Spelling suggestions: "subject:"[een] CONDITIONED FEAR"" "subject:"[enn] CONDITIONED FEAR""
1 |
Mechanisms of Secondary ExtinctionVurbic, Drina 16 June 2010 (has links)
Pavlov (1927) first reported that following appetitive conditioning of multiple stimuli, extinction of one CS attenuated responding to others which had not undergone direct extinction. Four experiments with rat subjects investigated potential mechanisms of this secondary extinction effect. Experiment 1 assessed whether secondary extinction would be more likely to occur with target CSs that have themselves undergone some prior extinction. Two CSs were initially paired with shock. One CS was subsequently extinguished before the second CS was tested. The target CS was partially extinguished for half the rats and not extinguished CS for the other half. A robust secondary extinction effect was obtained with the non-extinguished target CS. Experiment 2 investigated whether secondary extinction occurs if the target CS is tested outside the context where the first CS is extinguished. Despite the context switch secondary extinction was observed. Extinction of one CS was also found to thwart renewal of suppression to a second CS when it was tested in a neutral context. Experiment 3 examined whether secondary extinction can be attributed to mediated generalization caused by association of the CSs with a common US during conditioning. Rats received conditioning with three CSs and then extinction with one of them. Secondary extinction was observed with a shock-associated CS when the extinguished CS had been associated with either food pellets or shock, suggesting that secondary extinction is not US-specific and is thus not explained by this mediated generalization mechanism. Experiment 4 examined whether intermixing trials with the two stimuli during conditioning is necessary for secondary extinction to occur. Rats were either conditioned with intermixed trials as in Experiments 1-3, or with blocked trials of each CS presented in conditioning sessions separated by a day. Secondary extinction was observed only in the former condition. The results are consistent with the hypothesis that CSs must be associated with a common temporal context for secondary extinction to occur.
|
2 |
An analysis of late-developing learning and memory systems in rats: fear-potentiated startle and context-specific latent inhibition and extinctionYap, Carol Sue Lynn, Psychology, Faculty of Science, UNSW January 2006 (has links)
Eleven experiments examined two late-developing learning and memory systems in rats: fear-potentiated startle (FPS) and the contextual regulation of latent inhibition and extinction. The first study was based on three previous developmental findings on FPS: (1) FPS to an odour CS emerges at postnatal day (PN) 23; Rats conditioned at PN16 to an odour CS express freezing but not FPS when tested at PN23, and (3) FPS to an odour CS trained at PN16 is activated if rats are also trained to a difference odour at PN23 (Yap, Stapinski, & Richardson, 2005). Yap et al. (2005) hypothesised that the activation effect only occurs if rats are given training to the second odour at an age when FPS has emerged. Study 1 assessed this hypothesis and trained the second odour CS at either PN23 or PN20. Contrary to expectations, the results of this study showed the activation effect for both groups of rats. Surprisingly, the results also revealed a significant FPS effect to the odour CS trained at PN20. Subsequent experiments examined this unexpected result, and found that learning to odour 1 at PN16 facilitated the age of onset for FPS at PN20. The results of Study 1 are discussed in relation to past findings on enrichment, cumulative learning, and neurobiological models of conditioned fear. The second section of this thesis (Studies 2 and 3) examined the context-specificity of two memory interference paradigms, latent inhibition and extinction, in developing rats. The studies found that both phenomena were context-specific at PN23-25 but not at PN16-18. Moreover, the results suggest that the context-specificity of both latent inhibition depended on the age of the rat during the second phase of training, but not their age during the first phase of training or their age at test. The implications of these findings for theoretical and neural models of learning, as well as the occurrence of latent inhibition and extinction during development are discussed.
