The anterior thalamic nuclei (ATN) are a critical part of an extended hippocampal system that supports key elements of episodic memory. Damage or disconnection of the ATN is a component of clinical conditions associated with severe anterograde amnesisa such as the Korsakoff’s syndrome, thalamic stroke, and neurodegenerative disorders. Previous studies have demonstrated that the ATN and hippocampus are often interdependent, and that ATN damage can result in ‘covert pathology’ in ostensibly healthy distal regions of the extended hippocampal system. Adult male rats with neurotoxic bilateral ATN lesions or sham surgery were post-operatively housed in an enriched environment or standard housing after a lesion-induced spatial working memory deficit had been established. These rats were retested on cross-maze and then trained in radial-arm maze spatial memory tasks. Other enriched rats received pseudo-training only after the enrichment period. The detailed neuromorphology of neurons was subsequently examined in the hippocampal CA1. Soma characteristics were also examined in the retrosplenial granular b cortex and the prelimbic cortex. In Experiment 1, ATN lesions produced clear deficits in both the cross-maze and radial-arm maze tasks and reduced hippocampal CA1 dendritic complexity, length, and spine density, while increasing the average diameter of the dendrites. Post-operative enrichment reversed the ATN lesion-induced deficits in the cross-maze and radial-arm maze, and returned CA1 basal and apical spine density to a level comparable to that of sham standard housed trained rats. The sham enriched rats exhibited improved radial-arm maze performance and increased CA1 branching complexity and spine density in both basal and apical arbors compared to sham standard housed rats. The neuromorphological changes observed in the enriched ATN and sham rats may be in part responsible for the spatial working memory improvements observed. Experiment 2 provided support for this contention by demonstrating that the CA1 spine changes were explicitly relevant to spatial learning and memory, because trained enriched sham and ATN rats had increased spines, particularly in the basal tree when compared to closely comparable pseudo-trained enriched rats. Interestingly, spatial memory training increased the numbers of both thin and mushroom spines, whereas enrichment was only associated with an increase in thin spines. In Experiment 3, ATN lesions increased cell body size in layer II of the retrosplenial granular b cortex, whereas enrichment decreased cell body size in layer V of this region. Neither ATN lesions nor enrichment had any effect on cell body morphology in the prelimbic cortex. The current research provides some of the strongest evidence to date of ATN and hippocampal interdependence within the extended hippocampal system, and provides the first evidence of neuromorphological correlates of recovery after ATN lesions.

: Mon travail de thèse a porté sur l’étude neurocomportementale des actions et des habitudes chez le Rat. En effet, lors d’un apprentissage opérant la réponse peut être acquise selon deux systèmes associatifs. Le premier dépend d’une représentation des conséquences de la réponse, le second d’une association plus « simple » entre le stimulus et la réponse. Un premier axe de recherche a consisté à étudier plusieurs paramètres du conditionnement, afin de déterminer leur influence sur le contrôle de la réponse instrumentale par un système plutôt que l’autre. Le deuxième axe de recherche a porté sur l’étude des substrats neuronaux impliqués dans l’acquisition et l’expression d’une action, par l’intermédiaire de techniques d’inactivation cérébrale et d’étude immuno-histochimique de l’expression génique de la protéine Fos. / Previous research has established that instrumental conditioning, in both primates and rats, is mediated by two concurrent associative systems. In early stages of training, instrumental response is thought to be mediated by an association between the action and the outcome (A-O). While training proceeds however, as the response becomes less sensible to the outcome value, it is conceived as being mediated by an association between thestimulus and the response (S-R). Recent evidences suggest that the both systems operate in tandem and/or competition from the beginning of training. This work aimed at studying the mechanisms that coordinate the control of the instrumental response by the goal-directedsystem or the habit system. A first batch of results indicates no effect of the amount of training sessions on the goal-directed nature of the conditioned instrumental response. Indeed,the outcome devaluations by CTA or selective satiety reduced the instrumental performances,independently of the training procedure applied. The instrumental responses resulting from our 3 training procedures depend of an actualized representation of their outcomes. A secondbatch of results indicates that information about the context of instrumental conditioning isincluded in the incentive representation of the outcome. Indeed, we observed no sensitivity tooutcome devaluation when devaluation occurred outside the training context. These results offer new original hypotheses about context encoding and the nature of instrumental responding. A third batch of experiments investigates the role of the prelimbic cortex in acquisition vs. expression of goal-directed instrumental behaviour, using reversible neuronal inactivation. The results show that the prelimbic cortex plays a transient but crucial role in theacquisition of goal-directed responding and that the A-O and S-R systems can operate in a competitive fashion early in training. Using ex-vivo imaging, a last batch of experiments aimed to study the temporal cerebral activation throughout instrumental training with a focuson prefrontal and striatal regions. Results show levels of Fos expression that vary with regions. At the beginning of conditioning, the density of Fos positive nuclei is high in the prefrontal regions. It decreases with training. Labelling is denser in the dorsomedial striatumthan in the dorsolateral striatum. The weak activation in the dorsolateral striatum appears consistent with the absence of habit. These data are in accordance with data of the literature concerning dynamics of activation in cortico-striatal circuits. Furthermore, they are in agreement with the suggestion that activity in the prelimbic cortex could promote the acquisition of goal-directed action by the induction of neuronal plasticity in the dorsal striatum.

