Diss. (sammanfattning) Umeå : Umeå universitet, 2010.

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.

Healthy ageing has been found to be accompanied by changes in slow wave activity (SWA) and cognitive function. Furthermore, these changes have been seen predominantly in the prefrontal cortex (PFC) compared to other regions of the cortex. Current theories of cognitive ageing propose that this occurs due to a specified deterioration of neuronal substrates of the PFC, and as such, changes in SWA and cognitive function may decline at similar rates due to similar underlying aetiology. The main aim of the current thesis was to explore age-related differences in electroencephalographic (EEG) SWA during the first NREM period and cognitive performance that relies on the integrity of the PFC: executive function and social cognition. The extent to which executive function (reliant on dorsolateral PFC areas) and social cognitive function (reliant on ventromedial PFC regions) show similar age-related deterioration was investigated in Study 1. Here, 16 young (22.2 years) and 16 older (71.5 years) adults were administered with a cognitive testing battery including executive function measures: Verbal Fluency (VF) and Tower of London (TOL); as well as measures of social cognition: Go/No-go, Emotional Prosody and Ekman 60 Faces. Not all measures of PFC function were affected to the same extent. The older group performed significantly worse on the TOL, but not on the VF test. Additionally, simple aspects of social cognition did not display differences between the groups, but the older group performed significantly worse than the young group on more complex aspects of recognition of emotion from facial expression (Ekman 60 Faces) and Emotional Prosody. As most studies of cognitive ageing are cross-sectional and show large agerelated changes, the remainder of this thesis focused on age-related changes using a longitudinal design over a relatively small ageing period (mean = 6.29 years). The average age of participants at baseline was 67.1 years and the average age at follow-up was 73.4 years. In Study 2, in a sample of 11 participants, performance on executive function tests was measured (TOL, VF and Wisconsin Card Sorting Test: WCST). As found in the cross-sectional analyses reported in Study 1, the TOL task was found to be the most sensitive indicator of age-related changes, as this showed a decline with age; whereas, VF and WCST remained stable over time. Furthermore, in Study 3, localised SWA was recorded via EEG, and significant declines were found in low frequency delta (0.5 – 1 Hz), which was localised to the left frontal region.

