that human fear memory reconsolidation is amygdala-dependent, suggesting an evolutionary shared memory mechanism.

N-methyl-D-asparate (NMDA) receptors located within the basolateral complex of the amygdala are required for the consolidation and expression of Pavlovian conditioned fear. The events downstream of receptor activation that mediate these processes are not well defined. An intermediate step that may be of significance is the synthesis of the gas nitric oxide (NO). Nitric oxide is synthesised as a result of NMDA receptor activation and acts as an unconventional neurotransmitter freely diffusing across cell membranes interacting with its targets in a non-synaptic manner. The targets of NO include cellular components that play significant roles during the consolidation of conditioned fear and the neurotransmission associated with its expression. This implies that NO may be an important intermediary of NMDA receptor activation and both these processes. The current study sought to examine this possibility using fear potentiated startle to examine the expression of learned fear. Three experiments were conducted, fifty rats received intra-BSC microinfusions of the global nitric oxide synthase inhibitor L-NAME either prior to fear conditioning, fear testing, or examination of the shock sensitization of the acoustic startle affect. The results indicated that NO was indeed required for both the consolidation and expression of learned fear, whereas it was not required for shock enhanced startle responding. This study provides new information about the sub-cellular basis of conditioned fear, and highlights the pivotal role played by NO in processes associated with conditioned fear.

A extinção é uma forma de aprendizado inibitório que se origina na omissão do reforço ou estímulo incondicionado, inibindo a evocação de uma resposta ou comportamento aprendido anteriormente. Muitas formas de aprendizado são moduladas por receptores β- noradrenérgicos, D1-dopaminérgicos e H2-histaminérgicos no córtex pré-frontal ventromedial (vmPFC), no complexo basolateral da amígdala (BLA) e no hipocampo dorsal (DH). Assim, o objetivo do presente trabalho foi investigar a modulação da extinção de memória aversiva nestas três regiões cerebrais. Para isso, utilizamos ratos machos Wistar, que foram submetidos ao paradigma de esquiva inibitória (EI) ou condicionamento contextual ao medo (CCM). As diferentes drogas utilizadas foram infundidas através das cânulas guias implantadas estereotaxicamente no DH, BLA ou vmPFC imediatamente após a sessão de extinção e seus efeitos sobre a extinção foram avaliados em uma sessão de teste realizada 24 h depois. A DSerina (50 μg/lado), modulador positivo do receptor NMDA, e o SKF9188 (12.5 μg/lado), inibidor da enzima histamina metil-transferase, melhoraram a consolidação da memória de extinção nas tarefas de EI e CCM. Entretanto, o AP5 (5 μg/lado), antagonista do receptor glutamatérgico NMDA, e a ranitidina (17.5 μg/lado), antagonista do receptor histaminérgico H2, prejudicaram a extinção em ambos os paradigmas, indicando que os receptores glutamatérgicos do tipo NMDA estão envolvidos na consolidação dos dois paradigmas utilizados, e que os receptores histaminérgicos H2 modulam a extinção nas três estruturas estudadas. A noradrenalina (1 μg/lado), o antagonista β-adrenoreceptor, timolol (1 μg/lado), o agonista dos receptores D1, SKF38393 (12.5 μg/lado) e o antagonista dos receptores D1, SCH23390 (1.5 μg/lado) também afetam a extinção nas duas tarefas, porém, seus efeitos são variados dependendo da tarefa e do local da infusão, sugerindo que a modulação da extinção pelos receptores β- e D1 é mais complexa. Nossos resultados mostram que as três estruturas são ativadas durante o processo de extinção da memória e que os sistemas neuromodulatórios atuam de formas distintas nessas tarefas. / Extinction consists of the learned inhibition of retrieval of previously acquired memory. Many forms of learning are modulated by β-noradrenergic, D1-dopaminergic and H2-histaminergic receptors on ventromedial prefrontal cortex (vmPFC), basolateral amygdala (BLA) and dorsal hippocampus. Therefore, the aim of this work was investigated the modulation of aversive memory extinction in these