Oxytocin (OT) and vasopressin production are concentrated in the hypothalamic paraventricular and supraoptic nuclei. Fibers emanating from these cells innervate limbic brain areas that are involved in the control of social behavior. Several human diseases, like schizophrenia and autism, have prominent social manifestations that adversely affect the individuals suffering from these diseases. Approximately one-third of schizophrenic patients are afflicted with the negative symptoms of schizophrenia (e.g. asociality, anhedonia, avolition of speech), which are not treated by the currently available antipsychotic medications. The biological basis of these symptoms is unknown. My laboratory has developed a novel animal model that exhibits many aspects of the schizophrenia phenotype including compromised social drive and function. In this application, we propose to use this animal preparation to investigate the etiopathophysiology of the social incompetence exhibited by these animals and its relationship to schizophrenia. Our preliminary data point to an alteration in the brain OT system as the precipitating factor for the social dysfunction of prenatally stressed male rats. Therefore, our overarching hypothesis is that prenatal stress exposure compromises the development of the brain OT neurons and the dysfunction of the oxytocinergic neurons generate the social dysfunction present in the prenatally stressed rats, and potentially in schizophrenic patients with negative symptoms. To test this hypothesis the following specific aims are proposed.
Specific Aim 1. Examine the role of maternal factors, like maternal behavior and glucocorticoids, in the prenatal stress-induced changes in adult male rat social behavior, paraventricular nucleus OT expression and OT receptor binding in amygdala, lateral septum and bed nucleus of the stria terminalis.
Specific Aim 2. Examine the developmental timing of prenatal stress-induced changes in the brain OT system and social behavior.
Specific Aim 3. Examine whether prenatal stress alters the expression of genes that regulate OT components in the developing and adult rat brain.
Specific Aim 4. OT reverses the social deficit in prenatally stressed rats when injected into the amygdala. Examine the role of OT receptors in other brain regions to normalize prenatal stress-induced alterations in social behavior.
Specific Aim 5. Examine the state of the oxytocinergic system in human schizophrenic hypothalamic and amygdalar tissues. Together these studies will provide new information about a potential etiological agent for schizophrenia; a mechanism by which a schizophrenia-related behavioral abnormality arises and a putative treatment to restore normal social function to affected animals, and potentially human schizophrenics, also.
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