Le contrôle exécutif de l'action fait référence a la capacité de l'homme a contrôler et adapter son comportement de manière flexible, en lien avec ses états mentaux internes. Il repose sur l’évaluation des conséquences des actions pour ajuster les choix futurs. Les actions peuvent être renforcées ou dévalues en fonction de la valeur affective des conséquences, impliquant notamment les ganglions de la base et le cortex préfrontal médian. En outre, les conséquences des actions portent une information, qui permet d'ajuster le comportement en relation avec des croyances internes, impliquant le cortex préfrontal. Ainsi, les conséquences des actions portent deux types de signaux : (1) Une valeur affective, qui représente l’évaluation de la conséquence de l'action selon les préférences subjectives, issue de l'apprentissage par renforcement ; (2) Une valeur de croyance, mesurant comment les actions correspondent aux contingences externes, en lien avec l’inférence bayésienne. Cependant, la contribution de ces deux signaux a la prise de décision reste méconnue. Dans cette these, nous avons étudie la pertinence de cette dissociation aux niveaux comportemental et cérébral. Nous présentons plusieurs expériences comportementales permettant de dissocier ces deux signaux de valeur, sous la forme de taches d'apprentissage probabiliste avec des structures de récompense stochastiques et changeantes. Nous avons construit un modelé établissant les fondations fonctionnelles et computationnelles de la dissociation. Il combine deux systèmes en parallèle : un système d'apprentissage par renforcement modulant les valeurs affectives, et un système d’inférence bayésienne modulant les croyances. Le modèle explique mieux le comportement que de nombreux modèles alternatifs. Nous avons ensuite étudie, en IRM fonctionnelle, si les représentations dépendantes et indépendantes du choix des croyances et des valeurs affectives avaient des bases neurales distinctes. L’activité du cortex préfrontal ventromédian (VMPFC) et du cortex mid-cingulaire (MCC) corrélé avec les deux variables dépendantes du choix. Cependant, une double-dissociation a été identifiée concernant les représentations indépendantes du choix, le VMPFC étant spécifique des croyances alors que le MCC est spécifique des valeurs affectives. En outre, l’activité du cortex préfrontal latéral augmente lorsque les deux valeurs de décision sont proches et que le choix devient difficile. Ces résultats suggèrent qu'avant la décision, le cortex préfrontal ventromédian (VMPFC) et le cortex mid-cingulaire (MCC) encodent séparément les croyances et les valeurs affectives respectivement. Le cortex préfrontal latéral (LPFC) combine les deux signaux pour prendre une décision, puis renvoie l'information du choix aux régions médianes, probablement pour actualiser les deux signaux de valeur en fonction des conséquences du choix. Ces résultats contribuent a élucider les mécanismes cérébraux de la prise de décision dans le cortex préfrontal. / Executive control relates to the human ability to monitor and flexibly adapt behavior in relation to internal mental states. Specifically, executive control relies on evaluating action outcomes for adjusting subsequent action. Actions can be reinforced or devaluated given affective value of outcomes, notably in basal ganglia and medial prefrontal cortex. Additionally, outcomes convey information to adapt behavior in relation to internal beliefs, involving prefrontal cortex. Accordingly, action outcomes convey two major types of value signals: (1) Affective values, representing the valuation of action outcomes given subjective preferences and stemming from reinforcement learning; (2) Belief values about how actions map onto outcome contingencies and relating to Bayesian inference. However, how these two signals contribute to decision remains unclear, and previous experimental paradigms confounded them. In this PhD thesis, we investigated whether their dissociation is behaviorally and neurally relevant. We present several behavioral experiments dissociating these two signals, in the form of probabilistic reversal-learning tasks involving stochastic and changing reward structures. We built a model establishing the functional and computational foundations of such dissociation. It combined two parallel systems: reinforcement learning, modulating affective values, and Bayesian inference, monitoring beliefs. The model accounted for behavior better than many other alternative models. We then investigated whether beliefs and affective values have distinct neural bases using fMRI. BOLD signal was regressed against choice-dependent and choice-independent beliefs and affective values. Ventromedial prefrontal cortex (VMPFC) and midcingulate cortex (MCC) activity correlated with both choice-dependent variables. However, we found a double-dissociation regarding choice-independent variables, with VMPFC encoding choice-independent beliefs, whereas MCC encoded choice-independent affective values. Additionally, activity in lateral prefrontal cortex (LPFC) increased when decision values (i.e. mixture of beliefs and affective values) got closer to each other and action selection became more difficult. These results suggest that before decision, VMPFC and MCC separately encode beliefs and affective values respectively. LPFC combines both signals to decide, then feeds back choice information to these medial regions, presumably for updating these value signals according to action outcomes. These results provide new insight into the neural mechanisms of decision-making in prefrontal cortex.

A Cetamina, antagonista não competitivo de receptores de glutamato do tipo NMDA, é uma substância com propriedades dissociativas originalmente utilizada como anestésico que apresenta a característica de intensificar as experiências sensoriais. Apesar de seus conhecidos efeitos sobre os aspectos cognitivos e comportamentais, poucos estudos préclínicos foram conduzidos para tentar detectar os efeitos físicos e/ou comportamentais da abstinência de Cetamina após consumo prolongado. Partindo do princípio de que os efeitos da Cetamina sobre a neurotransmissão glutamatérgica induzem alguns dos sintomas observados durante surtos esquizofrênicos, como as alucinações auditivas, e sabendo que o colículo inferior tem sua função ligada ao processamento da informação sensorial a estímulos sonoros, neste estudo avaliamos os efeitos da modulação glutamatérgica na área cortical pré-límbica (PrL) sobre os potenciais evocados auditivos eliciados (PEAs) no colículo inferior. As medidas foram realizadas no fim do tratamento, ou seja, no 14° dia, 24 horas e 6 dias após a retirada da cetamina. Em nossos resultados obtivemos que a administração local de NMDA, foi capaz de diminuir a amplitude dos PEAs, os quais foram recuperados 24 horas após. A cetamina sistêmica não foi capaz de diminuir os PEAs, uma provável consequência da interação com outros receptores além do NMDA. Os testes realizados 6 dias após a interrupção ao tratamento crônico de cetamina, demonstraram uma forma inesperada de U, diferente da curva padrão de U invertido. Além disso, encontramos que as alterações provocadas pela cetamina são dependentes dos níveis dos mecanismos dopaminérgico e glutamatérgicos. Estes resultados demonstram que o processamento auditivo no colículo inferior está sob controle direto no Pré límbico e permitem ampliar o conhecimento atual da neurobiologia por evidenciar novas informações do efeito crônico da cetamina. / Ketamine is a non-competitive NMDA receptor antagonist. It is a substance with dissociative properties originally used as anesthetic, which can intensify sensory experiences, being also capable of accentuating the psychotic state in patients with schizophrenia. Despite its known effect on cognitive aspects and behavior, there are few preclinical studies conducted to identify physical and behavioral effects of ketamine withdrawal after its long-term use. Moreover, little is known about the impact of repetitive use of ketamine on brain structures and their functioning. The inferior colliculus, part of the midbrain tectum, is mainly related to auditory information processing, sending information to the motor centers and participating in the modulation and expression of specific behaviors, such as attack and predatory. Therefore, it is related to the biological importance of sounds to survival. The auditory hallucinations induced by schizophrenic psychotic crisis has as neural correspondent the activation of inferior colliculus and cortical areas. It is not yet known which cortical area is connected to the modulation of alterations induced by electrophysiological potential registered in inferior colliculus. Considering that the effects of ketamine on glutamate neurotransmission induces the symptoms observed during schizophrenic psychotic crisis, such as auditory hallucinations, and that inferior colliculus is related to the sensory information processing and auditory pathways, the present work evaluates the effects of glutamate modulation on pre-limbic cortical area on auditory evoked potential startle in inferior colliculus of rats tested during and after interruption of chronic treatment with ketamine