brain structures. Male Wistar rats were submitted to inhibitory avoidance paradigm (EI) or contextual fear conditioning (CCM). The drugs were infused through cannulae implanted into the DH, BLA or vmPFC immediately after the extinction session and their effects were evaluated 24 h later. D-serine (50 μg/side), a NMDA receptor stimulant, and SKF9188 (12.5 μg/side), a histamine methyl-transferase inhibitor, enhanced the consolidation of the extinction memory in EI and CCM tasks. However, AP5 (5 μg/side), a NMDA-antagonist, and ranitidine (17.5 μg/side), a H2- histaminergic antagonist, impaired the extinction of both tasks, indicated that NMDA receptors are involved in the consolidation of extinction of both tasks, and histamine H2 receptors modulate that process in all areas studied. Noradrenaline (1 μg/side), timolol 1 μg/side), a β-adrenergic antagonist, SKF38393 (12.5 μg/side) and SCH23390 (1.5 μg/side), D1 agonist and antagonist receptor, respectively, also affected the extinction, but their effects varied with the task and with the site of infusion, suggesting that extinction modulation by β- and D1 is more complex. In conclusion, the three structures investigated are activated in the aversive memory extinction and the neuromodulatory systems act of different forms in these structures.

Master of Science / Department of Psychological Sciences / Mary Cain / Research has demonstrated that an enriched rearing environment improves learning in many tasks. However, growing evidence suggests that an enriched environment may not provide the same benefits during a fear conditioning paradigm. In fact, it appears that an isolated rearing environment may facilitate acquisition of fear to an aversive stimulus. The neural mechanisms responsible for this disparity in fear learning among differentially reared animals are currently unknown. The NR2B subunit of the NMDA receptor has been shown to be involved in the acquisition of fear and influenced by differential rearing, making it a prime candidate to begin investigating these underlying neural mechanisms. Therefore, this study assessed the expression of the NR2B subunit in brain regions important for the acquisition of fear (amygdala and hippocampus) among differentially reared rats. Rats were reared in an enriched, an isolated, or a standard condition for 30 days. They received four tone-footshock pairings, after which their brains were removed and expression of the NR2B subunit was quantified in the basolateral amygdala (BLA), central nucleus of the amygdala (ACe), and the CA3 region of the hippocampus. Analyses found that the isolated rats began to acquire fear to the aversive stimulus faster than the enriched and standard housed rats. However, the isolated rats showed the least amount of NR2B expression in the BLA while there were no rearing differences in expression within the ACe or the CA3. The results from this study provide further insight to the importance of the rearing environment in learning and memory, especially the learning of fear, and its central neural basis.

A extinção é uma forma de aprendizado inibitório que se origina na omissão do reforço ou estímulo incondicionado, inibindo a evocação de uma resposta ou comportamento aprendido anteriormente. Muitas formas de aprendizado são moduladas por receptores β- noradrenérgicos, D1-dopaminérgicos e H2-histaminérgicos no córtex pré-frontal ventromedial (vmPFC), no complexo basolateral da amígdala (BLA) e no hipocampo dorsal (DH). Assim, o objetivo do presente trabalho foi investigar a modulação da extinção de memória aversiva nestas três regiões cerebrais. Para isso, utilizamos ratos machos Wistar, que foram submetidos ao paradigma de esquiva inibitória (EI) ou condicionamento contextual ao medo (CCM). As diferentes drogas utilizadas foram infundidas através das cânulas guias implantadas estereotaxicamente no DH, BLA ou vmPFC imediatamente após a sessão de extinção e seus efeitos sobre a extinção foram avaliados em uma sessão de teste realizada 24 h depois. A DSerina (50 μg/lado), modulador positivo do receptor NMDA, e o SKF9188 (12.5 μg/lado), inibidor da enzima histamina metil-transferase, melhoraram a consolidação da memória de extinção nas tarefas de EI e CCM. Entretanto, o