Stress-related diseases are accompanied by glucocorticoid and cardiovascular dyshomeostasis. In particular, glucocorticoid hypersecretion in depression is linked with both ongoing mood symptoms and with long-term physiological dysfunctions, including osteoporosis and visceral obesity. Decreased heart rate variability is associated with negative emotions in depressed patients, and contributes to the high incidence of cardiovascular pathology and mortality associated with the disorder. Thus, physiological consequences of depression contribute to both psychiatric symptoms and co-morbid disease processes. Neural and systemic effects of depression are linked to inappropriate processing of stressful information in the brain. The current proposal uses rodent chronic stress models to address mechanisms that control physiological adaptation and dysfunction following long-term stress. Our proposal tests the novel hypothesis that distinct brainstem neurons act as critical integrators of both stress habituation and sensitization, and are thereby responsible for adaptive as well as maladaptive hormonal and autonomic responses.
Aim 1 will determine whether noradrenergic neurons of the nucleus of the solitary tract (NTS) are responsible for driving HPA axis hyperactivity and autonomic dysfunction following chronic stress.
Aim 2 tests the hypothesis that neuroendocrine and autonomic stress pathologies are mediated through inappropriate drive of NTS noradrenergic neurons by forebrain stress-recruited pathways.
Aim 3 uses a NTS gene knockdown approach (lentiviral vectors) to examine the role of NTS glucagon-like peptide 1(GLP-1) neurons in long-term stress adaptation.
Aim 4 is designed to elucidate the role of NTS glucocorticoid receptor-mediated feedback in the control of stress adaptation and pathology. Understanding the role of the NTS in stress adaptation will add new insight into potential circuit pathology in affective disease, and provide novel molecular targets (GLP-1, brainstem glucocorticoid receptors) for development of therapeutic intervention strategies.

Public Health Relevance

Depression is accompanied by major disruption of homeostatic mechanisms, including glucocorticoid hypersecretion and cardiovascular dysfunction. Importantly, physiological pathologies are involved in generation of mood symptoms, indicating a tight linkage between systemic and neural aspects of depression. This proposal seeks to identify novel neural mechanisms responsible for generation of glucocorticoid and cardiovascular dysfunction in a rat chronic stress model of depression. Our studies are expected to provide preclinical data regarding new molecular targets for promoting stress resistance and adaptation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH069860-08
Application #
8270608
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Simmons, Janine M
Project Start
2003-12-01
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
8
Fiscal Year
2012
Total Cost
$353,040
Indirect Cost
$128,174
Name
University of Cincinnati
Department
Psychiatry
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
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
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
Smith, Brittany L; Morano, Rachel L; Ulrich-Lai, Yvonne M et al. (2017) Adolescent environmental enrichment prevents behavioral and physiological sequelae of adolescent chronic stress in female (but not male) rats. Stress :1-10
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; 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
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
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
Smith, Brittany L; Schmeltzer, Sarah N; Packard, Benjamin A et al. (2016) Divergent effects of repeated restraint versus chronic variable stress on prefrontal cortical immune status after LPS injection. Brain Behav Immun 57:263-270

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