À l’interface des neurosciences et de la psychologie sociale expérimentale, nos travaux explorent les bases neuronales de la « facilitation sociale » (effet facilitateur de la présence d’un congénère sur la performance) chez le singe à partir d'enregistrements électrophysiologiques unitaires dans le cortex préfrontal dorsolatéral et dans le cortex cingulaire antérieur. L'analyse de l’activité de 342 neurones liée au codage des résultats de l’action (signaux d'erreur et de succès) révèle que, dans leur grande majorité, les neurones de ces deux structures expriment une sensibilité différenciée à la présence du congénère. Trois populations de neurones sont découvertes: des neurones dits « sociaux », dont la décharge est plus ample en présence du congénère qu’en son absence, des neurones dits « asociaux », avec un pattern de décharge inverse, et une population plus minoritaire dite « neutre », dont l’amplitude de décharge est la même dans ces deux conditions. Il apparaît que les relations entre le comportement et l'activité neuronale lors du codage des signaux d’erreur dépendent de la nature plus ou moins compatible des populations neuronales identifiées avec les contextes de performance eux-mêmes. Nos résultats indiquent une implication majeure des neurones sociaux dans les effets de facilitation sociale étudiés depuis un siècle dans plusieurs espèces animales et offrent un nouveau regard sur le cerveau social. Sans nier l’idée de régions entières spécialisées dans le traitement des informations sociales, nos travaux suggèrent que des populations neuronales dotées d’une sensibilité plus ou moins sociale coexistent et probablement interagissent à l’échelle du cerveau entier. / At the interface of neuroscience and experimental social psychology, our work explores the neural bases of « social facilitation » (the facilitating effect of the presence of a conspecific on performance) in monkeys using single-unit electrophysiological recordings in the dorsolateral part of the prefrontal cortex (PFDL) and the anterior cingulate cortex (ACC). The analysis of the activity of 574 neurons coding for error signals and successes reveals that the vast majority of neurons in both structures express a differential sensitivity to social presence. Three populations of neurons are discovered : neurons called « social », exhibiting higher discharge rate in the presence of a conspecific than alone, neurons called « asocial », exhibiting a reverse discharge pattern, and neurons called « neutral », whose discharge magnitude is the same in both conditions. More importantly, it appears that the relationship between behavior and neural activity when encoding error feedback depends on whether the neuronal populations at stake are compatible or incompatible with the performance contexts themselves. Overall, our results indicate a major role of social neurons in social facilitation effects studied for a century in several animal species and offer a new look at the « social brain ». Without denying the idea of entire regions involved in the processing of social information, our work suggests that neuronal populations with varying degrees of social sensitivity actually coexist and probably interact across the whole brain.