Le cortex préfrontal médian (mPFC) est nécessaire pour la formation desreprésentations contextuelles et l’expression de la mémoire suite au conditionnementde peur. Des études récentes ont montré des changements dépendants del’apprentissage dans l’excitabilité intrinsèque des neurones du mPFC. Il n’estcependant pas établit, si ces changements se font à l’échelle régionale ou s’ils sontspécifiques du type neuronal. La connectivité spécifique et les propriétés intrinsèquesde différents types neuronaux pourraient entrainer certaines populations neuronales àêtre préférentiellement impliquées dans le traitement de l’information au cours d’unetâche d’apprentissage. Dans ce projet, nous avons étudié cette hypothèse par l’étudede la plasticité de l’excitabilité intrinsèque dans la partie prélimbique (PL) du mPFCdans deux groupes neuronaux bien définis : ceux projetant vers l’amygdaleipsilatérale et ceux projetant vers le mPFC controlatéral. Nous avons utilisé à la fois leconditionnement à la peur contextuelle, un traçage rétrograde, et des enregistrementsélectrophysiologiques en cellule entière des neurones pyramidaux marqués chez lessouris mâles C57bl/6J adultes âgées de 2 à 3 mois. Nous montrons que l’excitabilitédes neurones projetant vers l’amygdale présentent des changements dépendants del’apprentissage, suite au conditionnement de peur contextuelle. En revanche,l’excitabilité des neurones projetant vers le mPFC controlatéral ne présente pas dedifférence entre les animaux entrainés et témoins. Ensemble, ces résultats indiquentque les changements induits par l’apprentissage dans l’excitabilité intrinsèque ne sontpas généralisés à tous les neurones du PL mais sont par contre définis par les ciblesdes neurones qui projettent sur de longues distances. / The medial prefrontal cortex (mPFC) is necessary for the formation of contextualrepresentations and memory expression following fear conditioning. Recent studieshave shown learning-dependent changes in the intrinsic excitability of mPFC neurons.It is not clear, however, whether these changes are region-wide or neuron-typespecific. The specific connectivity and intrinsic properties of different neuronal typescould cause certain neuronal populations to be preferentially involved in informationprocessing in a learning paradigm. In this project, we investigated this hypothesis bystudying the plasticity of intrinsic excitability in the prelimbic (PL) part of the mPFCin two defined neuronal groups: those projecting to the ipsilateral amygdala and thoseprojecting to the contralateral mPFC. We used contextual fear conditioning togetherwith retrograde tracing and whole-cell electrophysiological recordings of labelledpyramidal neurons in adult 2-3 month old male C56BL/6J mice. We show thatneurons projecting to the amygdala display learning-dependent changes in neuronalexcitability following contextual fear conditioning. In contrast, the excitability ofneurons projecting to the contralateral mPFC does not differ between trained andcontrol animals. Together, these results indicate that learning-induced changes inintrinsic excitability are not generalised across all PL neurons but instead are definedby the neurons’ long-range projection targets.

A dor crônica (DC) é um problema global de saúde. A incidência da DC no mundo oscila entre 7 e 40% da população e, como consequência da mesma, cerca de 50 a 60% dos que sofrem dela ficam parcial ou totalmente incapacitados, de maneira transitória ou permanente, comprometendo de modo significativo a qualidade de vida. Sabe-se que a divisão pré-límbica (PrL) do córtex pré-frontal medial (CPFM) é uma região importante na elaboração da dor e de seus aspectos cognitivos e emocionais. Há evidências que a DC de origem neuropática (DN) é capaz de provocar mudanças morfológicas, resultando em uma reorganização nas redes neurais do CPFM, e existe alta relação de comorbidade entre ansiedade e DC. Sendo assim, necessita-se de estudos que forneçam aprimoramento dos modelos animais em DC para que, assim, investiguem-se as bases neuroanatômicas, neurofisiológicas e psicofarmacológicas da DN e a participação de áreas corticais na gênese e manutenção da dor. Para isso, o presente trabalho foi dividido em três etapas: 1) Avaliação dos aspectos nociceptivos, motores e afetivo-cognitivos de ratos submetidos a um modelo adaptado de injúria por constrição crônica do nervo isquiático (CCI: uma ligadura) comparando com o modelo clássico de Bennett e Xie (CCI: quatro ligaduras): nossos resultados mostraram que o modelo adaptado de CCI produziu hipersensibilidade ao frio (teste de acetona) e alodinia mecânica (teste de von Frey) semelhante ao causado pelo modelo de CCI com quatro ligaduras. Ambos os grupos CCI apresentaram comportamento do tipo ansioso, depressivo e déficits cognitivos, utilizando-se o modelo de campo aberto (open field), teste de nado forçado e teste de reconhecimento de objeto, respectivamente. Contudo, o modelo adaptado pode ser uma melhor opção, visto que uma simples ligadura não provoca prejuízos motores, nem tampouco o comportamento de autotomia, diferentemente dos animais com CCI em que foram realizadas 4 ligaduras. 2) A - Estudo do efeito da Indometacina (2mg/kg), um antiinflamatório não-esteroidal, administrada por via periférica (IP) sobre a DN: a indometacina diminuiu a alodinia mecânica no primeiro, segundo e quarto dias, mas não no décimo quarto, vigésimo primeiro e vigésimo oitavo dias após a CCI adaptada (1 ligadura). Esses dados sugerem que a COX-1 e a COX-2 estão envolvidas na mediação da indução, mas não na manutenção da DN. B - Envolvimento do córtex PrL sobre a geração, potencialização e manutenção da DN, através da microinjeção local de cloreto de cobalto (CoCl2: 1mM/200nL), um bloqueador do influxo de cálcio (causando bloqueio de sinapses). O CoCl2 atenuou a alodinia mecânica no vigésimo primeiro e vigésimo oitavo, mas não no sétimo e décimo quarto dias após a CCI com 1 ligadura. Nossos dados também indicam que córtex PrL participa na elaboração da fase tardia da alodinia mecânica em nosso modelo adaptado de DN. C - Investigação do papel do sistema glutamatérgico, endocanabinoide e endovaniloide do córtex PrL sobre a alodinia mecânica 21 dias após a CCI adaptada. Os presentes resultados mostraram que a microinjeção do agonista N-metil D-Aspartato (NMDA), nas concentrações de 1 e 4 nmol, foi capaz de aumentar a alodinia mecânica durante o teste de von Frey, enquanto que um antagonista de receptores de aminoácidos excitatórios do tipo NMDA, o LY235959, diminuiu a alodinia mecânica quando microinjetado na maior dose (8nmol) no córtex PrL. O AM251, um antagonista de receptores endocanabinoides do tipo CB1, aumentou a alodinia mecânica em todas as doses (50, 100 e 200pmol) quando microinjetado no PrL. O tratamento do PrL com a menor concentração de anandamida (AEA: 5pmol) não alterou a alodinia mecânica; contudo, a administração de AEA no PrL nas doses intermediárias (de 50 e de 100pmol) reduziu a alodinia mecânica, e este efeito foi bloqueado