AP5 (5 μg/lado), antagonista do receptor glutamatérgico NMDA, e a ranitidina (17.5 μg/lado), antagonista do receptor histaminérgico H2, prejudicaram a extinção em ambos os paradigmas, indicando que os receptores glutamatérgicos do tipo NMDA estão envolvidos na consolidação dos dois paradigmas utilizados, e que os receptores histaminérgicos H2 modulam a extinção nas três estruturas estudadas. A noradrenalina (1 μg/lado), o antagonista β-adrenoreceptor, timolol (1 μg/lado), o agonista dos receptores D1, SKF38393 (12.5 μg/lado) e o antagonista dos receptores D1, SCH23390 (1.5 μg/lado) também afetam a extinção nas duas tarefas, porém, seus efeitos são variados dependendo da tarefa e do local da infusão, sugerindo que a modulação da extinção pelos receptores β- e D1 é mais complexa. Nossos resultados mostram que as três estruturas são ativadas durante o processo de extinção da memória e que os sistemas neuromodulatórios atuam de formas distintas nessas tarefas. / Extinction consists of the learned inhibition of retrieval of previously acquired memory. Many forms of learning are modulated by β-noradrenergic, D1-dopaminergic and H2-histaminergic receptors on ventromedial prefrontal cortex (vmPFC), basolateral amygdala (BLA) and dorsal hippocampus. Therefore, the aim of this work was investigated the modulation of aversive memory extinction in these brain structures. Male Wistar rats were submitted to inhibitory avoidance paradigm (EI) or contextual fear conditioning (CCM). The drugs were infused through cannulae implanted into the DH, BLA or vmPFC immediately after the extinction session and their effects were evaluated 24 h later. D-serine (50 μg/side), a NMDA receptor stimulant, and SKF9188 (12.5 μg/side), a histamine methyl-transferase inhibitor, enhanced the consolidation of the extinction memory in EI and CCM tasks. However, AP5 (5 μg/side), a NMDA-antagonist, and ranitidine (17.5 μg/side), a H2- histaminergic antagonist, impaired the extinction of both tasks, indicated that NMDA receptors are involved in the consolidation of extinction of both tasks, and histamine H2 receptors modulate that process in all areas studied. Noradrenaline (1 μg/side), timolol 1 μg/side), a β-adrenergic antagonist, SKF38393 (12.5 μg/side) and SCH23390 (1.5 μg/side), D1 agonist and antagonist receptor, respectively, also affected the extinction, but their effects varied with the task and with the site of infusion, suggesting that extinction modulation by β- and D1 is more complex. In conclusion, the three structures investigated are activated in the aversive memory extinction and the neuromodulatory systems act of different forms in these structures.

A extinção é uma forma de aprendizado inibitório que se origina na omissão do reforço ou estímulo incondicionado, inibindo a evocação de uma resposta ou comportamento aprendido anteriormente. Muitas formas de aprendizado são moduladas por receptores β- noradrenérgicos, D1-dopaminérgicos e H2-histaminérgicos no córtex pré-frontal ventromedial (vmPFC), no complexo basolateral da amígdala (BLA) e no hipocampo dorsal (DH). Assim, o objetivo do presente trabalho foi investigar a modulação da extinção de memória aversiva nestas três regiões cerebrais. Para isso, utilizamos ratos machos Wistar, que foram submetidos ao paradigma de esquiva inibitória (EI) ou condicionamento contextual ao medo (CCM). As diferentes drogas utilizadas foram infundidas através das cânulas guias implantadas estereotaxicamente no DH, BLA ou vmPFC imediatamente após a sessão de extinção e seus efeitos sobre a extinção foram avaliados em uma sessão de teste realizada 24 h depois. A DSerina (50 μg/lado), modulador positivo do receptor NMDA, e o SKF9188 (12.5 μg/lado), inibidor da enzima histamina metil-transferase, melhoraram a consolidação da memória de extinção nas tarefas de EI e CCM. Entretanto, o AP5 (5 μg/lado), antagonista do receptor glutamatérgico NMDA, e a ranitidina (17.5 μg/lado), antagonista do receptor histaminérgico H2, prejudicaram a extinção em ambos os paradigmas, indicando que os receptores glutamatérgicos do tipo NMDA estão envolvidos na consolidação dos dois paradigmas utilizados, e que os receptores histaminérgicos H2 modulam a extinção nas três estruturas estudadas. A