Orientadora: Profa. Dra. Paula Ayako Tiba / Dissertação (mestrado) - Universidade Federal do ABC, Programa de Pós-Graduação em Neurociência e Cognição, 2016. / Memórias de extinção são um produto das variações nas condições de condicionamento e na quantidade de tempo e sessões de extinção. Aumentos de sono paradoxal após a exposição a sessões de extinção foram descritas anteriormente, contudo trabalhos anteriores não testaram mais de um dia de extinção e tão pouco testaram se a modificação do sono após a extinção dependeria do intervalo de tempo entre condicionamento e extinção. Nós exploramos modificações da arquitetura do sono em diferentes condições de aprendizagem a extinção do medo condicionado. Em primeiro lugar, usamos uma tarefa de condicionamento de medo ao contexto (CMC) a fim de explorar o efeito de um evento aversivo (o choque elétrico) e um possível efeito do intervalo de tempo entre a sessão condicionamento e a sessão de extinção no sono e comportamento. O primeiro grupo, chamado Extinção Múltipla recebeu um treino de CMC com uma apresentação de choque único seguido por cinco sessões de extinção. O segundo grupo, chamado extinção única, foi treinado no CMC e expostos à extinção sete dias após este treino. O terceiro grupo - chamado choque imediato - recebeu uma sessão de treinamento com um único choque aplicado imediatamente depois de entrar na caixa de condicionamento e seguiu o mesmo protocolo de extinção que o grupo de extinção múltipla. A resposta de congelamento foi o parâmetro comportamental analisado. Informações sobre sono-vigília foram registradas através da coleta de dados de ECOG e EMG e classificado entre três fases: vigília, sono de ondas lentas e sono paradoxal. Os resultados mostraram aumento do sono de ondas lentas após CMC e aumento do sono paradoxal depois de CMC e extinção entre os grupos T-múltipla e T-única. Nossas descobertas apoiam achados anteriores sobre a relação entre sono paradoxal e aprendizagem da extinção e sugerem que modificações de sono de ondas lentas para extinção antecipada sejam dependentes do tempo. / Extinction memory is a product of variations in fear conditioning and fear extinction procedure and the amount of time and sessions of extinction. Increases in paradoxical sleep (PS) after exposure to extinction sessions was previously described; however, previous works did not test more than one day of extinction and did not test whether sleep modifications after extinction are dependent upon the time interval between conditioning and extinction. We explored sleep architecture modifications on different conditions of conditioned fear extinction learning. We first adapted a contextual fear-conditioning task in order to explore the effect of an aversive event (the electric shock) and a possible effect of time interval between conditioning and extinction session on sleep and behaviour. The first group, named Multiple Extinction (T-10 Multiple) received a contextual fear conditioning (CFC) training with a single shock presentation followed by five sessions of extinction. The second group, named single extinction (T-Single), was trained in the same CFC procedure and exposed to one single extinction session, seven days after training. The third group ¿ named immediate shock ¿ received a training 1session with a single shock applied immediately after entering the conditioning box following the same protocol of extinction as the T-Multiple group. The freezing response was the behavioural parameter analysed. Sleep-wake information was recorded by collecting electrocorticogram (ECOG) and electromyogram (EMG) data and scored as one between three phases: awake, slow wave sleep (SWS) and PS. Results showed that SWS increased after CFC, and it also showed that PS increased after CFC and extinction for either T-Multiple and T- Single group. Our findings support previous findings on PS relation with extinction learning and suggest some time-dependent SWS modification for early extinction re-exposure. The discovery of the participation of PS in contextual fear extinction and SWS role on nuances of extinction procedure expands the understanding of behaviour and sleep relations and, at the same time, offer a behavioural model to study sleep dependent stressful memory related to PTSD or HPA axis without the unconditioned behavioural and physiological effects of ES.