pelo pré-tratamento do PrL com AM251 (200pmol). Digno de nota, o tratamento do PrL com a maior dose de AEA (200pmol) aumentou a alodinia mecânica, no entanto, este efeito foi atenuado pelo bloqueio prévio de receptores de potencial transitório vaniloide do tipo 1 (TRPV1), com microinjeções de 6 Iodo-nor-di-hidrocapsaicina (6-I-CPS) na dose de 3pmol no PrL. Esses dados sugerem que o córtex PrL está envolvido na potenciação e manutenção da DN crônica (DNC), através da ativação dos receptores NMDA e dos receptores TRPV1. O efeito da atenuação da alodinia mecânica foi causado pela ativação dos receptores endocanabinoides do tipo CB1 em roedores com DNC após 21 dias da CCI. 3) Investigação da comorbidade entre a DNC com ansiedade/pânico e o efeito dos agonistas e antagonistas de receptores NMDA e CB1 no PrL em roedores confrontados com serpente após 21 dias da CCI pelo método adaptado: o confronto entre roedores e serpentes constrictoras induziu nos ratos respostas relacionadas ao medo, tais como avaliação de risco, imobilidade defensiva e fuga em animais com DNC e Sham. Além disso, após terem sido confrontados com a serpente, os animais com DNC tiveram a alodinia mecânica aumentada. O pré-tratamento do PrL com NMDA (4nmol) aumentou o índice e porcentagem de avaliação de risco e a porcentagem de fuga, e a dose intermediária de NMDA (1nmol) aumentou o índice de fuga em animais neuropáticos confrontados com uma serpente constrictora. Além disso, a alodinia mecânica foi intensificada após o confronto em animais que receberam NMDA (4nmol) no PrL. Adicionalmente, os animais tratados com LY235959 diminuíram os comportamentos defensivos apresentados por animais com DNC quando confrontados com a salamanta. Além disso, esses animais pré-tratados com o antagonista de receptores NMDA tiveram seus limiares de von Frey aumentados após o confronto. O bloqueio de receptores endocanabionoides do tipo CB1, com o antagonista AM251, aumentou o comportamento de avaliação de riscos dos animais com DN crônica durante a exposição com a serpente e tiveram seus limiares de retirada de pata no teste de von Frey diminuídos após o confronto. Contudo, o pré-tratamento do PrL com AEA (100pmol) diminuiu os comportamentos defensivos de avaliação de risco, imobilidade defensiva e de fuga dos animais com DNC confrontados com a serpente, e esses animais também apresentaram aumento do limiar de retirada de pata no teste de von Frey após o confronto. Interessantemente, a dose de AEA (200pmol) não alterou comportamento defensivo, mas agravou DNC, através da diminuição do limiar de alodinia mecânica, apresentando um clássico efeito em \"U invertido\", pois menor e a maior dose de AEA (50 e 200pmol) induziram valores de comportamentos defensivo elevados, semelhante ao controle (veículo). Concluindo, os presentes dados obtidos no nosso trabalho, sugerem que o modelo adaptado de CCI, através da realização de uma ligadura do nervo isquiático, é um modelo animal eficaz para se estudarem as comorbidades entre DC e alterações cognitivas e emocionais. A diminuição da atividade das enzimas COX-1 e COX-2 atenuou a alodinia mecânica apenas durante a gênese da DN. Além disso, evidenciou-se que o córtex PrL é recrutado para elaborar a DN durante sua manutenção e potencialização. A ativação dos receptores glutamatérgicos do tipo NMDA e vaniloides do tipo TRPV1 potencializam a DNC e o sistema endocanabinoide via receptor CB1 a diminui. Finalmente, roedores com DNC tiveram seus limiares de alodinia mecânica diminuídos após o confronto com a serpente. Os comportamentos defensivos foram intensificados em animais com DNC, mostrando, assim, o estabelecimento da comorbidade entre DC e ansiedade/pânico e a participação do neocórtex na elaboração da DNC, em um modelo de neuropatia periférica induzida pela constrição crônica no nervo isquiático em ratos Wistar. A comorbidade entre ansiedade/pânico e DNC sensibiliza os animais, agravando o quadro de dor crônica. / Chronic pain (CP) is a global health problem. The incidence of CP in the world ranges from 7 to 40% of the population and, as a consequence, about 50% to 60% of those suffering from it are partially or totally incapacitated, in a transitory or permanent manner significantly compromising the quality of life. The prelimbic (PrL) division of the medial prefrontal cortex (mPFC) is an important region for the elaboration of cognitive and emotional aspects of pain. In addition, chronic neuropathic pain (CNP) can induce morphological changes, resulting in a reorganisation in the mPFC neurons. Moreover, there is an intrinsic relation between CP and anxiety disorder. Our study aims to investigate the effects of a modification of an animal model of CP and evaluate the neuroanatomical and pharmacological bases of neuropathic pain (NP). The role played by PrL cortex in the modulation of CNP was also investigated. Thus, the present work was divided into three steps: 1) Ethological analysis of nociceptive, motor and affective-cognitive aspects of rats submitted to an adapted model of chronic constriction of the ischiadicus nervus (CCI: a simple ligature) compared with the classic CCI model performed by Bennett and Xie (CCI: four ligatures): our results showed that the adapted-CCI model produced cold hypersensitivity and mechanical allodynia similar to those described in laboratory animals submitted to the model with four ligatures of the ischiadicus nervus. Both CCI groups displayed anxiety- and depression-like responses, and cognitive deficits, in the the open field test, forced swim test and object recognition test, respectively. However, the adapted model of CCI used in the present work may be a better choice, since a simple ligature of the ischiadicus nervus cause neither motor deficits, nor autotomy behaviour, unlike the animals with CCI induced by four ligatures of spinal nerves. 2) A- Effect of Indomethacin (2mg/kg) a non-steroidal anti-inflammatory drug peripherally administered (IP) on NP: The peripheral treatment with indomethacin reduced mechanical allodynia on the first, second, and fourth days, but not on the fourteenth, twenty-first, and twenty-eighth days after adapted CCI. These findings suggest that COX-1 and COX-2 are involved in the mediation of NP induction, but not in the maintainance of NP. B- Involvement of the PrL cortex on the generation, potentiation and maintenance of DN, through the microinjection of cobalt chloride (CoCl2: 1mM/200nL), a calcium influx blocker (synapse blocker): CoCl2 attenuated mechanical allodynia at twenty-first and twenty-eighth, but not at seventh and fourteenth days after CCI. Our data also indicate that PrL cortex participates in the elaboration of the chronic phase of mechanical allodynia in our adapted NP model. C- The role of the glutamatergic, endocannabinoid and endovanniloid systems of the PrL cortex on mechanical allodynia 21 days after CCI: The present data showed that microinjection of the N-methyl D-Aspartate agonist (NMDA), in a dose of 1 and 4nmol, was able to increase the