A ketamina, antagonista não competitivo de receptores NMDA, apresenta potentes efeitos psicomiméticos, sendo capaz de acentuar o estado psicótico de pacientes esquizofrênicos. Uma das áreas cerebrais afetadas por seu uso é o córtex pré-frontal, já que o desempenho em tarefas que dependem de sua atividade é profundamente alterado pela administração aguda de ketamina. Assim como na esquizofrenia, estas alterações podem sofrer influência de fatores hormonais, alterações estas que podem ser explicadas pelos efeitos dos hormônios sexuais femininos, como o estrogênio, os quais apresentam um papel regulador sobre os sistemas dopaminérgicos, serotonérgicos, glutamatérgicos e GABAérgicos, todos afetados pelos efeitos agudos e crônicos do uso de ketamina. Este projeto, portanto, teve como meta avaliar os possíveis efeitos da administração crônica e retirada de ketamina sobre a expressão de comportamentos relacionados à ansiedade humana em ratas da linhagem Wistar, assim como a influência dos hormônios estradiol e a progesterona sobre esta variável. As possíveis alterações farmacológicas induzidas pela administração crônica de ketamina sobre os sistemas dopaminérgicos e serotoninérgicos da divisão pré-límbica (PrL) do córtex pré-frontal medial serão avaliadas através da injeção local de antagonista/agonista específicos. Nossos dados reforçam a ideia de que a ketamina demonstra de forma significativa a expressão da resposta aprendida de medo. E também, os dados mostram que a abstinência da droga altera este comportamento, particularmente a capacidade cognitiva relacionada ao encadeamento de estímulos. Da mesma forma que outras drogas de abuso, estas alterações parecem envolver tanto o sistema dopaminérgico quanto serotoninérgico do CPFm. / Ketamine, a non-competitive antagonist of NMDA receptors, has potent psychomimetic effects, being able to accentuate the psychotic state of schizophrenic patients. One of the brain areas affected by its use is the prefrontal cortex, since performance in tasks that depend on its activity is profoundly altered by the acute administration of ketamine. As in schizophrenia, these changes may be influenced by hormonal factors, which can be explained by the effects of female sex hormones, such as estrogen, which play a role in the dopaminergic, serotonergic, glutamatergic and GABAergic systems, all affected acute and chronic effects of ketamine use. This project therefore aimed to evaluate the possible effects of chronic administration and withdrawal of ketamine on the expression of behaviors related to human anxiety in Wistar rats, as well as the influence of the hormones estradiol and progesterone on this variable. The possible pharmacological changes induced by chronic ketamine administration on the dopaminergic and serotonergic systems of the prelambial (PrL) division of the medial prefrontal cortex will be assessed by specific local antagonist / agonist injection. Our data reinforce the idea that ketamine demonstrates significantly the expression of the learned response of fear. Also, the data show that drug abstinence alters this behavior, particularly the cognitive capacity related to the chaining of stimuli. Like other drugs of abuse, these changes appear to involve both the dopaminergic and serotonergic system of CPFm.

O córtex pré-frontal (PFC) participa do controle do comportamento de busca por droga e se projeta para a coluna rostrolateral da substância cinzenta periaquedutal (PAGrl) que por sua vez se projeta para o sistema orexinérgico da área hipotalâmica lateral (LHA) que controla comportamentos que oferecem recompensa através de projeções para o sistema dopaminérgico mesolímbico. O objetivo do trabalho é investigar a participação da PAGrl e a sua relação com o PFC e com o sistema orexinérgico da LHA na expressão do comportamento de busca por droga. Submetemos ratos Wistar ao condicionamento de preferência por lugar para sulfato de morfina e notamos que o PFC, a PAGrl e a LHA estão ativados em animais que expressaram tal comportamento. Após, realizamos lesões neuroquímicas bilaterais no PFC e notamos a ausência da busca pela droga nestes animais e da diminuição da ativação da PAGrl e do sistema orexinérgico da LHA. Posteriormente realizarmos lesões neuroquímicas por NMDA na PAGrl e notamos a ausência do comportamento e diminuição de duplas marcações para Fos e orexina na LHA. Os resultados indicam que a PAGrl exerceria um papel crítico para o comportamento de busca por droga, integrando aferências provenientes do PFC para modular os neurônios orexinérgicos da LHA. / The prefrontal cortex (PFC) is involved with planning of the drug seeking behavior and projects itself to the rostrolateral periaqueductal gray (PAGrl) that through projections for the orexin neurons in the lateral hypothalamic area (LHA), participates in the control of behavior that offer rewards. The LHA controls drug reward through projections for the mesolimbic dopaminergic system. This study aims to investigate the relationship between the PFC, PAGrl and orexin neurons in the LHA in drug seeking behavior. We did a morphine conditioned place preference (CPP) procedure in intact, bilateral PAGrl-lesioned and bilateral PFC-lesioned Wistar rats and investigated the pattern of Fos expression. The intact animals displayed such behavior and presented an increase in Fos activation in the PFC, rlPAG and LHA orexinergic neurons. Conversely, PAGrl-lesioned and PFC-lesioned animals did not display this behavior and reduced the activation of orexin neurons in the LHA. PFC-lesioned animals presented a reduction of the Fos activation in the rlPAG. The results suggest a pathway involving the PFC, PAGrl and LHA orexinergic cell group underlying the CCP, where the rlPAG would integrate inputs from the PFC to control the LHA orexinergic cell group.