noradrenalina (1 μg/lado), o antagonista β-adrenoreceptor, timolol (1 μg/lado), o agonista dos receptores D1, SKF38393 (12.5 μg/lado) e o antagonista dos receptores D1, SCH23390 (1.5 μg/lado) também afetam a extinção nas duas tarefas, porém, seus efeitos são variados dependendo da tarefa e do local da infusão, sugerindo que a modulação da extinção pelos receptores β- e D1 é mais complexa. Nossos resultados mostram que as três estruturas são ativadas durante o processo de extinção da memória e que os sistemas neuromodulatórios atuam de formas distintas nessas tarefas. / Extinction consists of the learned inhibition of retrieval of previously acquired memory. Many forms of learning are modulated by β-noradrenergic, D1-dopaminergic and H2-histaminergic receptors on ventromedial prefrontal cortex (vmPFC), basolateral amygdala (BLA) and dorsal hippocampus. Therefore, the aim of this work was investigated the modulation of aversive memory extinction in these brain structures. Male Wistar rats were submitted to inhibitory avoidance paradigm (EI) or contextual fear conditioning (CCM). The drugs were infused through cannulae implanted into the DH, BLA or vmPFC immediately after the extinction session and their effects were evaluated 24 h later. D-serine (50 μg/side), a NMDA receptor stimulant, and SKF9188 (12.5 μg/side), a histamine methyl-transferase inhibitor, enhanced the consolidation of the extinction memory in EI and CCM tasks. However, AP5 (5 μg/side), a NMDA-antagonist, and ranitidine (17.5 μg/side), a H2- histaminergic antagonist, impaired the extinction of both tasks, indicated that NMDA receptors are involved in the consolidation of extinction of both tasks, and histamine H2 receptors modulate that process in all areas studied. Noradrenaline (1 μg/side), timolol 1 μg/side), a β-adrenergic antagonist, SKF38393 (12.5 μg/side) and SCH23390 (1.5 μg/side), D1 agonist and antagonist receptor, respectively, also affected the extinction, but their effects varied with the task and with the site of infusion, suggesting that extinction modulation by β- and D1 is more complex. In conclusion, the three structures investigated are activated in the aversive memory extinction and the neuromodulatory systems act of different forms in these structures.

A amígdala participa dos processos de aprendizagem e memória de natureza emocional, incluindo os comportamentos aversivos. Essa estrutura compreende vários núcleos que estabelecem diferentes conexões com outras estruturas do sistema nervoso. Seu núcleo basal (BA) é um dos principais alvos amigdalares de informações processadas pelo hipocampo. Evidências apontam que o hipocampo seria responsável pela aprendizagem contextual, construindo uma representação integrada dos diferentes estímulos do ambiente numa representação única, denominada representação configuracional do contexto, que inclui também representações do espaço. Congruente com essa hodologia, lesões seletivas do BA resultam em prejuízos comportamentais similares aos encontrados após lesão hipocampal. Por exemplo, ratos com lesão no BA exibem deficiências na tarefa de medo condicionado ao contexto, mas não ao som, indicando que essa região está envolvida no processo de condicionamento aversivo contextual. Porém, não está claro se esse prejuízo decorre da participação do BA na aquisição e/ou evocação e expressão do medo contextual. Os objetivos do presente estudo incluíram avaliar, por meio da inativação reversível do BA, (1) se ele é necessário na aquisição do condicionamento aversivo ao som e/ou ao contexto e (2) qual a natureza da sua participação no condicionamento aversivo ao contexto, isto é, se é necessário para a construção do contexto, para sua associação com o estímulo aversivo e/ou para a evocação da memória e expressão das respostas condicionadas. Num primeiro experimento, muscimol foi infundido no BA antes do treinamento na tarefa de condicionamento aversivo concorrente ao som e ao contexto, e os testes de medo condicionado ao som e ao contexto foram realizados separadamente, na ausência de muscimol. Como esperado, os resultados revelaram prejuízo de desempenho na tarefa de medo condicionado ao contexto, mas não na tarefa de medo condicionado ao som. Num segundo experimento, muscimol