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / Polyamines, such as spermidine and spermine, have been reported to improve memory retention through the activation of N-methyl-D-aspartate receptors (NMDAr). However whether polyamine agonists and antagonists alter extinction remains unclear. In the current study, we investigated whether spermidine and polyamine antagonists that selectively block the NR2B subunit at the NMDAr alter the extinction of contextual conditioned fear in male Wistar rats. While the bilateral intrahippocampal administration of exogenous spermidine (2 nmol/site) facilitated the extinction of fear conditioning, the injection of the antagonists arcaine (0.2 nmol/site), ifenprodil (20 nmol/site) and traxoprodil (0.2 nmol/site), disrupted fear extinction. NMDAr antagonists, at doses that had no effect per se, reversed the facilitatory effect of spermidine on fear extinction. These results suggest that exogenous and endogenous polyamines facilitate the extinction of contextual conditioned fear through activation of NR2B subunit-containing NMDAr in the hippocampus. Since extinction-based exposure therapy is widely used as treatment for a number of anxiety-related disorders, including phobias and post-traumatic stress, the currently reported facilitation of extinction by polyaminergic agents suggest these compounds as putative candidates for drug development. / As poliaminas, como espermidina e espermina, são aminas alifáticas que estão presentes no sistema nervoso central e que se ligam na subunidade NR2B do receptor N-metil-D-aspartato (rNMDA). Tem-se demonstrado que a administração sistêmica, intrahipocampal e intraamígdala de poliaminas melhoram a aquisição e retenção da memória em ratos. Entretanto, seu efeito sobre a extinção do medo condicionado não foi investigado. No presente estudo, investigamos se a administração intrahipocampal de espermidina e de antagonistas seletivos para a subunidade NR2B do rNMDA alteram a extinção do medo condicionado contextual em ratos Wistar machos. A administração intrahipocampal de espermidina (2 nmol/sítio) facilitou a extinção do medo condicionado, enquanto que a injeção dos antagonistas do rNMDA, arcaína (0,2 nmol/sítio), ifenprodil (20 nmol/sítio) e traxoprodil (0,2 nmol/sítio), bloquearam a extinção do medo condicionado contextual. Já a administração dos antagonistas do rNMDA, em doses sem efeito per se, reverteu a facilitação da extinção induzida por espermidina. Estes resultados sugerem que as poliaminas facilitam a extinção do medo condicionado contextual através da ativação da subunidade NR2B do rNMDA hipocampal. Tendo em vista que a terapia baseada em exposição é um método amplamente utilizado como tratamento para diversos tipos de distúrbios relacionados com ansiedade, incluindo fobias e estresse pós-traumático, a facilitação da extinção causada pela administração de espermidina coloca este composto com um possível candidato para o desenvolvimento de novos fármacos para o tratamento destas patologias.

No description available.

Insomnia is one of the most common health issues, with occasional symptoms affecting up to 50% of the general population. Lack of sleep is associated with many negative health effects. A new evolutionary hypothesis has been proposed to explain the mechanism behind insomnia symptoms. The evolutionary-emotional hypothesis proposes that while acute insomnia might be advantageous from an evolutionary perspective, chronic insomnia is maladaptive and may follow from a failure or delay of fear extinction. The aim of the current thesis was to investigate which neural mechanisms might be at work if one is to consider the evolutionaryemotional hypothesis about the causes of insomnia plausible and to review studies from cognitive neuroscience to discover what support there might be for the hypothesis. Studies have found heightened activation in fear-related brain areas in insomnia patients. Delayed fear extinction and altered emotion regulation circuitry, among other things, were also observed for insomnia patients. However, few experimental studies on the effect of fear extinction on sleep in insomnia patients have been conducted. At this time, some emerging evidence lends support for the evolutionary-emotional hypothesis of insomnia, but more studies that directly assess fear conditioning and fear extinction processes in insomnia patients are needed to assess the explanatory power of the theory.

