Neural Substrates /Socioemotional Disturbances /Develop.

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DESCRIPTION (provided by applicant): The goal of this proposal is to understand how early brain insults influence the short-term and long-term development of cognitive and socioemotional functions. This understanding is vital for the approach to neurodevelopmental disorders such as autism, and at the same time is relevant to an entire spectrum of behavioral disorders that emerge as a result of a host of neurological disturbances in children (epilepsy, cerebral palsy, cortical dysgenesis, etc.). The analysis of human cases and experiments in animals suggest the hypothesis that dysfunction in medial temporal lobes, and the amygdala in particular, is an etiological factor in autism. Therefore the goal of our proposal is to investigate the role of the amygdala and its specific subdivisions for socioemotional behavior and to identify the critical developmental periods and neural triggers for developmental abnormalities in an animal model of autism. The first Specific Aim concentrates on the effects of pharmacologically-induced imbalances in neurotransmission in the amygdala on social interactions in infant animals. Drugs known to either block or enhance GABA-ergic or glutamatergic transmission will be focally infused into specific subdivisions of the amygdala and social interactions in the experimental animals will be observed. The second Specific Aim is to compare the effects of drugs (as obtained in Aim I) with the effects of discrete lesions of subregions of the amygdala, when damaged by axon-sparing excitotoxic lesions, in infant monkeys. The third aim will evaluate the effects of early prolonged seizures, known to disrupt the function of the amygdala and its projection network, on the observed behavioral categories. This aim is directed to the understanding why certain seizure disorders in infants (e.g., infantile spasms) give rise to autism. An important facet of these studies will be the analysis of the extent to which socioemotional disturbances produced by various anatomically site-specific insults are accompanied by impairment in cognitive functions. Well standardized procedures will be used to evaluate various components of socioemotional interactions of infant and juvenile animals in dyads and to assess their emotional reactions to positive and negative stimuli. Cognitive tasks will include concurrent visual objects discrimination and auditory-visual crossmodal associations and memory. The results of the proposed studies will identify specific amygdaloid nuclei critical for regulation of social and emotional interactions and determine the critical stage(s) in development during which amygdala dysfunction (by lesions, drugs or seizures) can lead to long-term socioemotional abnormalities. This information will provide a rationale basis for the design of therapeutic interventions directed at correcting the underlying biological dysfunctions that give rise to autism and related socioemotional disorders.