|
3 |
Elucidating the fear - maintaining properties of the Ventral Tegmental AreaTaylor, Amanda Lee January 2008 (has links)
The ventral tegmental area (VTA) and its dopaminergic (DA) mesocorticolimbic projections are thought to be essential in the brain’s reward neurocircuitry. In humans and animal experimental subjects, mild electrical VTA stimulation increases dopamine levels and can induce euphoria. Paradoxically, aversive stimuli activate VTA neurons and forebrain DA activity, and excessive electrical stimulation of the VTA exaggerates fearfulness. Research suggests that experimental manipulation of either the amygdala or the VTA has similar effects on the acquisition and expression of Pavlovian conditioned fear. Recently it was demonstrated that electrical stimulation of the amygdala produced fear extinction deficits in rats. Fear extinction involves the progressive dissipation of conditioned fear responses by repeated non-reinforced exposure to a conditioned stimulus (CS). Maladaptive states of fear in fear-related anxiety disorders, such as post-traumatic stress disorders (PTSD) or specific phobias are thought to reflect fear extinction learning deficits.
The primary purpose of the present study was to examine the effects of intra-VTA stimulation on fear extinction learning. Using fear-potentiated startle as a behavioural index of conditioned fear, it was found that 120 VTA stimulations paired or unpaired with non-reinforced CS presentations impaired the extinction of conditioned fear. This effect was not apparent in rats that received electrical stimulation of the substantia nigra (SN), suggesting that not all midbrain regions respond similarly. Electrical stimulation parameters did not have aversive affects because rats failed to show fear conditioning when electrical VTA stimulation was used as the unconditioned stimulus. Also, VTA stimulation did not alter conditioned fear expression in non-extinguished animals. Based on the results it is suggested that VTA activation disinhibited conditioned fear responding. Therefore, VTA neuronal excitation by aversive stimuli may play a role in fear-related anxiety disorders thought to reflect extinction learning deficits.
|
4 |
Elucidating the fear - maintaining properties of the Ventral Tegmental AreaTaylor, Amanda Lee January 2008 (has links)
The ventral tegmental area (VTA) and its dopaminergic (DA) mesocorticolimbic projections are thought to be essential in the brain’s reward neurocircuitry. In humans and animal experimental subjects, mild electrical VTA stimulation increases dopamine levels and can induce euphoria. Paradoxically, aversive stimuli activate VTA neurons and forebrain DA activity, and excessive electrical stimulation of the VTA exaggerates fearfulness. Research suggests that experimental manipulation of either the amygdala or the VTA has similar effects on the acquisition and expression of Pavlovian conditioned fear. Recently it was demonstrated that electrical stimulation of the amygdala produced fear extinction deficits in rats. Fear extinction involves the progressive dissipation of conditioned fear responses by repeated non-reinforced exposure to a conditioned stimulus (CS). Maladaptive states of fear in fear-related anxiety disorders, such as post-traumatic stress disorders (PTSD) or specific phobias are thought to reflect fear extinction learning deficits. The primary purpose of the present study was to examine the effects of intra-VTA stimulation on fear extinction learning. Using fear-potentiated startle as a behavioural index of conditioned fear, it was found that 120 VTA stimulations paired or unpaired with non-reinforced CS presentations impaired the extinction of conditioned fear. This effect was not apparent in rats that received electrical stimulation of the substantia nigra (SN), suggesting that not all midbrain regions respond similarly. Electrical stimulation parameters did not have aversive affects because rats failed to show fear conditioning when electrical VTA stimulation was used as the unconditioned stimulus. Also, VTA stimulation did not alter conditioned fear expression in non-extinguished animals. Based on the results it is suggested that VTA activation disinhibited conditioned fear responding. Therefore, VTA neuronal excitation by aversive stimuli may play a role in fear-related anxiety disorders thought to reflect extinction learning deficits.