Classical fear conditioning – including acquisition and extinction – is a model for fear learning and memory in health and disease. Moreover, trauma-related disorders can be viewed as comprising fear acquisition under severe stress. Yet, in humans, we know comparatively little about how acute stress affects fear conditioning. Therefore, the first aim of this thesis was to investigate the effect of stress on fear acquisition or extinction. Stress induces multiple hormonal and neurotransmitter changes dynamically developing over time, including a fast first-wave and a slower second-wave stress response. Models derived from avoidance learning and declarative memory studies suggest that stress effects on memory depend on the temporal proximity between learning and stressor: encoding close to the stressor will be enhanced, but encoding and recall later in time (during the second-wave) will be suppressed (e.g., Schwabe, Joëls, Roozendaal, Wolf, & Oitzl, 2012). So far, these predictions were not related to fear conditioning. Therefore, we investigated if the model-based predictions are also valid in human fear conditioning. We used two stressors to investigate first-wave and second-wave stress effects: the cold pressor test (CPT) inducing a strong first-wave but little second-wave activation and a psychosocial stressor, reliably inducing both, first- and second-wave stress responses. Conditioning was measured via skin conductance responses (SCRs). Investigating the first-wave (Experiment 2), we placed fear acquisition and immediate extinction directly after the CPT (n = 20) or after the control treatment (n = 20). We found no group difference in acquisition performance, but significantly increased extinction resistance in the stressed CPT group. In Experiment 3, CPT (n = 20) or control (n = 20) was placed after acquisition but directly prior to extinction training. Here, we found improved extinction and 24h-delayed extinction recall after CPT. Investigating the second-wave (Experiment 1), we placed fear acquisition and immediate extinction 45 min after the psychosocial stressor (i.e., at the peak of salivary cortisol, n = 12) or after control (n = 12). Here, we found no significant stress effects. Sex and female sex hormones also influence fear conditioning: Women are at a higher risk to develop anxiety and stressor-related disorders than men. Interestingly, patients with these disorders show impaired fear extinction and extinction recall, and low levels of the sex hormone 17β-estradiol (E2) are linked to impaired extinction in both, healthy and patient female samples. So far, there is little data on how acute stress and circulating E2-levels might interact in fear acquisition and especially in fear extinction. Therefore, the second aim of this thesis was to explore this possible interaction in healthy women in different cycle phases compared to men. Thus, in Experiment 4, we included hormone status as a quasi-experimental variable and compared free cycling women in the midcycle phase (high E2, low progesterone, n = 24), women in the early follicular phase of the menstrual cycle (low E2, low progesterone, n = 24), and men (n = 24). We placed fear acquisition and extinction 45 min after the psychosocial stressor (n = 36) or control (n = 36), and tested extinction recall after 24 h. In line with Experiment 1, the second-wave stressor did not affect fear acquisition and immediate extinction. However, we found a stress by hormone status interaction within women at the 24h-delayed extinction recall test: in the stressed group, early follicular women showed impaired extinction recall and a higher return of fear compared to midcycle women, whereas there was no difference between early follicular and midcycle women after control treatment. Collectively our results support a different role for the first- and second-wave stress response in human fear conditioning. Fear acquisition near the first-wave stress response results in enhanced fear memory, which is resistant to extinction. Extinction training near the first-wave enhances extinction learning. In contrast, fear conditioning at the peak of the peripheral second-wave cortisol response had no effect on acquisition or extinction performance. However, second-wave stress interacted with the hormone status of women, where only women in a low E2 state were vulnerable to negative stress effects in extinction recall. The last result will encourage further investigation of the interplay between E2 and stress in fear extinction. Enhancement of extinction by the CPT could – if replicated – be translated into strategies for optimizing exposure therapy.

Après un évènement potentiellement traumatique, si pour la plupart des individus les symptômes associés disparaissent rapidement, pour d’autres ils persistent. On parle alors d’état de stress post-traumatique. L’une des prises en charge les plus efficaces, basée sur le modèle de l’extinction de la peur conditionnée, est l’exposition répétée au souvenir traumatique. Cependant, tout comme pour la peur conditionnée qui peut réapparaître après son extinction, les symptômes psychotraumatiques peuvent également resurgir quelques temps après leur réduction ou leur élimination. L’objectif de cette thèse, à l’interface entre recherche fondamentale et clinique, est d’établir des liens entre le fonctionnement du cortex préfrontal ventromédian et la prédiction et la prévention du retour de la peur éteinte.Nos études chez le rat ont ainsi montré un rôle protecteur de la stimulation à haute fréquence du cortex préfrontal ventromédian sur le retour de la peur. Nos travaux chez l’humain, avec ou sans symptôme, ont permis d’identifier un certain nombre de prédicteurs physiologiques, cognitifs, cliniques et sociodémographiques de ce retour de la peur.Nous avons également pu déterminer des différences interindividuelles et ainsi caractériser des profils psychologiques plus qualitatifs. Sur le plan fondamental, nous avons pu mettre en évidence différentes conditions d’implication du cortex préfrontal ventromédian dans le rappel de la mémoire de l’extinction de la peur. Du point de vue clinique, nous proposons une base pour le développement d’outils visant à détecter les individus prédisposés à un déficit de rappel de cette mémoire, autrement dit, à la rechute psychotraumatique. / Consequences of a potentially traumatic event may be different depending on the person affected. While most of the people will recover after the event, others will develop a post-traumatic stress disorder (PTSD). Exposure therapy is one of the best treatments of this disorder and is based on fear extinction training. However, both conditioned fear response and psychotraumatic symptoms may appear again some time after the end of the therapy. Combining fundamental and clinical research, this thesis is aimed at investigating how activity of the ventromedial prefrontal cortex may be related to indicators of prediction and prevention of the return of fear. A consequent objective is to highlight some new possibilities to prevent relapse.Our rat experiments showed that high frequency stimulation of the ventromedial prefrontal cortex reduces the likelihood of return of fear responses. Our experiments with human, with or without post-traumatic stress disorder symptoms, revealed several physiological, cognitive, clinical and socio-demographic predictors.Moreover, we found interpersonal differences that allowed us to characterize qualitative profiles.To sum up, our work demonstrates that the ventromedial prefrontal cortex is involved in multiple ways in the recall of fear extinction. From a clinical perspective, our findings provide suggestions for an innovative development of tools capable to detect individual tendencies to have some deficit in fear extinction recall. This study has, thus, important implications in improving prevention of relapse in post-traumatic stress disorder.