mechanical allodynia threshold during mechanical stimulation by von Frey test filaments, whereas the NMDA receptors antagonist LY235959 decreased mechanical allodynia when microinjected at the highest dose (8nmol) in the PrL. The PrL cortex pretreatment with the CB1-cannabinoid receptor antagonist AM251 increased mechanical allodynia at all doses (50, 100 and 200 pmol). Microinjections of anandamide (AEA) at the smaller dose (5pmol) in PrL did not cause influence in the mechanical allodynia. However, the PrL treatment with AEA at the intermediate doses (50 and 100pmol) reduced mechanical allodynia and that effect were blocked by the pretreatment of the PrL cortex with AM251 (200pmol). Interestingly, the higher dose of AEA (200pmol) increased mechanical allodynia. Furthermore, this effect was attenuated by the PrL pretreatment with the transient potential receptor antagonist type 1 (TRPV1) ion channel selective antagonist 6 Iodonordihidrocapsaicin (6-I-CPS) in a dose of 3 pmol. These findings suggest that the PrL cortex is involved in the potentiation and maintenance of CNP through the activation of NMDA receptors and TRPV1 receptors in PrL cortex. The effect of attenuation of mechanical allodynia was caused by the activation of CB1 endocannabinoid receptors in rodents with CNP after 21 days of CCI. 3) Investigation of the comorbidity between CNP with anxiety/panic and the effect of NMDA glutamatergic and CB1 endocannabinoid receptors on PrL cortex after 21 days of CCI in rodents. The confrontation between a constrictor snake and the rodent elicited innate fear-related responses in prey, such as risk assessment, defensive immobility, and escape behaviour that were enhanced in CNP rodents and Sham. Also, after a confrontation with a potential predator, the CNP animals increased their mechanical allodynia thresholds. In adition, the microinjection of NMDA (4nmol) PrL, increased innate fear-related responses, such as risk assessment, and the treatment of PrL with NMDA at 1nmol incresed escape behaviour in rodents with CNP. The treatment of the PrL with NMDA in a dose of 4nmol increased the mechanical allodynia threshold during mechanical stimulation by von Frey test filaments, after confrontantion, whereas PrL pretreatment with LY235959 decreased innate fear-related responses, such risk assessment, defensive immobility, and escape behavior and decreased mechanical allodynia when microinjected (4 and 8nmol). The PrL Pretreatment with the CB1-cannabinoid receptor antagonist AM251 (all doses) increased unconditioned fear-related responses, such as risk assessment. Moreover, AM251 (100 and 200pmol) microinjections in the PrL increased mechanical allodynia after prey versus predator confrontation. The microinjections of AEA (100pmol) in the PrL decreased risk assessment, defensive immobility, and escape behaviour and reduced mechanical allodynia. Interestingly, the pretreatment of the PrL with the higher dose of AEA (200pmol) did not change the fear-induced behaviour elicited by predators, but increased the CNP. There was a classical inverted U-shape curve from the lower to the higher dose of AEA. These data suggest that the anxiety/panic and pain comorbidity increases CNP symptoms. The present findings also indicate that the CCI-adapted model, by ischiadicus nervus ligation with a single ligature is an effective animal model for studying comorbidities between CP and cognitive/emotional disturbances. In conclusion, we observed that nonsteroidal anti-inflammatory drugs are efficient to attenuate the mechanical allodynia only during NP genesis. The PrL cortex is recruited during the maintenance and potentiation of NP. The PrL glutamatergic system via NMDA activation and endovaniloid mechanisms related to TRPV1 ion channel activation potentiate CNP, and the endocannabinoid mechanisms via CB1 receptors recruitment decrease the CNP. Finally, rodents with CNP had their mechanical allodynia thresholds decreased after the confrontation with wild snakes. In addition, their defensive behaviours were itemised, thus showing the anxiety/panic and CNP potential comorbidity and the participation of the neocortex in the elaboration of CP in a model of peripheral neuropathy induced by injury of the ischiadicus nervus through its chronic constriction in Wistar rats.

Extensos dados na literatura têm assinalado a importância da serotonina (5-HT) na modulação de comportamentos de medo e ansiedade em roedores, a grande maioria utilizando ratos machos como sujeitos experimentais. No presente trabalho, foi analisada a influência da neurotransmissão 5-HT periférica e central sobre a expressão da resposta de medo condicionado e incondicionado de ratos machos e fêmeas, previamente selecionados pelo fenótipo como animais de baixa (BA) ou de alta (AA) reatividade emocional. Para este fim foi utilizado o teste do sobressalto potencializado pelo medo (SPM). A influência global e central de 5-HT foi avaliada pela utilização da administração sistêmica ou intraventricular aguda do inibidor irreversível da enzima triptofano hidroxilase PCPA (p-clorofenilalanina) nas doses de 200 mg/mL (i.p.) e 200 µg/5 µL (i.v.), ou através de infusões locais de 5-HT (10 nmol/0.2 µL) ou do agonista seletivo de receptores 5-HT1A 8-hidroxi-2-(di-n-propilamino)-tetralina (8-OH-DPAT) na dose de 0,3 µg/0.2 µL, diretamente em áreas encefálicas conhecidas por sua influência na modulação do medo e ansiedade a saber: o córtex pré-limbico (CPL), o núcleo basolateral da amígdala (BLA), e a substância cinzenta periaqueductal dorsal (SCPd) do mesencéfalo. As variáveis dependentes registradas foram a amplitude e a latência das respostas incondicionadas e condicionadas de sobressalto e a amplitude do SPM. / Extensive data in the literature have signaled the importance of serotonin (5-HT) on the modulation of fear and anxiety-like behaviors in rodents. In the present study, we have analyzed the influence of peripheral and central 5-HT neurotransmission on the expression of the conditioned and unconditioned fear, and on the fear-potentiated startle in male and female rats previously selected as low- (LA) or high-anxiety (HA). For this purpose, we used the fear-potentiated startle (FPS) test. The global and central influence of 5-HT was evaluated by using the acute systemic or intraventricular administration of the irreversible tryptophan hydroxylase inhibitor PCPA (p-chlorophenylalanine - 200 mg/mL i.p., or 200 µg/5 µL i.v.). Local effects were evaluated through local infusions of 5-HT itself (10 nmol/0.2 µL) or the selective 5-HT1A receptors agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT 0.3 µg/0.2 µL) in the prelimbic cortex (PrL), basolateral amygdala (BLA) or the dorsal periaqueductal gray (DPAG). These brain regions were chosen for the present study based on their great importance in the modulation and expression of conditioned and unconditioned fear. Dependent variables recorded were the amplitude and latency of unconditioned and conditioned fear, and fear-potentiated startle (FPS).

