A wealth of evidence has suggested that psychological stress can precipitate or exacerbate many medical conditions, including psychiatric illnesses. One brain system that is thought to be very important for responses to stress, fear and anxiety is the central extended amygdala. This proposal is based on the assumption that knowledge of how a major output nucleus of the amygdala (the central nucleus, CEA) and a related brain region, the bed nucleus of the stria terminalis (BST) normally responds to psychological stress will ultimately help us to understand the etiology of some disorders influenced by stress. Because of the demonstrated role in fear and anxiety behaviors, a significant effort has previously been directed at demonstrating activation of the CEA. However, it has recently been shown that exposure to the psychological stress of novelty, loud noise or restraint results in a decrease (~50 percent) in amphetamine-induced c-fos mRNA expression in enkaphalin-containing neurons of the oval nucleus of the BST (BSTov) and lateral division of the CEA (CEAI), suggesting that psychological stress in fact inhibits these brain regions. Potentially, inhibition of these neurons, that are also GABAergic, would result in disinhibition of their efferent targets. These targets include the fusiform nucleus of the BST, the lateral parabrachial nucleus, and the medial CEA that collectively regulate several autonomic, endocrine, and behavioral responses that are altered by stress and anxiety. The experiments described in this application are designed to further characterize the effects of psychological stress on the BSTov and CEA. In Aim 1, potential changes in gene expression (immediate early genes, enkephalin, CRH, substance P or glutamic acid decarboxylase 65 and 67) that occur in the BSTov and CEA as a direct result of exposure to psychological stress will be assessed by semi-quantitative in situ hybridization. These changes could be used as an alternative independent measure in subsequent experiments. In addition, it will be determined if stress inhibition of the BSTov and CEAI generalizes to conditioned versus unconditioned stress and to corticotropin releasing hormone- (CRH) versus enkephalin-containing cells in these regions. Experiments in Aim 2 are designed to assess the neural circuitry involved in psychological stress effects on the BSTov and CEA. A combination of retrograde and anterograde tracing, dual immunohistochemistry, neurochemical lesions and glutamate injections will be used to determine if there is at least one brain region that projects to both the CEAI and the BSTov, that is activated by stress, and that is necessary and sufficient for the stress-induced gene expression changes in these brain regions. The potential role of GABA (y-amino butyric acid) in these stress-induced changes will also be assessed by determination of GABAergic inputs to the BSTov and CEAI, in vivo microdialysis for GABA during stress, and intracranial injection of GABAA and GABAC receptor antagonists into the BSTov and CEA prior to stress exposure. Ultimately, it is hoped that knowledge of the basic neural circuitry normally engaged following exposure to stress might help to identify some of the neural processes involved in the etiology of some psychiatric disorders.

R01MH067988

2005-01-01

2009-12-31