La plasticité cérébrale est régulée de façon dynamique au cours d’une vie : atteignant des sommets au cours de l’enfance, elle est réduite chez l’adulte. Toutefois, des circonstances particulières appellent à vouloir stimuler la malléabilité du cerveau adulte : pour favoriser la réhabilitation suite à un accident vasculaire cérébral ou un traumatisme crânien, pour aider l’adaptation spécifique nécessaire pour vivre avec une nouvelle prothèse ou encore pour améliorer l’efficacité de la thérapie cognitivo-comportementale suite à un traumatisme émotionnel qui a laissé un souvenir de peur qui s’est développé en syndrome de choc post-traumatique. Toutes ces situations demandent des capacités d’adaptation et une flexibilité exceptionnelles au système nerveux central. Or, pour retrouver une plasticité cérébrale telle qu’au niveau juvénile, la littérature nous apprend qu’il faut diminuer la puissance inhibitrice générée par un type d’interneurones particuliers, ceux exprimant la parvalbumine (PV+). Les fonctions des interneurones PV+ dépendent autant de leur patron de connectivité que de l’environnement extracellulaire dans lequel ils évoluent. En effet, en innervant des centaines de neurones cibles, délivrant une forte inhibition périsomatique en formant de multiples synapses autour de leur corps cellulaire et de leurs dendrites proximales, ils ont été impliqués dans l’intégration synaptique des neurones pyramidaux et dans la synchronisation des circuits corticaux. Toute manipulation ciblant cette arborescence axonale complexe pourrait s’avérer efficace à l’augmentation de la plasticité cérébrale en diminuant l’inhibition qu’elle génère. Ainsi, comprendre la signalisation moléculaire restreignant la croissance de l’arborescence axonale et la formation de boutons fonctionnels au cours de la longue phase développementale qui caractérise les interneurones PV+ aiderait à identifier des méthodes efficaces afin d’activer cette signalisation moléculaire chez l’adulte. De plus, comprendre les régulations épigénétiques liées au développement et à la maturation structurelle et fonctionnelle des interneurones PV+ offrirait une cible de choix afin de dématurer ces circuits inhibiteurs et lever un frein sur la plasticité cérébrale adulte. Nous démontrons ici que l’expression du récepteur des neurotrophines p75NTR chez les interneurones PV+ au cours de leur développement restreint la maturation de leur arborescence axonale, autant in vitro que in vivo, ainsi que l’agglomération des filets périneuronaux, autour de leur corps cellulaire. Aussi, en utilisant une version modifiée du test de ligation de proximité, nous avons résolu une controverse et démontré que le récepteur est toujours exprimé chez les interneurones PV+ du cortex adulte. Enfin, l’activation de la signalisation via p75NTR des interneurones PV+ par son ligand proBDNF est suffisante pour déstabiliser leur connectivité et restaurer la plasticité du cortex visuel suite à une privation monoculaire. Également, l’inactivation d’un régulateur épigénétique, l’histone déacétylase Hdac2, spécifiquement chez les interneurones PV+ suffit à diminuer leur connectivité efférente ainsi que l’agglomération des filets périneuronaux autour de leurs corps cellulaire tout en augmentant la rétention de l’extinction des souvenirs de peur, témoignant d’une augmentation de la plasticité cérébrale adulte. Par le séquençage d’ARNm en cellule unique, suivi de l’hybridation in situ RNAscope, nous avons identifié le gène Acan, codant pour aggrécane, une composante protéique des filets périneuronaux, comme étant exprimé de façon autonome à la cellule par les interneurones PV+ du cortex préfrontal adulte. Enfin, nous avons démontré qu’une seule injection d’un nouvel inhibiteur spécifique pour Hdac2 avant le paradigme d’extinction suffit à augmenter la rétention des souvenirs d’extinction chez l’adulte, tout en réduisant l’expression de Acan et l’agglomération des filets périneuronaux dans le cortex préfrontal. En somme, nos travaux ont montré que le remodelage des circuits des interneurones