|
5 |
Rôle tonique du récepteur CB1 dans les conséquences émotionnelles de l'exercice physique et du stress répété / Tonic role of CB1 receptors in the emotional consequences of physical exercise and repeated stressDubreucq, Sarah 12 December 2011 (has links)
Le système endocannabinoïde régule de nombreuses fonctions physiologiques. Dans le cerveau, cette régulation est exercée principalement par l’activation des récepteurs CB1. En effet, ces derniers jouent un rôle clef dans la régulation des neurotransmissions excitatrices et inhibitrices, y compris dans des régions cérébrales impliquées dans la gestion des processus émotionnels. Les données existantes indiquent que les récepteurs CB1 exercent un contrôle tonique sur certaines dimensions de l’émotion (e.g. anxiété, peur), mais le rôle joué par ces récepteurs dans les conséquences émotionnelles de l’exposition répétée à des stimuli attractifs ou aversifs n’a été que peu analysé. L’objectif de nos travaux a donc été d’examiner chez la souris le rôle des récepteurs CB1 (i) dans l’adhérence à un exercice physique volontaire répété, et dans les impacts émotionnels (ii) de l’exercice volontaire répété, et (iii) du stress par défaites sociales répété. Cet examen a été réalisé principalement à l’aide d’outils génétiques (mutants constitutifs et conditionnels du récepteur CB1) mais également à l’aide d’outils pharmacologiques (antagonistes sélectifs des récepteurs CB1). L’utilisation de ces outils nous a permis d’identifier un rôle spécifique des récepteurs CB1 des neurones GABAergiques de l’aire tegmentale ventrale dans le contrôle des performances d’exercice physique volontaire sur roue chez la souris. De plus, les données comportementales obtenues indiquent que les récepteurs CB1 portés par les neurones glutamatergiques corticaux jouent un rôlecrucial dans les profils d’anxiété et d’extinction de peur observés après un exercice physique volontaire répété. Enfin, une dernière série d’études a permis de distinguer les impacts respectifs del’enrichissement de l’hébergement d’une part, et de la pratique de l’exercice d’autre part, dans les conséquences de l’exercice volontaire sur les comportements émotionnels et la neurogenèse hippocampique.Un second volet de recherche a permis de définir les rôles respectifs des récepteurs CB1 portés pardifférentes populations neuronales dans l’impact psychoneuroendocrinien (comportement, métabolisme, réactivité corticotrope) du stress social par défaites répétées. En particulier, ce travail asouligné l’impact majeur des récepteurs CB1 des neurones sérotonergiques dans les modifications depoids corporel et d’appétence pour le sucre induites par le stress répété. De plus, les résultats obtenus chez des animaux contrôles et des animaux stressés ont mis en avant le rôle des récepteursCB1 des neurones glutamatergiques corticaux et des neurones exprimant le facteur Sim1 (i.e. majoritairement hypothalamiques) dans les processus d’extinction de la mémoire de peur conditionnée au son. / The endocannabinoid system regulates a plethora of physiological functions. In the central nervoussystem, such a regulation is mainly achieved through the stimulation of CB1 receptors. Thus, these receptors exert a key control over excitatory and inhibitory transmissions, including in brain areas ubserving emotional processes. The data gathered so far have provided evidence for a tonic controlof several dimensions of emotionality (e.g. anxiety, fear) by CB1 receptors, but the role played by these receptors in the emotional consequences of the repeated exposure to positive or to negative stimuli has been poorly addressed. Thus, the aims of this work were to examine the role of CB1 receptors (i) in voluntary exercise (wheel running) performance, and in several emotional effects of(ii) repeated voluntary exercise and (iii) repeated social stress in mice. This task was mainly achievedthrough the use of genetic (constitutive and conditional CB1 receptor mutants) and, albeit to a lowerextent, pharmacological (CB1 receptor antagonists) tools.The aforementioned tools allowed us to assign to CB1 receptors located on ventral tegmental area GABAergic neurons a tonic stimulatory influence on voluntary running performance. Moreover, behavioural experiments led us to conclude that CB1 receptors located on cortical glutamatergic neurons are involved in the anxiety and fear extinction patterns observed in animals given repeatedaccess to exercise. Lastly, a series of studies allowed us to distinguish between the respective impacts of housing enrichment and exercise in the consequences of wheel running on emotional behaviours and hippocampal neurogenesis.A second set of experiments defined the respective roles played by distinct neuronal CB1 receptor populations in the psychoneuroendocrine effects of repeated social stress. Thus, this work presentedevidence for a tonic role exerted by CB1 receptors located on central serotonergic neurones in stresselicited changes in body weight growth and hedonia for sucrose. Besides, CB1 receptors located on cortical glutamatergic neurons or on Sim1-expressing neurons (which are mainly present in the paraventricular hypothalamus) were found to exert major roles in the extinction of cued fear memory in unstressed and/or stressed animals.
