Caracterização comportamental e distribuição de neurônios inibitórios em um modelo animal de autismo induzido por ácido valpróico

Autism comprises a heterogeneous group of neurodevelopmental disorders that affects the brain maturation and produces sensorial, motor, language and social interaction deficits in early childhood. Several studies have shown a major involvement of genetic factors leading to a predisposition to autism, which are possibly affected by environmental modulators during embryonic and post-natal life. Recent studies in animal models indicate that alterations in epigenetic control during development can generate neuronal maturation disturbances and produce a hyper-excitable circuit, resulting in typical symptoms of autism. In the animal model of autism induced by valproic acid (VPA) during rat pregnancy, behavioral, electrophysiological and cellular alterations have been reported which can also be observed in patients with autism. However, only a few studies have correlated behavioral alterations with the supposed neuronal hyper-excitability in this model. The aim of this project was to generate an animal model of autism by pre-natal exposure to VPA and evaluate the early post-natal development and pre-puberal (PND30) behavior in the offspring. Furthermore, we quantified the parvalbumin-positive neuronal distribution in the medial prefrontal cortex and Purkinje cells in the cerebellum of VPA animals. Our results show that VPA treatment induced developmental alterations, which were observed in behavioral changes as compared to vehicle-treated controls. VPA animals showed clear behavioral abnormalities such as hyperlocomotion, prolonged stereotipies and reduced social interaction with an unfamiliar mate. Cellular quantification revealed a decrease in the number of parvalbumin-positive interneurons in the anterior cingulate cortex and in the prelimbic cortex of the mPFC, suggesting an excitatory/inhibitory unbalance in this animal model of autism. Moreover, we also observed that the neuronal reduction occurred mainly in the cortical layers II/III and V/VI. We did not detect any change in the density of Purkinje neurons in the Crus I region of the cerebellar cortex. Together, our results strengthens the face validity of the VPA model in rats and shed light on specific changes in the inhibitory circuitry of the prefrontal cortex in this autism model. Further studies should address the challenges to clarify particular electrophysiological correlates of the cellular alterations in order to better understand the behavioral dysfunctions

Avaliação comportamental e neuroquímica de ratos em dessincronização forçada: possíveis implicações para um modelo animal de oscilações no humor

Bipolar disorder has been growing in several countries. It is a disease with high mortality and has been responsible by the social isolation of the patients. Bipolar patients have alterations in circadian timing system, showing a phase shift in various physiological variables. There are several arguments demonstrating alterations in circadian rhythms may be part of the bipolar disorder pathophysiology. Given the necessity for further elucidation, the goal of this study was to validate the forced desynchronization protocol as an animal model for bipolar disorder. To do this, Wistar rats were submitted to a forced desynchronization protocol which consists in a symmetrical light dark cycle with 22h. Under this protocol, rats dissociate the locomotor activity rhythm into two components: one synchronized to the light / dark cycle with 22h, and another component with period longer than 24 hours following the animal endogenous period. These rhythms with different periods sometimes there is coincidence, which we named CAP (Coincidence Active Phase) and the opposite phase, non-coincidence, called NCAP (Non-Concidence Active Phase). The hypothesis is that in CAP animals present a mania-like behavior and animals in NCAP depressive-like behavior. We found some evidence described in detail throughout this thesis. In sum, the animals under forced desynchronization protocol were more stressed, showed an increase in stereotypic behaviors such as grooming and reduction in other behaviors such as risk assessment and vertical exploration when compared to the control group. The CAP animals showed increased locomotor activity, especially during the dark phase when compared to controls (rats under T24) and less depressive behavior in the forced swim test. The animals in NCAP showed a higher anxiety in elevated plus maze, but they don t have ahnedonia. The animals under dissociation have more labeled 5HT1A cells at the amygdala area, which appoint that they have more amygdala inhibition. Taking these data together, we could partially validated the forced desynchronization protocol as an animal model for mood oscillations

Efeito de ligantes do receptor NOP no modelo animal de mania induzido por metilfenidato

Bipolar disorder is a chronic psychopathology that reaches from 1 to 4% of the world population. This mood disorder is characterized by cyclical mood changes, in which an individual alternates between states of depression and mania. Mania is described in the literature as an abnormal state of exacerbation of humor, in which the subject presents an expansive, euphoric behavior, but with increased irritability, psychomotor agitation and a feeling of invincibility, which will contribute to risks exposure. The treatment of this psychopathology is complex and it is not effective in all cases, and it evokes many side effects. In this respect, the system of Nociceptin/Orphanin FQ (N/OFQ) can be studied as a possible therapeutic target for the treatment of bipolar disorder, due to its modulatory role on monoaminergic systems and on mood. This study aims to investigate the effect of NOP receptor ligands in an animal model of mania induced by methylphenidate. To this aim, locomotor activity was assessed in an open field, in mice treated with methylphenidate (10 mg/kg, sc, 15 min). Valproate (300 mg / kg, ip, 30 min), standard treatment of mania, prevented methylphenidate-induced hyperlocomotion. The acute treatment with the antagonist of NOP receptor UFP-101 (1-10 nmol, icv, 5 min) per se did not affect the spontaneous locomotion of mice, but it was able of attenuating hyperlocomotion induced by methylphenidate. The acute treatment with N/OFQ (1 and 0.1 nmol, icv, 5 min) did not alter the distance moved, but when tested at a dose of 1 ηmol, N/OFQ slightly reduced methylphenidate-induced hiperlocomotion. In conclusion, the administration of UFP-101 and N/OFQ produced antimanic-like actions. Furthermore, these data suggest that the system of N/OFQ performs a complex modulation of voluntary movement, and consequently on dopaminergic neurotransmission.