PV+ en ciblant soit le récepteur p75NTR, soit l’histone déacétylase Hdac2, peut efficacement augmenter la plasticité cérébrale chez l’adulte. / Brain plasticity is dynamically regulated during a lifespan: it reaches a peak during juvenile age and decreases in adulthood. However, exceptional circumstances can drive the need to foster adult brain plasticity: to help rehabilitation after a stroke or a head trauma, to increase the adaptability of an individual facing a new life with a prosthetic, to improve the efficiency of cognitive behavioral therapy to cope with the indelible fear memory trace created by an emotional trauma. All these situations require exceptional adaptation capabilities and cognitive flexibility. Several studies have suggested that reducing inhibitory drive, in particular of a specific GABAergic interneuron population, the parvalbumin-expressing interneurons (PV+), could be an effective approach to recover juvenile brain plasticity, thereby increasing adult brain plasticity. PV+ interneuron functions depend on their axonal connectivity pattern as well as their specific extracellular environment. Indeed, by contacting hundreds of postsynaptic neurons and delivering a strong perisomatic inhibitory drive by forming multiple synapses on their somata and proximal dendrites, PV+ interneurons strongly regulate pyramidal cell synaptic integration and cortical circuit synchronisation. PV+ interneuron maturation is a prolonged process, which reaches plateau only after the end of adolescence, and correlates with the decline of developmentally regulated- brain plasticity. We hypothesize that manipulations specifically targeting PV+ interneuron highly complex axonal arborisation, and thus reducing their inhibitory drive, could be efficient tools to foster adult brain plasticity. Understanding the molecular signalling that restricts PV+ cell axonal arborisation growth and the formation of functional presynaptic boutons during their long developmental phase may help identifying efficient methods to activate this molecular pathway, thus reducing PV+ interneuron connectivity, in adults. In addition, understanding the epigenetic regulation of structural and functional maturation of PV+ interneurons may offer a choice target to dematurate these inhibitory circuits and lift a brake on adult brain plasticity. Here, we demonstrate that the expression levels of neurotrophin receptor p75NTR during PV+ interneurons development constrain the maturation of their connectivity as well as the perineuronal net agglomeration around their cell bodies in a cell-autonomous fashion, both in vitro and in vivo. Also, by using a modified version of the proximity ligand assay, we solve a long-standing debate by demonstrating p75NTR expression in PV+ interneurons in adult cortex. Finally, we show that promoting p75NTR signalisation in PV+ cortical interneurons by its ligand proBDNF is sufficient to destabilize their connectivity and restore cortical plasticity following monocular deprivation in the adult visual cortex. We further show that the deletion of the epigenetic regulator histone deacetylase 2 (Hdac2), specifically in PV+ interneurons, is sufficient to decrease their efferent connectivity and perineuronal net agglomeration around their cell bodies, while increasing fear extinction retention, a measure of brain plasticity. By single-cell RNA sequencing, followed by RNAscope in situ hybridization, we found that the Acan gene, which encodes for aggrecan, a critical perineuronal net protein component, is expressed cell-autonomously by PV+ interneurons in adult prefrontal cortex. Finally, we showed that a single injection of a novel Hdac2 specific inhibitor before extinction training is sufficient to increase fear extinction retention in adults, while reducing Acan expression and perineuronal net agglomeration in prefrontal cortex. In summary, our work shows that increasing remodeling of PV+ interneuron circuits by targeting either p75NTR receptor or histone deacetylase Hdac2 efficiently foster adult brain plasticity.

