Accumulating evidence indicates that stress can produce pathological changes suspected to play a role in the etiology of a number of psychiatric disorders. This proposal is based on the assumption that a better understanding of the brain systems mediating processive stressors (emotional, psychological situations) might help to identify some of the neural processes involved in the etiology of certain psychiatric disorders. The proposed studies employ animal models of processive stress to begin to trace and identify the neural systems that mediate the activation of a specific stress-responsive system,the hypothalamo-pituitary-adrenocortical (HPA) axis, that ultimately results in the release of the stress-related hormones glucocorticoids. The first aim is designed to assess which brain regions are specifically activated by exposure to two different processive stressors: audiogenic and predator odor stress. The usefulness of both these stimuli rests on the knowledge of their primary sensory neural pathways and the ability to employ intensities and concentrations that can be varied from non-stressful to stressful levels. This last characteristic can be exploited to tease apart the neural machinery that simply senses the stimuli from the brain areas specifically recruited when these stimuli reach stressful levels. With the help of this distinguishing feature, semi-quantitative in situ hybridization histochemistry will be used to detect the induction of the immediate-early gene c-fos, a marker of cellular activation, to determine brain regions specifically recruited by stressful levels of noise and predator odor. The second aim will determine if any of the brain regions specifically activated by the stressful component of noise and predator odor project directly to the "motor" neurons (paraventricular nucleus of the hypothalamus) of the HPA axis, using a combination of tract-tracing and Fos immunohistochemistry, in response to loud noise and predator odor. The functional relevance of the recruited regions projecting directly to the paraventricular hypothalamic nucleus will then be tested by ablating the cell bodies of these projecting neurons and determining if audiogenic and predator odor stress can still trigger an HPA axis response. The basic neurochemical phenotype of the cellular groups that project directly to the hypothalamic paraventricular nucleus and are necessary for HPA axis activation in response to processive stress will then be tested for the presence of the neurotransmitters GABA or glutamate, using a dual in situ hybridization technique.

R01MH065327

2002-06-01

2008-03-31