Extensos dados na literatura têm assinalado a importância da serotonina (5-HT) na modulação de comportamentos de medo e ansiedade em roedores, a grande maioria utilizando ratos machos como sujeitos experimentais. No presente trabalho, foi analisada a influência da neurotransmissão 5-HT periférica e central sobre a expressão da resposta de medo condicionado e incondicionado de ratos machos e fêmeas, previamente selecionados pelo fenótipo como animais de baixa (BA) ou de alta (AA) reatividade emocional. Para este fim foi utilizado o teste do sobressalto potencializado pelo medo (SPM). A influência global e central de 5-HT foi avaliada pela utilização da administração sistêmica ou intraventricular aguda do inibidor irreversível da enzima triptofano hidroxilase PCPA (p-clorofenilalanina) nas doses de 200 mg/mL (i.p.) e 200 µg/5 µL (i.v.), ou através de infusões locais de 5-HT (10 nmol/0.2 µL) ou do agonista seletivo de receptores 5-HT1A 8-hidroxi-2-(di-n-propilamino)-tetralina (8-OH-DPAT) na dose de 0,3 µg/0.2 µL, diretamente em áreas encefálicas conhecidas por sua influência na modulação do medo e ansiedade a saber: o córtex pré-limbico (CPL), o núcleo basolateral da amígdala (BLA), e a substância cinzenta periaqueductal dorsal (SCPd) do mesencéfalo. As variáveis dependentes registradas foram a amplitude e a latência das respostas incondicionadas e condicionadas de sobressalto e a amplitude do SPM. / Extensive data in the literature have signaled the importance of serotonin (5-HT) on the modulation of fear and anxiety-like behaviors in rodents. In the present study, we have analyzed the influence of peripheral and central 5-HT neurotransmission on the expression of the conditioned and unconditioned fear, and on the fear-potentiated startle in male and female rats previously selected as low- (LA) or high-anxiety (HA). For this purpose, we used the fear-potentiated startle (FPS) test. The global and central influence of 5-HT was evaluated by using the acute systemic or intraventricular administration of the irreversible tryptophan hydroxylase inhibitor PCPA (p-chlorophenylalanine - 200 mg/mL i.p., or 200 µg/5 µL i.v.). Local effects were evaluated through local infusions of 5-HT itself (10 nmol/0.2 µL) or the selective 5-HT1A receptors agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT 0.3 µg/0.2 µL) in the prelimbic cortex (PrL), basolateral amygdala (BLA) or the dorsal periaqueductal gray (DPAG). These brain regions were chosen for the present study based on their great importance in the modulation and expression of conditioned and unconditioned fear. Dependent variables recorded were the amplitude and latency of unconditioned and conditioned fear, and fear-potentiated startle (FPS).

A dor crônica (DC) é um problema global de saúde. A incidência da DC no mundo oscila entre 7 e 40% da população e, como consequência da mesma, cerca de 50 a 60% dos que sofrem dela ficam parcial ou totalmente incapacitados, de maneira transitória ou permanente, comprometendo de modo significativo a qualidade de vida. Sabe-se que a divisão pré-límbica (PrL) do córtex pré-frontal medial (CPFM) é uma região importante na elaboração da dor e de seus aspectos cognitivos e emocionais. Há evidências que a DC de origem neuropática (DN) é capaz de provocar mudanças morfológicas, resultando em uma reorganização nas redes neurais do CPFM, e existe alta relação de comorbidade entre ansiedade e DC. Sendo assim, necessita-se de estudos que forneçam aprimoramento dos modelos animais em DC para que, assim, investiguem-se as bases neuroanatômicas, neurofisiológicas e psicofarmacológicas da DN e a participação de áreas corticais na gênese e manutenção da dor. Para isso, o presente trabalho foi dividido em três etapas: 1) Avaliação dos aspectos nociceptivos, motores e afetivo-cognitivos de ratos submetidos a um modelo adaptado de injúria por constrição crônica do nervo isquiático (CCI: uma ligadura) comparando com o modelo clássico de Bennett e Xie (CCI: quatro ligaduras): nossos resultados mostraram que o modelo adaptado de CCI produziu hipersensibilidade ao frio (teste de acetona) e alodinia mecânica (teste de von Frey) semelhante ao causado pelo modelo de CCI com quatro ligaduras. Ambos os grupos CCI apresentaram comportamento do tipo ansioso, depressivo e déficits cognitivos, utilizando-se o modelo de campo aberto (open field), teste de nado forçado e teste de reconhecimento de objeto, respectivamente. Contudo, o modelo adaptado pode ser uma melhor opção, visto que uma simples ligadura não provoca prejuízos motores, nem tampouco o comportamento de autotomia, diferentemente dos animais com CCI em que foram realizadas 4 ligaduras. 2) A - Estudo do efeito da Indometacina (2mg/kg), um antiinflamatório não-esteroidal, administrada por via periférica (IP) sobre a DN: a indometacina diminuiu a alodinia mecânica no primeiro, segundo e quarto dias, mas não no décimo quarto, vigésimo primeiro e vigésimo oitavo dias após a CCI adaptada (1 ligadura). Esses dados sugerem que a COX-1 e a COX-2 estão envolvidas na mediação da indução, mas não na manutenção da DN. B - Envolvimento do córtex PrL sobre a geração, potencialização e manutenção da DN, através da microinjeção local de cloreto de cobalto (CoCl2: 1mM/200nL), um bloqueador do influxo de cálcio (causando bloqueio de sinapses). O CoCl2 atenuou a alodinia mecânica no vigésimo primeiro e vigésimo oitavo, mas não no sétimo e décimo quarto dias após a CCI com 1 ligadura. Nossos dados também indicam que córtex PrL participa na elaboração da fase tardia da alodinia mecânica em nosso modelo adaptado de DN. C - Investigação do papel do sistema glutamatérgico, endocanabinoide e endovaniloide do córtex PrL sobre a alodinia mecânica 21 dias após a CCI adaptada. Os presentes resultados mostraram que a microinjeção do agonista N-metil D-Aspartato (NMDA), nas concentrações de 1 e 4 nmol, foi capaz de aumentar a alodinia mecânica durante o teste de von Frey, enquanto