Le fonctionnement du cortex cérébral nécessite l'action coordonnée de deux principaux types de neurones : les cellules principales excitatrices glutamatergiques (PC) (∼80%) et les interneurones inhibiteurs GABAergiques (IN) (∼20%). Le sous-type le plus courant d'interneurones (IN) GABAergiques, les IN exprimant la parvalbumine (Pv+), innervent le soma et les dendrites proximales d'environ 100 PC voisins. Ainsi, ils délivrent une forte impulsion inhibitrice périsomatique et, à ce titre, jouent un rôle essentiel dans l'intégration synaptique et la synchronisation des circuits corticaux. La maturation des Pv+ IN est un processus prolongé, qui n'atteint un plateau qu'après la fin de l'adolescence. Des altérations de la connectivité et de la fonction des Pv+ IN au cours du développement, en particulier dans le cortex préfrontal (PFC), ont été systématiquement signalées dans plusieurs troubles psychiatriques associés à la rigidité cognitive, ce qui suggère que des déficits des Pv+ IN pourraient être un phénotype cellulaire central de ces troubles. Une autre classe d’IN majeure est constituée par les IN exprimant la somatostatine (Sst+). Malgré des origines neurodéveloppementales similaires, les IN Sst+ présentent une morphologie et une physiologie distinctes des IN Pv+. Les IN Sst+ ciblent les dendrites apicales des PC, modulant ainsi directement les entrées excitatrices sous-jacentes aux différentes fonctions corticales. Comme pour les IN Pv+, le dysfonctionnement des IN Sst+ a été associé aux NDD. Ici, nous étudions les mécanismes moléculaires sous-jacents à la maturation de ces circuits d’IN et comment les altérations de ces mécanismes affectent la fonction corticale. Nous avons précédemment montré que la réductionde l'expression du récepteur de la neurotrophine p75 (p75NTR) par les Pv+ IN au cours du premier mois postnatal régule l'évolution temporelle de leur maturation morphologique cellulaire de façon autonome. Toutefois, il restait à déterminer si l'expression de p75NTR au cours du développement postnatal a un effet à long terme sur la connectivité des cellules Pv+ et la fonction cognitive dans le PFC. En utilisant des stratégies de knock-out conditionnel et virales, nous avons montré que l'expression de p75NTR dans les IN Pv+ du cerveau adolescent contribue à l'établissement de leurs connections afférentes et de leur plasticité dans le PFC. De plus, la délétion postnatale de p75NTR spécifiquement aux cellules Pv+ entraîne 1) une augmentation de la production efférente sur les PC, 2) une augmentation de l'agglomération des PNN autour de leurs corps cellulaires dans le PFC adulte, 3) une altération de l'engagement des cellules Pv+ dans le circuit préfrontal suite à des stimuli sensoriels et 4) une altération des oscillations γ et de la rigidité cognitive chez la souris adulte. Un autre facteur moléculaire qui joue un rôle important dans la connectivité et la fonction des IN est la cadhérine-13 (Cdh13). Cdh13 est un membre unique ancré au glycosylphosphatidylinositol de la famille des cadhérines qui est exprimé à la fois par les IN Pv+ et Sst+ et régule la transmission inhibitrice basale dans l'hippocampe. Cdh13 est un gène à risque pour les NDD ; cependant, le mécanisme par lequel Cdh13 affecte la fonction et la cognition au niveau du réseau cortical et la pathogenèse de ces troubles reste insaisissable. Nous avons utilisé la transcriptomique unicellulaire et montré que l'ARNm de Cdh13 est sélectivement enrichi en Sst+ IN corticaux chez les souris juvéniles. Nous avons ensuite analysé le patrond'expression de Cdh13 dans les IN Pv+ et Sst+ à l'aide de l’hybridation in situ de type RNAscope et avons constaté que les deux types cellulaires expriment Cdh13 à des niveaux différents. Enfin, nous avons généré des modèles de souris knock- out conditionnels SstcKO (Sst_Cre+/-; Cdh13loxP/loxP) et Pv-cKO (PV_Cre+/-; Cdh13loxP/ loxP) et effectué des enregistrements intracorticaux in vivo à partir de souris éveillées. Nous avons identifié des altérations significatives dans le traitement auditif, spécifiquement chez les souris SstcKO. Ainsi, Cdh13 joue un rôle critique et spécifique dans la fonction IN Sst+. En résumé, la compréhension des mécanismes cellulaires et moléculaires régissant le bon développement et la maturation des circuits inhibiteurs met en lumière les mécanismes par