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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH069860-02
Application #
6830223
Study Section
Special Emphasis Panel (ZRG1-IFCN-4 (04))
Program Officer
Vicentic, Aleksandra
Project Start
2003-12-01
Project End
2008-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
2
Fiscal Year
2005
Total Cost
$340,186
Indirect Cost
Name
University of Cincinnati
Department
Psychiatry
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
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Herman, James P (2018) Regulation of Hypothalamo-Pituitary-Adrenocortical Responses to Stressors by the Nucleus of the Solitary Tract/Dorsal Vagal Complex. Cell Mol Neurobiol 38:25-35
Ghosal, Sriparna; Packard, Amy E B; Mahbod, Parinaz et al. (2017) Disruption of Glucagon-Like Peptide 1 Signaling in Sim1 Neurons Reduces Physiological and Behavioral Reactivity to Acute and Chronic Stress. J Neurosci 37:184-193
Smith, Brittany L; Lyons, Carey E; Correa, Fernanda Guilhaume et al. (2017) Behavioral and physiological consequences of enrichment loss in rats. Psychoneuroendocrinology 77:37-46
Myers, Brent; McKlveen, Jessica M; Morano, Rachel et al. (2017) Vesicular Glutamate Transporter 1 Knockdown in Infralimbic Prefrontal Cortex Augments Neuroendocrine Responses to Chronic Stress in Male Rats. Endocrinology 158:3579-3591
Myers, Brent; Scheimann, Jessie R; Franco-Villanueva, Ana et al. (2017) Ascending mechanisms of stress integration: Implications for brainstem regulation of neuroendocrine and behavioral stress responses. Neurosci Biobehav Rev 74:366-375
Wulsin, Aynara C; Wick-Carlson, Dayna; Packard, Benjamin A et al. (2016) Adolescent chronic stress causes hypothalamo-pituitary-adrenocortical hypo-responsiveness and depression-like behavior in adult female rats. Psychoneuroendocrinology 65:109-17
McKlveen, Jessica M; Morano, Rachel L; Fitzgerald, Maureen et al. (2016) Chronic Stress Increases Prefrontal Inhibition: A Mechanism for Stress-Induced Prefrontal Dysfunction. Biol Psychiatry 80:754-764
Myers, Brent; Carvalho-Netto, Eduardo; Wick-Carlson, Dayna et al. (2016) GABAergic Signaling within a Limbic-Hypothalamic Circuit Integrates Social and Anxiety-Like Behavior with Stress Reactivity. Neuropsychopharmacology 41:1530-9
Herman, James P; McKlveen, Jessica M; Ghosal, Sriparna et al. (2016) Regulation of the Hypothalamic-Pituitary-Adrenocortical Stress Response. Compr Physiol 6:603-21

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