|
6 |
Organização do sistema neural mesencefálico responsável pela resposta de congelamento. / Neural organization of the mesencephalic system responsible for the freezing behavior.Vianna, Daniel Machado Luiz 18 March 2003 (has links)
O congelamento a um contexto previamente associado ao choque nas patas é atenuado pela lesão da matéria cinzenta periaquedutal ventrolateral (MCPvl). Por outro lado, a estimulação elétrica ou microinjeção de compostos que diminuem a neurotransmissão GABAérgica na matéria cinzenta dorsolateral (MCPdl) provocam congelamento e fuga. O presente estudo examinou a possibilidade deste congelamento provocado pela estimulação da MCPdl ser resultado da ativação indireta da MCPvl. Ratos com lesão da MCPvl ou falsooperados foram eletricamente estimulados na MCPdl para a aferição dos limiares de resposta para o congelamento e a fuga. Os mesmos animais foram também submetidos ao condicionamento aversivo ao contexto através de choque nas patas, visando a validação de nossas condições experimentais. Um segundo grupo de ratos lesados e falso-operados receberam microinjeções de semicarbazida, um bloqueador da síntese do GABA, na MCPdl. Os resultados mostram que a lesão da MCPvl atenua o congelamento condicionado ao contexto, mas é ineficaz em alterar os efeitos da estimulação elétrica ou química da MCPdl sobre o congelamento e a fuga. A MCPvl é o alvo preferencial do núcleo central da amígdala na MCP, enquanto que a MCPdl recebe aferências principalmente dos núcleos do hipotálamo relacionados à defesa. Estas evidências são coerentes com a participação da MCPvl nas respostas de defesa ao perigo potencial, e da MCPdl ao perigo imediato. / Freezing to a context previously associated to footshock is attenuated by ventrolateral periaqueductal gray (vlPAG) lesion. Moreover, electrical stimulation or microinfusion of compounds that interfere with GABA neurotransmission in the dorsolateral periaqueductal gray (dlPAG) provoke freezing and escape. The present study examined the possibility of this freezing being the result of an indirect activation of vlPAG through dlPAG stimulation. Rats bearing vlPAG or sham lesions were electrically stimulated at dlPAG sites to have their freezing and escape threshold currents measured. The same animals were also submitted to a contextual fear-conditioning paradigm through footshock to validate our experimental setting. A second group of vlPAG- and sham-lesion rats received infusions of semicarbazide, a GABA-synthesis blocker, in the MCPdl. The results obtained show that vlPAG lesions do attenuate conditioned freezing, but are ineffective against dlPAG-stimulation freezing and escape. The vlPAG is the main PAG target to central nucleus of amygdala projections, while the dlPAG receives afferents primarily from hypothalamic nuclei related to defense. This evidence is coherent with vlPAG mediating responses to potential danger, while dlPAG would be more related to immediate danger.
