Estabelecimento de modelos de déficit de interação social em zebrafish (Danio rerio) : avaliação de parâmetros neuroquímicos, moleculares e comportamentais

Abstract

Several psychiatric and neurological diseases are characterized by impairments in social function, such as autism spectrum disorders (ASD) and schizophrenia (SCZ). In this study, we conducted a behavioral screening at different times of zebrafish development at 6, 30, 70 and 120 dpf (postfertilization days) to establish a social interaction deficit model induced by valproic acid (VPA) at 48 μM concentration to investigate social behavior, locomotion, aggression and anxiety. To analyze the social behavior of each fish was placed in an experimental tank. On one side of the experimental tank, an empty fish tank was placed; on the other side, a tank of identical size held 15 zebrafish, which were designed the “stimulus fish”. We quantify the time of the experimental fish from the side of the tank "fish stimulus" in relation to empty tank. The locomotion of the animals was assessed by evaluating the following parameters: distance traveled, average speed, number of crossings and the time spent in each tank position (bottom vs. upper levels) was considered an index of anxiety. To analyze the aggression the animals were individually placed in an experimental tank. A mirror was placed at the side of the tank at an angle of 22.5° to the backwall of the tank so that the left vertical edge of the mirror touched the side of the tank and the right edge was further away.Thus, when the experimental fish swam to the left side of the tank, their mirror image appeared closer to them. indicating preference for the opponent.Our results showed that exposure to VPA induced changes on locomotor activity and anxiety in different periods of development in zebrafish. In addition, VPA-treated animals presented a deficit in social interaction to 70 dpf and 120 dpf. Exposure to VPA did not affect aggression in the adult stage after 70 dpf and 120 dpf. This study also investigated the purinergic signaling in a model of embryonic exposure to VPA, which induced deficit in social interaction in adult zebrafish. This study demonstrates the first evidence that exposure to VPA in embryonic zebrafish in 120 dpf can modulate the hydrolysis of nucleotide and nucleoside and adenosine deamination in zebrafish brain membranes. In addition, we analyzed the effects of oxytocin, the oxytocin receptor agonist (carbetocin) and oxytocin receptor antagonist (L-368,899) on the reversal of behavioral effects induced by MK-801 in zebrafish regarding behavior social, such as, changes in social interaction and aggression. These results support the role of NMDA receptors and oxytocinergic system in the regulation of social behavior and aggression. This study can contribute to a better understanding of social behavior and purinergic signaling on the main neuropsychiatric disorders that affect social behavior; autism and schizophrenia, as well as to present social interaction deficit models induced by embryological exposure to VPA and exposure to MK-801 in adult zebrafish. These findings reinforce the involvement of oxytocinergic system and its pharmacological potential on diseases that affect social behavior.