que um antagonista de receptores de aminoácidos excitatórios do tipo NMDA, o LY235959, diminuiu a alodinia mecânica quando microinjetado na maior dose (8nmol) no córtex PrL. O AM251, um antagonista de receptores endocanabinoides do tipo CB1, aumentou a alodinia mecânica em todas as doses (50, 100 e 200pmol) quando microinjetado no PrL. O tratamento do PrL com a menor concentração de anandamida (AEA: 5pmol) não alterou a alodinia mecânica; contudo, a administração de AEA no PrL nas doses intermediárias (de 50 e de 100pmol) reduziu a alodinia mecânica, e este efeito foi bloqueado pelo pré-tratamento do PrL com AM251 (200pmol). Digno de nota, o tratamento do PrL com a maior dose de AEA (200pmol) aumentou a alodinia mecânica, no entanto, este efeito foi atenuado pelo bloqueio prévio de receptores de potencial transitório vaniloide do tipo 1 (TRPV1), com microinjeções de 6 Iodo-nor-di-hidrocapsaicina (6-I-CPS) na dose de 3pmol no PrL. Esses dados sugerem que o córtex PrL está envolvido na potenciação e manutenção da DN crônica (DNC), através da ativação dos receptores NMDA e dos receptores TRPV1. O efeito da atenuação da alodinia mecânica foi causado pela ativação dos receptores endocanabinoides do tipo CB1 em roedores com DNC após 21 dias da CCI. 3) Investigação da comorbidade entre a DNC com ansiedade/pânico e o efeito dos agonistas e antagonistas de receptores NMDA e CB1 no PrL em roedores confrontados com serpente após 21 dias da CCI pelo método adaptado: o confronto entre roedores e serpentes constrictoras induziu nos ratos respostas relacionadas ao medo, tais como avaliação de risco, imobilidade defensiva e fuga em animais com DNC e Sham. Além disso, após terem sido confrontados com a serpente, os animais com DNC tiveram a alodinia mecânica aumentada. O pré-tratamento do PrL com NMDA (4nmol) aumentou o índice e porcentagem de avaliação de risco e a porcentagem de fuga, e a dose intermediária de NMDA (1nmol) aumentou o índice de fuga em animais neuropáticos confrontados com uma serpente constrictora. Além disso, a alodinia mecânica foi intensificada após o confronto em animais que receberam NMDA (4nmol) no PrL. Adicionalmente, os animais tratados com LY235959 diminuíram os comportamentos defensivos apresentados por animais com DNC quando confrontados com a salamanta. Além disso, esses animais pré-tratados com o antagonista de receptores NMDA tiveram seus limiares de von Frey aumentados após o confronto. O bloqueio de receptores endocanabionoides do tipo CB1, com o antagonista AM251, aumentou o comportamento de avaliação de riscos dos animais com DN crônica durante a exposição com a serpente e tiveram seus limiares de retirada de pata no teste de von Frey diminuídos após o confronto. Contudo, o pré-tratamento do PrL com AEA (100pmol) diminuiu os comportamentos defensivos de avaliação de risco, imobilidade defensiva e de fuga dos animais com DNC confrontados com a serpente, e esses animais também apresentaram aumento do limiar de retirada de pata no teste de von Frey após o confronto. Interessantemente, a dose de AEA (200pmol) não alterou comportamento defensivo, mas agravou DNC, através da diminuição do limiar de alodinia mecânica, apresentando um clássico efeito em \"U invertido\", pois menor e a maior dose de AEA (50 e 200pmol) induziram valores de comportamentos defensivo elevados, semelhante ao controle (veículo). Concluindo, os presentes dados obtidos no nosso trabalho, sugerem que o modelo adaptado de CCI, através da realização de uma ligadura do nervo isquiático, é um modelo animal eficaz para se estudarem as comorbidades entre DC e alterações cognitivas e emocionais. A diminuição da atividade das enzimas COX-1 e COX-2 atenuou a alodinia mecânica apenas durante a gênese da DN. Além disso, evidenciou-se que o córtex PrL é recrutado para elaborar a DN durante sua manutenção e potencialização. A ativação dos receptores glutamatérgicos do tipo NMDA e vaniloides do tipo TRPV1 potencializam a DNC e o sistema endocanabinoide via receptor CB1 a diminui. Finalmente, roedores com DNC tiveram seus limiares de alodinia mecânica diminuídos após o confronto com a serpente. Os comportamentos defensivos foram intensificados em animais com DNC, mostrando, assim, o estabelecimento da comorbidade entre DC e ansiedade/pânico e a participação do neocórtex na elaboração da DNC, em um modelo de neuropatia periférica induzida pela constrição crônica no nervo isquiático em ratos Wistar. A comorbidade entre ansiedade/pânico e DNC sensibiliza os animais, agravando o quadro de dor crônica. / Chronic pain (CP) is a global health problem. The incidence of CP in the world ranges from 7 to 40% of the population and, as a consequence, about 50% to 60% of those suffering from it are partially or totally incapacitated, in a transitory or permanent manner significantly compromising the quality of life. The prelimbic (PrL) division of the medial prefrontal cortex (mPFC) is an important region for the elaboration of cognitive and emotional aspects of pain. In addition, chronic neuropathic pain (CNP) can induce morphological changes, resulting in a reorganisation in the mPFC neurons. Moreover, there is an intrinsic relation between CP and anxiety disorder. Our study aims to investigate the effects of a modification of an animal model of CP and evaluate the neuroanatomical and pharmacological bases of neuropathic pain (NP). The role played by PrL cortex in the modulation of CNP was also investigated. Thus, the present work was divided into three steps: 1) Ethological analysis of nociceptive, motor and affective-cognitive aspects of rats submitted to an adapted model of chronic constriction of the ischiadicus nervus (CCI: a simple ligature) compared with the classic CCI model performed by Bennett and Xie (CCI: four ligatures): our results showed that the adapted-CCI model produced cold hypersensitivity and mechanical allodynia similar to those described in laboratory animals submitted to the model with four ligatures of the ischiadicus nervus. Both CCI groups displayed anxiety- and depression-like responses, and cognitive deficits, in the the open field test, forced swim test and object recognition test, respectively. However, the adapted model of CCI used in the present work may be a better choice, since a simple ligature of the ischiadicus nervus cause neither motor deficits, nor autotomy behaviour, unlike the animals with CCI induced by four ligatures of spinal nerves. 