|
7 |
Organização do sistema neural mesencefálico responsável pela resposta de congelamento. / Neural organization of the mesencephalic system responsible for the freezing behavior.Daniel Machado Luiz Vianna 18 March 2003 (has links)
O congelamento a um contexto previamente associado ao choque nas patas é atenuado pela lesão da matéria cinzenta periaquedutal ventrolateral (MCPvl). Por outro lado, a estimulação elétrica ou microinjeção de compostos que diminuem a neurotransmissão GABAérgica na matéria cinzenta dorsolateral (MCPdl) provocam congelamento e fuga. O presente estudo examinou a possibilidade deste congelamento provocado pela estimulação da MCPdl ser resultado da ativação indireta da MCPvl. Ratos com lesão da MCPvl ou falsooperados foram eletricamente estimulados na MCPdl para a aferição dos limiares de resposta para o congelamento e a fuga. Os mesmos animais foram também submetidos ao condicionamento aversivo ao contexto através de choque nas patas, visando a validação de nossas condições experimentais. Um segundo grupo de ratos lesados e falso-operados receberam microinjeções de semicarbazida, um bloqueador da síntese do GABA, na MCPdl. Os resultados mostram que a lesão da MCPvl atenua o congelamento condicionado ao contexto, mas é ineficaz em alterar os efeitos da estimulação elétrica ou química da MCPdl sobre o congelamento e a fuga. A MCPvl é o alvo preferencial do núcleo central da amígdala na MCP, enquanto que a MCPdl recebe aferências principalmente dos núcleos do hipotálamo relacionados à defesa. Estas evidências são coerentes com a participação da MCPvl nas respostas de defesa ao perigo potencial, e da MCPdl ao perigo imediato. / Freezing to a context previously associated to footshock is attenuated by ventrolateral periaqueductal gray (vlPAG) lesion. Moreover, electrical stimulation or microinfusion of compounds that interfere with GABA neurotransmission in the dorsolateral periaqueductal gray (dlPAG) provoke freezing and escape. The present study examined the possibility of this freezing being the result of an indirect activation of vlPAG through dlPAG stimulation. Rats bearing vlPAG or sham lesions were electrically stimulated at dlPAG sites to have their freezing and escape threshold currents measured. The same animals were also submitted to a contextual fear-conditioning paradigm through footshock to validate our experimental setting. A second group of vlPAG- and sham-lesion rats received infusions of semicarbazide, a GABA-synthesis blocker, in the MCPdl. The results obtained show that vlPAG lesions do attenuate conditioned freezing, but are ineffective against dlPAG-stimulation freezing and escape. The vlPAG is the main PAG target to central nucleus of amygdala projections, while the dlPAG receives afferents primarily from hypothalamic nuclei related to defense. This evidence is coherent with vlPAG mediating responses to potential danger, while dlPAG would be more related to immediate danger.
|
8 |
Diferenças associadas ao ciclo estral na reatividade emocional de ratas a estímulos incondicionados e condicionados de medo / Sex and estrous cycle-linked differences in responsiveness to unconditioned, but not conditioned fear stimuli in rats.Figueiredo, Rebeca Machado de 07 October 2016 (has links)
O desequilíbrio da homeostase emocional tem sido considerado como um mecanismo subjacente aos transtornos de ansiedade e humor. Em fêmeas, as alterações na secreção hormonal durante as diferentes fases do ciclo estral podem ser a base das alterações na reatividade emocional a eventos estressantes. Estudos comportamentais sobre diferenças sexuais no processamento das emoções mostram resultados conflitantes em fêmeas devido às dificuldades na seleção dos melhores modelos animais para testar as diferenças associadas ao ciclo estral. Uma vez que os testes comportamentais foram desenvolvidos em animais do sexo masculino, eles podem não ser apropriados para fêmeas. O presente estudo foi desenvolvido para contribuir nessa linha de pesquisa usando diferentes modelos de animais de medo incondicionado e condicionado, considerando as diferentes fases do ciclo estral das ratas. Comparou-se o desempenho de machos e fêmeas nas quatro fases do ciclo estral em dois testes de medo incondicionado: o switch-off, em que ratos cruzam uma caixa vai-e-vem para desligar uma luz aversiva, e o registro de vocalizações ultrassônicas (VUSs) a 22 kHz emitidos por animais sob o estresse agudo de restrição. Nos testes de medo condicionado, registrou-se o sobressalto potencializado pelo medo e a resposta decongelamento a um contexto aversivo. Em ambos os testes de medo condicionado, a reatividade emocional não se mostrou diferente entre os sexos. No entanto, no que diz respeito ao medo incondicionado, ratas em diestro tardio apresentaram maior reatividade emocional em desligar a luz intensa e maior emissão de VUSs em resposta à restrição em relação a outras fases do ciclo. Estes achados sugerem que o perfil hormonal durante a fase do diestro 2 pode aumentar a reatividade emocional de ratas frente a estímulos inatos, porém não àqueles aprendidos. / Dysfunctional emotional regulation has been implicated as a potential mechanism underlying anxiety and mood disorders. Changes in hormonal secretion during the different phases of the estrous cycle may underlie changes in emotional reactivity to stressful events in female animals. Previous behavioral studies of sex differences in emotion processing in females have yielded conflicting results. This may be due to the range of different behavioral tests used and difficulties in selecting the best animal models to test for estrous cycle-linked differences in responsiveness. Furthermore, the commonly used behavioral tests were developed in male animals and it may not be appropriate to translate directly the protocols from males to females. In the present study we have attempted to address these problems by using different animal models of anxiety based on tests for unconditioned or conditioned fear. We compared the performance of male rats and female rats at four stages of the estrous cycle defined by differences in vaginal cytology. To test for unconditioned fear, we used two tests: a light switch- off test, in which rats escape to the other compartment of a shuttle-box to turn off an aversive light and recordings of 22 kHz ultrasound vocalizations (USVs) during acute restraint stress. For the conditioned fear paradigm, we used fear potentiated startle in an aversive context and conditioned freezing using an aversive context as the conditioned stimulus. In both tests of conditioned fear there were no gender or estrous cycle-linked differences in emotional reactivity. However, with respect to unconditioned fear, female rats in late diestrus showed greater emotional reactivity expressed as switch-off responses to a light environment and USVs in response to restraint compared to other phases of the cycle. These findings suggest that the hormonal profile during the late diestrous phase may predispose to up-regulated emotional reactivity in rats facing emotional challenges to unconditioned, but not conditioned fear- inducing stimuli.
|
9 |
Diferenças associadas ao ciclo estral na reatividade emocional de ratas a estímulos incondicionados e condicionados de medo / Sex and estrous cycle-linked differences in responsiveness to unconditioned, but not conditioned fear stimuli in rats.Rebeca Machado de Figueiredo 07 October 2016 (has links)
O desequilíbrio da homeostase emocional tem sido considerado como um mecanismo subjacente aos transtornos de ansiedade e humor. Em fêmeas, as alterações na secreção hormonal durante as diferentes fases do ciclo estral podem ser a base das alterações na reatividade emocional a eventos estressantes. Estudos comportamentais sobre diferenças sexuais no processamento das emoções mostram resultados conflitantes em fêmeas devido às dificuldades na seleção dos melhores modelos animais para testar as diferenças associadas ao ciclo estral. Uma vez que os testes comportamentais foram desenvolvidos em animais do sexo masculino, eles podem não ser apropriados para fêmeas. O presente estudo foi desenvolvido para contribuir nessa linha de pesquisa usando diferentes modelos de animais de medo incondicionado e condicionado, considerando as diferentes fases do ciclo estral das ratas. Comparou-se o desempenho de machos e fêmeas nas quatro fases do ciclo estral em dois testes de medo incondicionado: o switch-off, em que ratos cruzam uma caixa vai-e-vem para desligar uma luz aversiva, e o registro de vocalizações ultrassônicas (VUSs) a 22 kHz emitidos por animais sob o estresse agudo de restrição. Nos testes de medo condicionado, registrou-se o sobressalto potencializado pelo medo e a resposta decongelamento a