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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH073826-04
Application #
7545910
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Meinecke, Douglas L
Project Start
2006-01-01
Project End
2010-12-31
Budget Start
2009-01-01
Budget End
2010-12-31
Support Year
4
Fiscal Year
2009
Total Cost
$227,106
Indirect Cost
Name
University of Maryland Baltimore
Department
Psychiatry
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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Taylor, S B; Taylor, A R; Koenig, J I (2013) The interaction of disrupted type II neuregulin 1 and chronic adolescent stress on adult anxiety- and fear-related behaviors. Neuroscience 249:31-42
Markham, Julie A; Mullins, Sylvina E; Koenig, James I (2013) Periadolescent maturation of the prefrontal cortex is sex-specific and is disrupted by prenatal stress. J Comp Neurol 521:1828-43
Markham, Julie A; Koenig, James I (2011) Prenatal stress: role in psychotic and depressive diseases. Psychopharmacology (Berl) 214:89-106
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Taylor, Sara B; Markham, Julie A; Taylor, Adam R et al. (2011) Sex-specific neuroendocrine and behavioral phenotypes in hypomorphic Type II Neuregulin 1 rats. Behav Brain Res 224:223-32
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Tamashiro, Kellie L K; Terrillion, Chantelle E; Hyun, Jayson et al. (2009) Prenatal stress or high-fat diet increases susceptibility to diet-induced obesity in rat offspring. Diabetes 58:1116-25
Koenig, James I (2009) Corticotropin-releasing factor, serotonin, and sex: keys to the castle of depressive illness. Endocrinology 150:3440-2

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