ABSTRACT
The sensorimotor gating is a nervous system function that modulates the acoustic startle response (ASR). Prepulse inhibition (PPI) phenomenon is an operational measure of sensorimotor gating, defined as the reduction of ASR when a high intensity sound (pulse) is preceded in milliseconds by a weaker stimulus (prepulse). Brainstem nuclei are associated with the mediation of ASR and PPI, whereas cortical and subcortical regions are associated with their modulation. However, it is still unclear how the modulatory units can influence PPI. In the present work, we developed a computational model of a neural circuit involved in the mediation (brainstem units) and modulation (cortical and subcortical units) of ASR and PPI. The activities of all units were modeled by the leaky-integrator formalism for neural population. The model reproduces basic features of PPI observed in experiments, such as the effects of changes in interstimulus interval, prepulse intensity, and habituation of ASR. The simulation of GABAergic and dopaminergic drugs impaired PPI by their effects over subcortical units activity. The results show that subcortical units constitute a central hub for PPI modulation. The presented computational model offers a valuable tool to investigate the neurobiology associated with disorder-related impairments in PPI.
ABSTRACT
The disruption of neurodevelopment is a hypothesis for the emergence of schizophrenia. Some evidence supports the hypothesis that a redox imbalance could account for the developmental impairments associated with schizophrenia. Additionally, there is a deficit in glutathione (GSH), a main antioxidant, in this disorder. The injection of metilazoximetanol acetate (MAM) on the 17th day of gestation in Wistar rats recapitulates the neurodevelopmental and oxidative stress hypothesis of schizophrenia. The offspring of rats exposed to MAM treatment present in early adulthood behavioral and neurochemical deficits consistent with those seen in schizophrenia. The present study investigated if the acute and chronic (250 mg/kg) treatment during adulthood with N-acetyl-L-cysteine (NAC), a GSH precursor, can revert the behavioral deficits [hyperlocomotion, prepulse inhibition (PPI), and social interaction (SI)] in MAM rats and if the NAC-chronic-effects could be canceled by L-arginine (250 mg/kg, i.p, for 5 days), nitric oxide precursor. Analyses of markers involved in the inflammatory response, such as astrocytes (glial fibrillary acid protein, GFAP) and microglia (binding adapter molecule 1, Iba1), and parvalbumin (PV) positive GABAergic, were conducted in the prefrontal cortex [PFC, medial orbital cortex (MO) and prelimbic cortex (PrL)] and dorsal and ventral hippocampus [CA1, CA2, CA3, and dentate gyrus (DG)] in rats under chronic treatment with NAC. MAM rats showed decreased time of SI and increased locomotion, and both acute and chronic NAC treatments were able to recover these behavioral deficits. L-arginine blocked NAC behavioral effects. MAM rats presented increases in GFAP density at PFC and Iba1 at PFC and CA1. NAC increased the density of Iba1 cells at PFC and of PV cells at MO and CA1 of the ventral hippocampus. The results indicate that NAC recovered the behavioral deficits observed in MAM rats through a mechanism involving nitric oxide. Our data suggest an ongoing inflammatory process in MAM rats and support a potential antipsychotic effect of NAC.
