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 lesion and stimulation 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 combined lesion-stimulation 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. The medial prefrontal cortex is implicated in stress-related diseases, such as depression and PTSD. This proposal is designed to delineate neurocircuit mechanisms of stress control by this region. The project will shed new light on the role of the prefrontal cortex in stress processing, and identify anatomical and neurochemical targets for intervention in stress-related pathologies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH049698-20
Application #
8217160
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Simmons, Janine M
Project Start
1992-09-15
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
20
Fiscal Year
2012
Total Cost
$339,232
Indirect Cost
$116,482
Name
University of Cincinnati
Department
Psychiatry
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
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 57:263-70
Myers, Brent; Scheimann, Jessie R; Franco-Villanueva, Ana et al. (2016) Ascending mechanisms of stress integration: Implications for brainstem regulation of neuroendocrine and behavioral stress responses. Neurosci Biobehav Rev :
Herman, James P; McKlveen, Jessica M; Ghosal, Sriparna et al. (2016) Regulation of the Hypothalamic-Pituitary-Adrenocortical Stress Response. Compr Physiol 6:603-21
Ulrich-Lai, Yvonne M; Christiansen, Anne M; Wang, Xia et al. (2016) Statistical modeling implicates neuroanatomical circuit mediating stress relief by 'comfort' food. Brain Struct Funct 221:3141-56
Wulsin, Aynara C; Solomon, Matia B; Privitera, Michael D et al. (2016) Hypothalamic-pituitary-adrenocortical axis dysfunction in epilepsy. Physiol Behav 166:22-31
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
Makinson, Ryan; Lundgren, Kerstin H; Seroogy, Kim B et al. (2015) Chronic social subordination stress modulates glutamic acid decarboxylase (GAD) 67 mRNA expression in central stress circuits. Physiol Behav 146:7-15
McKlveen, J M; Myers, B; Herman, J P (2015) The medial prefrontal cortex: coordinator of autonomic, neuroendocrine and behavioural responses to stress. J Neuroendocrinol 27:446-56

Showing the most recent 10 out of 44 publications