Acredita-se que quantidades elevadas de glutamato estejam relacionadas à neurobiologia da depressão e trabalhos recentes indicam que a quantidade de glutamato cortical está aumentada em pacientes depressivos quando comparada a indivíduos sadios. Dentre as estruturas corticais, o córtex pré-frontal medial ventral (CPFMv), dividido em infralímbico (IL) e pré-límbico (PL), tem sido mais frequentemente implicado no desenvolvimento de transtornos mentais, como a depressão. Considerando evidências de que o IL e o PL podem agir de forma diferente quanto ao controle emocional em resposta ao estresse, o presente trabalho visou avaliar a hipótese de participação da neurotransmissão glutamatérgica do CPFMv, IL e PL, no desenvolvimento das respostas comportamentais ao estresse de nado forçado, um modelo preditivo de efeitos antidepressivos. Para tal, investigamos os efeitos induzidos pela administração no IL ou no PL, de LY 235959, um antagonista dos receptores glutamatérgicos do tipo NMDA, em três momentos diferentes, em animais submetidos ao teste do nado forçado. A administração de LY 235959, no IL ou PL, produziu efeitos do tipo antidepressivo, sendo esse efeito sensível ao tempo de administração da droga em relação à exposição ao nado forçado. Sendo assim, foi observado efeito antidepressivo quando o bloqueio glutamatérgico no PL ocorreu imediatamente após o nado ou antes da re-exposição ao estresse; enquanto no IL, o tratamento promoveu efeito antidepressivo apenas quando administrado antes da re-exposição ao nado. Portanto, os resultados sugerem que a neurotransmissão glutamatérgica mediada por receptores NMDA no CPFMv contribui para o desenvolvimento de consequências comportamentais do estresse, de modo que o bloqueio desses receptores facilitaria a adaptação ao estresse e induziria efeitos do tipo-antidepressivo. Os resultados sugerem, ainda, que o PL e o IL participam de maneira semelhante na modulação desses processos. / It is believed that high amounts of glutamate are related to the neurobiology of depression. Recent studies indicate that the amount of cortical glutamate is increased in depressed patients compared to healthy subjects. Among the cortical structures, the ventral medial prefrontal cortex (CPFMv), divided into infralimbic (IL) and prelimbic (PL) has been most often implicated in the development of mental disorders, such as depression. Considering that IL and PL play different roles on the emotional control in response to stress, this study was aimed to evaluate the hypothesis that the activation of glutamate NMDA receptors within the CPFMv, IL and PL, would facilitate the development of forced swimming-induced behavioral responses, an animal model predictive of antidepressants effects. To this end, we investigated the effects induced by the administration in the PL or the IL of LY 235959, an antagonist of NMDA receptors, at three different times, in animals submitted to the forced swimming test. The administration of LY 235959, in the IL or PL, produced antidepressant-like effects, and this effect is sensitive to moment of drug administration in relation to exposure to forced swimming. Thus, the antidepressant-like effect was observed when blocking the NMDA blockade into the PL occurred immediately after swimming or before re-exposure to stress, whereas in the IL, such treatment promoted antidepressant-like effect only when administered before re-exposure to swimming. Therefore, the results suggest that the glutamatergic neurotransmission mediated by NMDA receptors in the CPFMv contributes to the development of behavioral consequences of stress, so that blocking these receptors would facilitate the adaptation to stress and induce antidepressant-like effects. The results also suggest that PL and IL may be similarly involved in modulating these processes.

A new, biologically plausible model of task-set learning that reproduces effects from both rule-learning experiments and task-switching experiments.<br>