2) A- Effect of Indomethacin (2mg/kg) a non-steroidal anti-inflammatory drug peripherally administered (IP) on NP: The peripheral treatment with indomethacin reduced mechanical allodynia on the first, second, and fourth days, but not on the fourteenth, twenty-first, and twenty-eighth days after adapted CCI. These findings suggest that COX-1 and COX-2 are involved in the mediation of NP induction, but not in the maintainance of NP. B- Involvement of the PrL cortex on the generation, potentiation and maintenance of DN, through the microinjection of cobalt chloride (CoCl2: 1mM/200nL), a calcium influx blocker (synapse blocker): CoCl2 attenuated mechanical allodynia at twenty-first and twenty-eighth, but not at seventh and fourteenth days after CCI. Our data also indicate that PrL cortex participates in the elaboration of the chronic phase of mechanical allodynia in our adapted NP model. C- The role of the glutamatergic, endocannabinoid and endovanniloid systems of the PrL cortex on mechanical allodynia 21 days after CCI: The present data showed that microinjection of the N-methyl D-Aspartate agonist (NMDA), in a dose of 1 and 4nmol, was able to increase the mechanical allodynia threshold during mechanical stimulation by von Frey test filaments, whereas the NMDA receptors antagonist LY235959 decreased mechanical allodynia when microinjected at the highest dose (8nmol) in the PrL. The PrL cortex pretreatment with the CB1-cannabinoid receptor antagonist AM251 increased mechanical allodynia at all doses (50, 100 and 200 pmol). Microinjections of anandamide (AEA) at the smaller dose (5pmol) in PrL did not cause influence in the mechanical allodynia. However, the PrL treatment with AEA at the intermediate doses (50 and 100pmol) reduced mechanical allodynia and that effect were blocked by the pretreatment of the PrL cortex with AM251 (200pmol). Interestingly, the higher dose of AEA (200pmol) increased mechanical allodynia. Furthermore, this effect was attenuated by the PrL pretreatment with the transient potential receptor antagonist type 1 (TRPV1) ion channel selective antagonist 6 Iodonordihidrocapsaicin (6-I-CPS) in a dose of 3 pmol. These findings suggest that the PrL cortex is involved in the potentiation and maintenance of CNP through the activation of NMDA receptors and TRPV1 receptors in PrL cortex. The effect of attenuation of mechanical allodynia was caused by the activation of CB1 endocannabinoid receptors in rodents with CNP after 21 days of CCI. 3) Investigation of the comorbidity between CNP with anxiety/panic and the effect of NMDA glutamatergic and CB1 endocannabinoid receptors on PrL cortex after 21 days of CCI in rodents. The confrontation between a constrictor snake and the rodent elicited innate fear-related responses in prey, such as risk assessment, defensive immobility, and escape behaviour that were enhanced in CNP rodents and Sham. Also, after a confrontation with a potential predator, the CNP animals increased their mechanical allodynia thresholds. In adition, the microinjection of NMDA (4nmol) PrL, increased innate fear-related responses, such as risk assessment, and the treatment of PrL with NMDA at 1nmol incresed escape behaviour in rodents with CNP. The treatment of the PrL with NMDA in a dose of 4nmol increased the mechanical allodynia threshold during mechanical stimulation by von Frey test filaments, after confrontantion, whereas PrL pretreatment with LY235959 decreased innate fear-related responses, such risk assessment, defensive immobility, and escape behavior and decreased mechanical allodynia when microinjected (4 and 8nmol). The PrL Pretreatment with the CB1-cannabinoid receptor antagonist AM251 (all doses) increased unconditioned fear-related responses, such as risk assessment. Moreover, AM251 (100 and 200pmol) microinjections in the PrL increased mechanical allodynia after prey versus predator confrontation. The microinjections of AEA (100pmol) in the PrL decreased risk assessment, defensive immobility, and escape behaviour and reduced mechanical allodynia. Interestingly, the pretreatment of the PrL with the higher dose of AEA (200pmol) did not change the fear-induced behaviour elicited by predators, but increased the CNP. There was a classical inverted U-shape curve from the lower to the higher dose of AEA. These data suggest that the anxiety/panic and pain comorbidity increases CNP symptoms. The present findings also indicate that the CCI-adapted model, by ischiadicus nervus ligation with a single ligature is an effective animal model for studying comorbidities between CP and cognitive/emotional disturbances. In conclusion, we observed that nonsteroidal anti-inflammatory drugs are efficient to attenuate the mechanical allodynia only during NP genesis. The PrL cortex is recruited during the maintenance and potentiation of NP. The PrL glutamatergic system via NMDA activation and endovaniloid mechanisms related to TRPV1 ion channel activation potentiate CNP, and the endocannabinoid mechanisms via CB1 receptors recruitment decrease the CNP. Finally, rodents with CNP had their mechanical allodynia thresholds decreased after the confrontation with wild snakes. In addition, their defensive behaviours were itemised, thus showing the anxiety/panic and CNP potential comorbidity and the participation of the neocortex in the elaboration of CP in a model of peripheral neuropathy induced by injury of the ischiadicus nervus through its chronic constriction in Wistar rats.