um contexto aversivo. Em ambos os testes de medo condicionado, a reatividade emocional não se mostrou diferente entre os sexos. No entanto, no que diz respeito ao medo incondicionado, ratas em diestro tardio apresentaram maior reatividade emocional em desligar a luz intensa e maior emissão de VUSs em resposta à restrição em relação a outras fases do ciclo. Estes achados sugerem que o perfil hormonal durante a fase do diestro 2 pode aumentar a reatividade emocional de ratas frente a estímulos inatos, porém não àqueles aprendidos. / Dysfunctional emotional regulation has been implicated as a potential mechanism underlying anxiety and mood disorders. Changes in hormonal secretion during the different phases of the estrous cycle may underlie changes in emotional reactivity to stressful events in female animals. Previous behavioral studies of sex differences in emotion processing in females have yielded conflicting results. This may be due to the range of different behavioral tests used and difficulties in selecting the best animal models to test for estrous cycle-linked differences in responsiveness. Furthermore, the commonly used behavioral tests were developed in male animals and it may not be appropriate to translate directly the protocols from males to females. In the present study we have attempted to address these problems by using different animal models of anxiety based on tests for unconditioned or conditioned fear. We compared the performance of male rats and female rats at four stages of the estrous cycle defined by differences in vaginal cytology. To test for unconditioned fear, we used two tests: a light switch- off test, in which rats escape to the other compartment of a shuttle-box to turn off an aversive light and recordings of 22 kHz ultrasound vocalizations (USVs) during acute restraint stress. For the conditioned fear paradigm, we used fear potentiated startle in an aversive context and conditioned freezing using an aversive context as the conditioned stimulus. In both tests of conditioned fear there were no gender or estrous cycle-linked differences in emotional reactivity. However, with respect to unconditioned fear, female rats in late diestrus showed greater emotional reactivity expressed as switch-off responses to a light environment and USVs in response to restraint compared to other phases of the cycle. These findings suggest that the hormonal profile during the late diestrous phase may predispose to up-regulated emotional reactivity in rats facing emotional challenges to unconditioned, but not conditioned fear- inducing stimuli.
|
10 |
Cell Type-Specific Control of Memory Functions by CB1 Cannabinoid Receptors / Spécificité du Type Cellulaire dans le Contrôle des Fonctions de Mémoire par les Récepteurs Cannabinoïdes CB1Metna-Laurent, Mathilde 26 June 2012 (has links)
Le système endocannabinoïde est un important modulateur des fonctions physiologiques. Dans le cerveau, son contrôle s’exerce essentiellement par les récepteurs cannabinoïdes de type 1 (CB1). Les récepteurs CB1 sont abondamment exprimés sur les neurones excitateurs glutamatergiques et les interneurones inhibiteurs GABAergiques et leur stimulation inhibe la libération du glutamate et du GABA. Récemment, l’activité des récepteurs CB1 sur les astrocytes a été proposée comme facilitant la transmission excitatrice. Par ce contrôle général de la neurotransmission, l’activité des récepteurs CB1 induit différents phénomènes de plasticté synaptique associés aux processus de mémoire. Les récepteurs CB1 jouent un rôle complexe dans les fonctions de mémoire. En particulier, la stimulation exogène des récepteurs CB1 perturbe la mémoire de travail. D’autre part, la signalisation endogène des récepteurs CB1 est nécessaire à l’adaptation des réponses de peur apprises. Cependant, les mécanismes par lesquels les récepteurs CB1 régulent ces processus de mémoire n’ont été que peu analysés. L’objectif de ce travail fut de caractériser les mécanismes cellulaires par lesquels les récepteurs CB1 contrôlent la mémoire de travail et les réponses de peur apprises. Nous avons utilisé les modèles de mutation constitutive et conditionnelle des récepteurs CB1 chez la souris afin d’analyser les conséquences de la délétion de ces récepteurs sur des types cellulaires particuliers. Dans une première étude, nous avons montré que les cannabinoïdes exogènes tels que le