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; Bundzikova-Osacka, Jana; Dolgas, C Mark et al. (2014) Glucocorticoid receptors in the nucleus of the solitary tract (NTS) decrease endocrine and behavioral stress responses. Psychoneuroendocrinology 45:142-53
Flak, Jonathan N; Myers, Brent; Solomon, Matia B et al. (2014) Role of paraventricular nucleus-projecting norepinephrine/epinephrine neurons in acute and chronic stress. Eur J Neurosci 39:1903-11
Ryan, Karen K; Mul, Joram D; Clemmensen, Christoffer et al. (2014) Loss of melanocortin-4 receptor function attenuates HPA responses to psychological stress. Psychoneuroendocrinology 42:98-105
Myers, Brent; McKlveen, Jessica M; Herman, James P (2014) Glucocorticoid actions on synapses, circuits, and behavior: implications for the energetics of stress. Front Neuroendocrinol 35:180-96
Uchoa, E T; Aguilera, G; Herman, J P et al. (2014) Novel aspects of glucocorticoid actions. J Neuroendocrinol 26:557-72
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Myers, Brent; Mark Dolgas, C; Kasckow, John et al. (2014) Central stress-integrative circuits: forebrain glutamatergic and GABAergic projections to the dorsomedial hypothalamus, medial preoptic area, and bed nucleus of the stria terminalis. Brain Struct Funct 219:1287-303
Grayson, B E; Fitzgerald, M F; Hakala-Finch, A P et al. (2014) Improvements in hippocampal-dependent memory and microglial infiltration with calorie restriction and gastric bypass surgery, but not with vertical sleeve gastrectomy. Int J Obes (Lond) 38:349-56
Ressler, Ilana B; Grayson, Bernadette E; Seeley, Randy J (2014) Metabolic, behavioral, and reproductive effects of vertical sleeve gastrectomy in an obese rat model of polycystic ovary syndrome. Obes Surg 24:866-76
Kopp, Brittany L; Wick, Dayna; Herman, James P (2013) Differential effects of homotypic vs. heterotypic chronic stress regimens on microglial activation in the prefrontal cortex. Physiol Behav 122:246-52

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