Inappropriate processing of psychological stress is a major causal or complicating factor in affective disorders. Stress dysfunction takes the form of behavioral hyperreactivity and glucocorticoid hypersecretion, mediated by amygdalar and hypothalamic effector circuits, respectively. Previous work has suggested that psychogenic stressors are predominantly processed in the forebrain, relayed to the effector neurons by descending corticolimbic inputs. Our group has recent findings that challenge this view, and thereby offer a potential new approach to treatment of stress-related disorders. Our results indicate that glucagon-like peptide-1 (GLP-I), a neuropeptide synthesized only in the brainstem, plays a major role in promoting both neuroendocrine and behavioral responses to psychogenic stressors. This has led us to hypothesize that the brainstem GLP-1 system may comprise a general coordinator of stress responses. To test this hypothesis, we propose four Specific Aims.
In Aim 1, we will perform anatomical studies to evaluate the hypothesis that the GLP- 1 system selectively targets corticotropin-releasing hormone effector neurons in hypothalamic and amygdalar circuits, and determine whether GLP-1 neurons have collateral projections to both regions.
Aim 2 will test the hypothesis that GLP-1 neurons are activated by psychogenic, interoceptive and conditioned stressors, and thus occupy a central role in generalized stress integration. Specific experiments will assess Fos expression in GLP-1 neurons as a measure of neuronal activation, address potential signaling pathways affecting GLP-1 neuronal activation, and demonstrate stress effects on transcription of the preproglucagon gene expression.
Aim 3 will test the hypothesis that GLP-1 systems are persistently activated by chronic stress or glucocorticoids, providing a mechanism whereby prolonged stimulation can promote inappropriate behavioral and neuroendocrine responses. Finally, Aim 4 will test whether GLP-1 systems are necessary and sufficient for chronic stress-induced pathologies, testing the ability of exogenous GLP- 1 or a GLP- 1 receptor antagonist to cause or block, respectively, behavioral and endocrine changes characteristic of chronic stress. The results of these studies are expected to establish a major role for GLP-1 systems in stress regulation, and identify the GLP-1 system as a target for future therapeutic interventions.
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