foi infundido, em grupos independentes de animais, antes de cada fase da variante do condicionamento aversivo ao contexto que envolve facilitação pela pré-exposição ao contexto, a qual permite distinguir entre a construção configuracional do contexto (fase 1), sua associação com o estímulo aversivo (fase 2) e posterior evocação e expressão do medo condicionado (fase 3). Resultados mostraram que somente os ratos que receberam muscimol antes da fase 2, mas não os que receberam muscimol antes das fases 1 e 3, apresentaram prejuízo de desempenho na tarefa de medo condicionado ao contexto. No conjunto, esses resultados indicam que o BA participa do condicionamento aversivo ao contexto sendo imprescindível no processo de associação da representação configuracional do contexto com o estímulo aversivo, mas não nos processos de construção da representação sobre o contexto e nem de evocação da memória e expressão das respostas condicionadas de medo / The amygdala is involved in emotional learning and memory, including fear conditioning. This brain structure includes several nuclei with distinct hodology. The basal nucleus (BA) receives processed information from the hippocampal formation. Evidence indicates that the hippocampus integrates environmental stimuli in a single representation thus rendering it involved in contextual (including spatial) learning and memory. Congruent with this hodological evidence, selective damage to the BA results in behavioral impairments similar to those found after hippocampal damage. For instance, rats with BA damage exhibit performance impairments in contextual, but not auditory, fear conditioning tasks. However, it is not clear to which extent this disruption is related to the BA involvement in either acquisition of contextual fear or retrieval of memory and fear expression, or both. This study aimed at investigating, by way of reversible inactivation of the BA, (1) its involvement in acquisition of auditory and contextual fear conditioning, and (2) the nature of its participation in contextual fear conditioning, that is, if it is necessary for building a representation about the context, for associating the context with the aversive stimulus and/or for memory retrieval and expression of contextual fear conditioning. In the first experiment, muscimol was infused into the BA before training in a concurrent auditory and contextual fear conditioning task, and testing for auditory and contextual fear conditioning was run separately in the absence of muscimol. As expected, results revealed disruption of performance in the contextual, but not in the auditory, conditioning task. In the second experiment, muscimol was infused into the BA, in independent groups of animals, before each of the three phases of a contextual fear conditioning variant that involves context pre-exposure facilitation, thus allowing to evaluate if functional reversible inactivation of the BA interfered with (1) building an integrated representation of the environment (the context), (2) its association with the aversive stimulus, and/or (3) memory retrieval and expression of fear conditioning. Results showed that muscimol infusion into BA before phase 2, but not phases 1 and 3, impaired performance in the contextual fear conditioning task. Together, these results indicate that a functional BA is required for acquisition of contextual fear conditioning in order to establish an association between the context and the aversive stimulus, but not for building a context neither for memory retrieval and expression of fear conditioned responses

Uma das causas mais importantes de lesão encefálica em neonatos na atualidade é a anóxia neonatal. Este é um dos problemas mais graves e comuns nos serviços de perinatologia dos hospitais no mundo, sendo ainda pior em países subdesenvolvidos, devido à carência de precauções e cuidados requeridos. Há relativamente pouco tempo estudos têm indicado que a hipotermia promove um importante efeito neuroprotetor, podendo ser usada como tratamento alternativo promissor para danos causados pela anóxia neonatal. Porém, embora diversas pesquisas mostrem a ação neuroprotetora da hipotermia, não existem evidencias consistentes do seu papel preventivo em relação