Les enfants qui ont subi une asphyxie périnatale modérée (MPA) risquent de développer des déficits cognitifs et comportementaux subtils et durables, notamment des troubles d'apprentissage et des problèmes émotionnels. Comprendre les mécanismes sous-jacents est une étape essentielle pour concevoir une thérapie ciblée. Déterminer comment le développement du cerveau est corrélé entre les humains et les rongeurs n'est pas simple, mais il existe également un alignement inter-espèces considérable en termes d'étapes clés du développement. Sur la base des changements biochimiques et neuroanatomiques au cours du développement précoce, le consensus général est qu'un cerveau de rongeur P8-10 correspond à peu près au cerveau d'un enfant à terme ; par conséquent, nous avons utilisé cette fenêtre temporelle comme référence pour développer un modèle préclinique de MPA chez la souris. Nous avons d'abord établi un protocole qui nous permet d'observer de manière fiable les crises induites par l'hypoxie chez les souris postnatales. Nous avons constaté que l'exposition de chiots P8-9 directement à 4 % d'O2 pendant 8 minutes induit de manière fiable des crises avec une latence d'environ 5 minutes chez 3 souches de souris (FVB, C57Bl/6, 129S6). Cet aspect est cliniquement pertinent car les convulsions sont la caractéristique néonatale la plus importante de l'encéphalopathie de stade 2 (modérée) telle que définie par l'échelle de Sarnat. Les souris MPA adultes présentent des séquelles à long terme sur des performances cognitives spécifiques, notamment des déficits de la mémoire de reconnaissance et de la flexibilité cognitive, mais aucune altération du comportement moteur et émotionnel. Le cortex préfrontal (PFC) régule la flexibilité cognitive et le comportement émotionnel. Les neurones qui libèrent la sérotonine (5-HT) projettent vers le PFC, et les composés modulant l'activité 5-HT influencent l'émotion et la cognition. On ne sait pas si les dérégulations de la 5-HT contribuent aux problèmes cognitifs induits par le MPA. Dans une première étude, nous avons trouvé que les niveaux d'expression de 5-HT, quantifiés par immunohistochimie, et de libération de 5-HT, quantifiés par microdialyse in vivo chez des souris éveillées, sont réduits dans le PFC de souris MPA adultes. Les souris MPA présentent également une régulation de la température corporelle altérée après l'injection de l'agoniste des récepteurs 5-HT1A, 8-OH-DPAT, suggérant la présence de déficits dans la fonction des auto-récepteurs 5-HT sur les neurones du raphé. Enfin, le traitement chronique de souris MPA adultes avec de la fluoxétine, un inhibiteur du transporteur de recapture de la 5-HT, ou l'agoniste des récepteurs 5-HT1A, la tandospirone, sauve la flexibilité cognitive et les troubles de la mémoire. Ensemble, ces données démontrent que le développement de la fonction du système 5-HT est vulnérable à une asphyxie périnatale modérée. L'hypofonctionnement de la 5-HT pourrait à son tour contribuer à une déficience cognitive à long terme à l'âge adulte, indiquant une cible potentielle pour les thérapies pharmacologiques. Les circuits GABAergiques comprennent une variété étonnante de différents types de cellules, qui sont probablement recrutées par différents événements comportementaux. Un sous-type important de cellules GABAergiques, les cellules positives à la parvalbumine (PV), génèrent des potentiels d'action à haute fréquence et synchronisent l'activité des neurones pyramidaux excitateurs. Les cellules PV sont particulièrement importantes pour la génération d'oscillations gamma, qui à leur tour régulent de nombreuses fonctions cognitives, notamment le traitement attentionnel axé sur les objectifs et la mémoire de travail. Des découvertes récentes indiquent que les cellules PV utilisent beaucoup plus d'énergie que les autres neurones corticaux, ce qui peut les rendre très vulnérables aux conditions de stress métabolique et oxydatif causées par le MPA. Nos données ont montré que l'expression de PV est altérée chez les souris MPA adultes. Nous avons en outre constaté que le niveau d'expression du récepteur de la neurotrophine p75NTR, qui limite la maturation des cellules PV au cours de la première semaine postnatale, est augmenté chez les souris MPA. La suppression génétique de p75NTR dans les neurones GABAergiques exprimant le facteur de transcription Nkx2.1, qui comprend les cellules PV, protège les souris de la perte de niveaux de PV et des effets cognitifs à long terme du MPA. Enfin, un traitement d'une semaine avec un inhibiteur de p75NTR commençant après le MPA sauve complètement les déficits d'activité cognitive et corticale chez les souris adultes. L'ensemble de ces données révèle une cible moléculaire potentielle pour le traitement des altérations cognitives causées par le MPA. / Children who experienced moderate perinatal asphyxia (MPA) are at risk of developing long lasting subtle cognitive and behavioral deficits, including learning disabilities and emotional problems. Understanding the underlying mechanisms is an essential step for designing targeted therapy. Determining how brain development correlates between humans and rodents is not straightforward, however there is also considerable cross-species alignment in terms of key developmental milestones. Based on biochemical and neuroanatomical changes during early development, the general consensus is that a P8-10 rodent brain corresponds roughly to the brain of a term infant; therefore, we used this time window as reference to develop a preclinical model of MPA in mouse. We first established a protocol that allows us to reliably observe hypoxia-induced seizures in postnatal mice. We found that exposing P8-9 pups directly to 4% O2 for 8 minutes reliably induces seizures with a latency of about 5’ in 3 mouse strains (FVB, C57Bl/6, 129S6). This aspect is clinically relevant as seizures are the most prominent neonatal hallmark of Stage 2 (Moderate) encephalopathy as defined by the Sarnat Scale. Adult MPA mice show long-term sequelae on specific cognitive performance, including deficits in recognition memory and cognitive flexibility, but no impairment in motor and emotional behavior. The prefrontal cortex (PFC) regulates cognitive flexibility and emotional behavior. Neurons that release serotonin (5-HT) project to the PFC, and compounds modulating 5-HT activity influence emotion and cognition. Whether 5-HT dysregulations contribute to MPA-induced cognitive problems is unknown. In a first study, we found that 5-HT expression levels, quantified by immunohistochemistry, and 5-HT release, quantified by in vivo microdialysis in awake mice, are reduced in PFC of adult MPA mice. MPA mice also show impaired body temperature regulation following injection of the 5-HT1A receptor agonist 8-OH-DPAT, suggesting the presence of deficits in 5-HT auto-receptor function on raphe neurons. Finally, chronic treatment of adult MPA mice with fluoxetine, an inhibitor of 5-HT reuptake transporter, or the 5-HT1A receptor agonist tandospirone rescues cognitive flexibility and memory impairments. All together, these data demonstrate that the development of 5-HT system function is vulnerable to moderate perinatal asphyxia. 5-HT hypofunction might in turn contribute to long-term cognitive impairment in adulthood, indicating a potential target for pharmacological therapies. GABAergic circuits comprise an astonishing variety of different cell types, which are likely recruited by different behavioral events. An important subtype of GABAergic cells, the fast-spiking, parvalbumin-positive (PV) cells, generate action potentials at high frequency and synchronize the activity of excitatory pyramidal neurons. PV cells are particularly important for the generation of gamma oscillations, which in turn regulate many cognitive functions including goal-directed attentional processing and working memory. Recent findings indicate that PV cells utilize much more energy than other cortical neurons, which may render them highly vulnerable to conditions of metabolic and oxidative stress caused by MPA. Our data showed that PV expression is impaired in adult MPA mice. We further found that the expression level of the neurotrophin receptor p75NTR, which limits PV cell maturation during the first postnatal week, is increased in MPA mice. Genetic deletion of p75NTR in GABAergic neurons expressing the transcription factor Nkx2.1, which include PV cells, protects mice from PV levels loss and the long-term cognitive effects of MPA. Finally, one week treatment with a p75NTR inhibitor starting after MPA completely rescues the cognitive and cortical activity deficits in adult mice. All together this data reveals a potential molecular target for the treatment of the cognitive alterations caused by MPA.

No description available.