lesquels l'inhibition GABAergique contribue aux opérations du réseau cortical et à la fonction cognitive. Ces études indiquent en outre des substrats subcellulaires, potentiellement affectés dans les NDD et les troubles neuropsychiatriques et ouvrent la voie à des stratégies de diagnostic et de traitement plus efficaces. / The proper functioning of the cerebral cortex requires the coordinated action of two main types of neurons: the principal excitatory glutamatergic cells (PCs) (∼80%) and the GABAergic inhibitory interneurons (INs) (∼20%). The most common subtype of GABAergic INs, the parvalbumin-expressing (Pv+) INs, innervate the soma and proximal dendrites of around 100 neighboring PCs. Thus, they deliver a strong perisomatic inhibitory drive and, as such, play an essential role in synaptic integration and cortical circuit synchronization. Pv+ INs maturation is a prolonged process, which reaches a plateau only after the end of adolescence. Alterations in Pv+ INs connectivity and function during development, especially in the prefrontal cortex (PFC), have been consistently reported in several psychiatric disorders associated with cognitive rigidity, suggesting that Pv+ INs deficits may be a core cellular phenotype in these disorders. Another major IN class, not overlapping with Pv+ cells, is constituted by somatostatin-expressing (Sst+) INs. Despite sharing similar neurodevelopmental origins, Sst+ INs exhibit distinct morphology and physiology from Pv+ INs. Sst+ INs target apical dendrites of PCs, thus directly modulating excitatory inputs underlying different cortical functions. Like Pv+ INs, the dysfunction of Sst+ INs has been associated with NDDs. Here, we investigate the molecular mechanisms underlying the maturation of these INs circuits and how alterations of these mechanisms affect cortical function. We have previously shown that the downregulation of the p75 neurotrophin receptor (p75NTR) expression in Pv+INs during the first postnatal month regulates the time course of their morphological maturation in a cell-autonomous fashion. Whether p75NTR expression during postnatal development has a long-term effect on Pv+ cell connectivity and cognitive function in the PFC is unknown. Using conditional knock-out and viral strategies, we showed that p75NTR expression in adolescent Pv+ INs contributes to the establishment of their output and plasticity in the PFC. In addition, Pv cell-specific postnatal deletion of p75NTR leads to 1) increased efferent output onto PCs, 2) increased perineuronal net (PNN) agglomeration around their somata in adult PFC, 3) altered Pv+ cell engagement in the prefrontal circuit following sensory stimuli and 4) altered γ oscillations and cognitive rigidity in adult mice. Another molecular factor that plays a significant role in the connectivity and function of INs is Cadherin-13 (Cdh13). Cdh13 is a unique glycosylphosphatidylinositol-anchored member of the cadherin family that is expressed by both Pv+ and Sst+ INs and regulates basal inhibitory transmission in the hippocampus. Cdh13 is a risk gene for NDDs; however, the mechanism whereby Cdh13 affects cortical network function and cognition and how its dysfunction influences the pathogenesis of these disorders remains elusive. We used single-cell transcriptomics and showed that Cdh13 mRNA is selectively enriched in juvenile mice's cortical Sst+ INs. We then analyzed the expression pattern of Cdh13 in cPv+ and cSst+ INs using RNAscope and found that both cell types express Cdh13 at different levels. Finally, we generated conditional knock-out mice models (Sst_Cre+/-; Cdh13loxP/loxP; Sst-cKO and Pv_Cre+/-; Cdh13 loxP/loxP; Pv-cKO mice) and performed in vivo intracortical recording from awake mice. This approach identified significant alterations in auditory processing, specifically in Sst-cKO mice. Thus, Cdh13 plays a critical and specific role in the Sst+ INs function. In summary, understanding the cellular and molecular rules governing proper inhibitory circuitry development and maturation shed light on the mechanisms by which GABAergic inhibition contributes to cortical network operations and cognitive function. These studies further indicate subcellular substrates, potentially affected in NDDs and neuropsychiatric disorders and pave the road for more effective diagnosis and treatment strategies.