as alterações comportamentais decorrentes da anóxia neonatal. O objetivo deste trabalho foi avaliar se a hipotermia previne alterações comportamentais decorrentes da anóxia neonatal, incluindo funções de memória espacial, condicionamento aversivo e ansiedade. Foram incluídos no estudo 91 ratos Wistar machos organizados em 4 grupos: anóxia com hipotermia (AH), anóxia sem hipotermia (AC), controle (para anóxia) com hipotermia (CH) e controle sem hipotermia (CC). O protocolo de anóxia neonatal foi iniciado 24 horas após o nascimento dos ratos, usando uma câmara semi-hermética saturada com nitrogênio gasoso. A temperatura da câmera foi mantida a 37°C e o tempo de exposição à anóxia foi de 25 minutos. Animais controle para anóxia foram expostos à mesma câmera, exceto pelo nitrogênio que foi substituído por ar. O tratamento com hipotermia foi iniciado imediatamente após da anóxia em uma câmara a 30°C, onde os animais permaneceram durante 5 horas. O tratamento controle para hipotermia envolveu o mesmo protocolo, exceto pela temperatura da câmera que foi mantida a 37°C. No final do período, os neonatos foram colocados em uma câmara aquecida a 37°C por 40 minutos até se recuperarem. Quando os animais atingiram 70 dias de idade foram submetidos ao paradigma teste-reteste no labirinto em cruz elevado, para avaliar níveis de ansiedade, atividade locomotora e memória aversiva. Subsequentemente, quando os animais fizeram 75 dias, iniciou-se o teste de memória espacial no Labirinto Aquático de Morris. Finalmente, quando os animais atingiram 115 dias de idade, realizou-se o teste de condicionamento de medo ao som e ao contexto. A anóxia neonatal e a hipotermia não interferiram nos níveis de ansiedade no Labirinto em cruz elevado. Porém, a hipotermia aumentou a atividade locomotora e comportamentos de avaliação de risco. Os resultados obtidos no Labirinto Aquático de Morris indicam que a hipotermia previne prejuízos na memória espacial induzidos pela anóxia neonatal. Finalmente, a anóxia neonatal reduziu a taxa de extinção de memória aversivas, efeito que foi prevenido pela hipotermia. No conjunto, esses resultados mostram, por um lado, que a hipotermia previne alterações da memória espacial e de medo condicionado. Por outro lado, eles mostram que a hipotermia induz aumento da atividade locomotora e de comportamentos de avaliação de risco em ratos / Neonatal anoxia is one of the main causes of brain injury in newborns. This is among the most serious problems in many hospitals around the world and is even worse in developing countries due to the lack of required precautions and care. Recent studies have indicated that hypothermia promotes important neuroprotective effects. Thus, it could constitute a promising alternative treatment to dysfunctions caused by neonatal anoxia. Although there have been studies demonstrating that hypothermia promotes neuroprotection following neonatal anoxia, there is no solid evidence showing to which extent this neuroprotection prevents behavioral changes. This study aimed at evaluating to which extent behavioral changes induced by neonatal anoxia are prevented by hypothermia, focusing on anxiety, spatial memory and fear conditioning, in rats. The study included 91 male Wistar rats organized in 4 groups: anoxia with hypothermia (AH), anoxia without hypothermia (AC), control (for anoxia) with hypothermia (CH) and control without hypothermia (CC). Neonatal anoxia protocol started 24 hours after birth, using a semi-hermetic chamber saturated with nitrogen gas. The chamber temperature was maintained at 37°C and the time of exposure to anoxic conditions was 25 minutes. Hypothermia treatment started immediately after the anoxia protocol, within a chamber at 30°C, where the newborns remained for 5 hours. At the end of this period, newborns were transferred to a chamber at 37°C for 40 minutes until its recovery. Control treatment for anoxia involved the same protocol except for the nitrogen that was substituted for air. Control treatment for hypothermia involved to maintain the subjects in the same chamber at 37°C for 5 hours. When the animals were 70 days old, they were subjected to the elevated plus maze, in order to evaluate their anxiety, locomotor activity and aversive