Major depressive disorder is accompanied by dysfunctional cognitive and neuroendocrine processing of stressful information. The neurocircuitry underlying aberrant stress processing remains to be elucidated. Human imaging data and rodent stress studies suggest that limbic cortical regions are well-positioned to mediate hypothalamic-pituitary-adrenocortical (HPA) axis pathology seen in depression. The current proposal uses a functional/anatomical approach to test the hypothesis that limbic cortical regions, including the prelimbic and infralimbic cortices, use separate yet complementary mechanisms to integrate psychological and physiological stimuli into appropriate stress responses. The neuroendocrine and mood changes seen in depression likely reflect a failure of these cortical regions to appropriately interpret relevant stressful stimuli. This hypothesis will be tested in four Specific Aims.
Aim 1 will use anatomical approaches to delineate monosynaptic and multisynaptic neural pathways connecting limbic cortices with hypothalamic stress effectors.
Aim 2 will use neurocircuit targeting approaches to test the necessity and sufficiency of defined limbic cortical subregions in inhibiting responses to psychological vs. physiological stressors.
Aim 3 tests the involvement of specific limbic cortical-hypothalamic and limbic cortical-hippocampal circuits in mediating responses to stress, using a targeted intervention design. Finally, Aim 4 tests for interactions between limbic cortices and other limbic stress-regulatory regions, to determine whether limbic stress integration involves convergent projections or separate ?labeled lines? to the hypothalamus. These studies are expected to identify limbic cortical circuits and mechanisms involved in stress integration, and thereby provide clear neuroanatomical targets for development of improved behavioral/pharmacological interventions for depression and other stress-related disease states.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH049698-19
Application #
8019075
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Vicentic, Aleksandra
Project Start
1992-09-15
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
19
Fiscal Year
2011
Total Cost
$339,976
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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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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