Δ9-tetrahydocannabinol (THC, principal composé psychoactif du cannabis) induisent des déficits de mémoire de travail spatiale par la stimulation des récepteurs CB1 exprimés sur les astrocytes. Les cannabinoides induisent une forme de dépression à long-terme dans l’hippocampe dont plusieurs mécanismes cellulaires sont similaires à ceux supportant les déficits de mémoire mis en évidence par l’analyse comportementale. Ces résultats suggèrent que les cannabinoïdes altèrent la mémoire de travail spatiale par une modification de la plasticité synaptique de l’hippocampe induite par la stimulation des récepteurs CB1 astrogliaux. Dans une seconde étude, nous avons mis en évidence que les récepteurs CB1 localisés sur les neurones GABAergiques et glutamatergiques exercent un contrôle opposé sur le type de réponse élicité par un stimulus conditioné aversif. La ré-expression sélective des récepteurs CB1 dans l’amygdale des souris mutantes constitutives a permis de préciser l’implication de cette structure dans la régulation des réponses de peur conditionnées par les récepteurs CB1.L’ensemble de ces travaux indiquent que le système endocannabinoïde contrôle les fonctions de mémoire par une régulation de l’activité de cellules spécifiques dans le cerveau. L’implication des astrocytes dans les effets des cannabinoïdes sur la mémoire souligne l’importance de ces cellules dans les processus cognitifs et suggère que les récepteurs CB1 astrogliaux jouent un rôle dans d’autres fonctions cérébrales. Nos résulats révèlent également l’importance de l’évaluation de différents comportements dans le cadre des modèles expérimentaux d’adaptation à la peur. / The endocannabinoid system is an important regulator of physiological functions. In the brain, this control is mainly exerted through the type-1-cannabinoid (CB1) receptors. CB1 receptors are abundant at excitatory glutamatergic and inhibitory GABAergic neuron terminals where their stimulation inhibits neurotransmitter release. The activity of CB1 receptors on astrocytes has been recently proposed as facilitating excitatory transmission. Through this general control on brain neurotransmission, CB1 receptors mediate distinct forms of synaptic plasticity that are associated with memory processing. Indeed, CB1 receptors control memory functions. In particular, the exogenous stimulation of CB1 receptors impairs working memory. Moreover, the endogenous CB1 receptor signalling ensures the adaptation of learned fear responses. However, the brain mechanisms of this CB1-mediated control of memory functions are poorly characterized. The goals of this research work were to dissect the cellular mechanisms by which CB1 receptors control both working memory and learned fear responses. We used constitutive and conditional mutagenesis in mice to address the roles of CB1 receptors on particular cell types in these functions. We first showed that exogenous cannabinoids, including Δ9-tetrahydocannabinol (THC, the main psychoactive constituent of cannabis), impairs spatial working memory through the stimulation of astroglial CB1 receptors. Cannabinoids also induce a form of in vivo long-term depression in the hippocampus that shares several cellular mechanisms with the cannabinoid-induced working memory impairments. These results suggest that cannabinoids disrupt spatial working memory by altering hippocampal synaptic plasticity through astroglial CB1 receptor stimulation. We then showed that CB1 receptors expressed on GABAergic and glutamatergic neurons oppositely control fear coping strategies in the presence of fear conditioned stimuli. The selective and local re-expression of CB1 receptors in the amygdala of constitutive CB1 mutant mice allowed to precise the involvement of this brain structure in the regulation of conditioned fear responses by CB1 receptors. Altogether, these studies indicate that the endocannabinoid system differentially controls memory functions through its distinct modulation of the activity of specific brain cells. The involvement of astrocytes in the effects of cannabinoids on memory highlights their key roles in cognitive processes and further suggests that astroglial CB1 receptors might play a role in other high order brain functions. Our results also point the importance of performing thorough behavioral analyses in the experimental models of fear adaptation.
|
Page generated in 0.0973 seconds