memory. Subsequently, when the animals were 75 days old, their spatial memory was evaluated in the Morris Water Maze. Finally, when the animals were 115 days old, they were subjected to an auditory and contextual fear conditioning task. Neonatal anoxia did not interfere with anxiety as evaluated in the elevated plus maze. In contrast, hypothermia by itself increased risk assessment behavior in the elevated plus maze. Performance in the Morris water maze task indicated that hypothermia prevents anoxia-induced disruption of spatial memory. Extinction of both auditory and contextual fear conditioning were slowed by anoxia, and this effect was prevented by hypothermia treatment. Therefore, the present experiments show that hypothermia prevents anoxia-induced (1) disruption of spatial memory and (2) slowing of extinction of fear conditioning; however, by itself, hypothermia increases risk assessment, in rats

Conditionnement à la peur est un paradigme réussi pour comprendre les substrats neuronaux de l’apprentissage et de l’émotion. Dans cette thèse, je présente deux modèles informatiques des structures du cerveau qui sous-tendent l'acquisition de la peur conditionnée. Le première modèle est utilisé pour enquêter sur l’effet des changements de l’inhibition tonique sur le traitement des informations reçues. On confirme que la diminution de l’inhibition tonique d’une population augmente la réactivité du réseau. Ensuite, le modèle est analysé d’une perspective fonctionnelle et des prédictions qui découlent de cette proposition sont discutées. En outre, je présenterai un modèle systématique, basé sur un type de modèle de conditionnement récemment introduit utilisant des variables latentes. Je propose que l’interaction entre les neurones dans l’amygdale basale code pour l’interface entre ces variables latentes. Le modèle couvre une large gamme d’effets et l’analyse produit un certain nombre de prédictions vérifiables. / Fear conditioning is a successful paradigm for studying neural substrates of emotional learning. In this thesis, two computational models of the underlying neural circuitry are presented. First, the effects of changes in neuronal membrane conductance on input processing are analyzed in a biologically realistic model. We show that changes in tonic inhibitory conductance increase the responsiveness of the network to inputs. Then, the model is analyzed from a functional perspective and predictions that follow from this proposition are discussed. Next, a systems level model is presented based on a recent high-level approach to conditioning. It is proposed that the interaction between fear and extinction neurons in the basal amygdala is a neural substrate of the switching between latent states, allowing the animal to infer causal structure. Important behavioral and physiological results are reproduced and predictions and questions that follow from the main hypothesis are considered.

The mechanisms underlying cannabinoid impairment of fear memory is not clear. This study investigated the effects of the synthetic cannabinoid HU210 and the endocannabinoid hydrolysis inhibitor JZL 195 on fear memory following contextual fear conditioning (CFC; an animal model of fear). The long-term depression (LTD)-blocking peptide Tat-GluR2 was utilized to investigate whether the expression of cannabinoid-induced LTD (CB-LTD) is required for the cannabinoid impairment of acquisition and consolidation of contextual fear memory. HU210 reduced freezing throughout the test phase of the acquisition protocol, which was not affected by pre-administration of Tat-GluR2. High and moderate doses of HU210 reduced freezing during the first and last half, respectively, of the test phase of the consolidation protocol, which was prevented by pre-treatment with Tat-GluR2. HU210 did not affect freezing during the test phase of the retrieval protocol. Thus, these results suggest that HU210 impairs acquisition and consolidation, but not retrieval of contextual fear memory, and that in vivo CB-LTD expression is required for HU210 impairment of the consolidation, but not acquisition, of contextual fear memory. We also observed that HU210 and JZL 195 do not facilitate the acquisition of contextual fear memory extinction.