Stress is a major determinant of onset and susceptibility to affective diseases, such as post-traumatic stress disorder (PTSD), anxiety disorders and depression. Chronic stress exposure leads to frank changes in glucocorticoid homeostasis, which in turn has major impact on emotional state and decision-making. Studies focused on defining brain mechanisms of stress-related disease have defined a link between physical/ behavioral manifestations of stress pathology and medial prefrontal cortex dysfunction. Importantly, chronic stress leads to hypofunction of prefrontal cortex circuits that mediate successful downstream processing of emotional information. In turn, reduced prefrontal output contributes to increased fear and anxiety seen in diseases such as PTSD. Using rodent stress models, studies during our last funding period indicate that loss of prefrontal function during chronic stress may be linked to enhanced inhibition of prefrontal projection neurons. Functional and morphological studies further suggest that reduced prefrontal output is associated with loss of prefrontal glucocorticoid receptor signaling, impairing the ability of the prefrontal cortex to respond appropriately in the context of stress. This proposal seeks to understand the mechanism underlying stress- induced prefrontal dysfunction, testing the overarching hypothesis that chronic stress attenuates glucocorticoid-mediated inhibition of cortical interneurons, essentially silencing prefrontal cortex projection neurons that normally promote stress adaptation and behavioral flexibility.
Aim 1 uses lentiviral overexpression and cell type-specific knock-down strategies to test the requirement of the prefrontal glucocorticoid receptor for appropriate behavioral and physiologic responses to chronic stress. Given the lasting impact of stress on emotional behavior in humans, we will assess both immediate and persistent effects of chronic stress.
Aim 2 uses physiological and anatomical methods to assess mechanisms whereby chronic stress enhances inhibitory drive onto primary prefrontal output neuron. Finally, Aim 3 uses an anterograde lentiviral tracing strategy to assess the impact of stress on down-stream targets of prefrontal cortex neurons in the amygdala. Given the link between the prefrontal cortex and stress-related disease, understanding the mechanism of stress-induced prefrontal dysfunction is of major significance for future treatment options, either invasive (deep brain stimulation, gene therapy) or pharmacological (GR targeting).

Public Health Relevance

Stress-related diseases, such as post-traumatic stress disorder (PTSD) and depression, are debilitating mental illnesses that affect a substantial proportion of the population and have relatively few effective treatment options. Recent studies suggest that cognitive and physiologic deficits observed in stress-related disorders are accompanied by 'silencing'of the prefrontal cortex, a brain structure critical for mood regulation behavioral flexibility, and top-down control of amygdala responsiveness (a region critically involved in fear). This proposal uses rodent models to examine the functional and anatomical mechanisms underlying stress-induced cortical silencing, focusing on the role of stress hormone signaling in control of prefrontal function and downstream modulation of the amygdala. Data obtained will provide novel information on brain circuits and mechanisms mediating stress effects on emotion, which will be of considerable value in the design of interventions and therapies designed to attenuate the public health impact of emotional pathologies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH049698-21A1
Application #
8785984
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Simmons, Janine M
Project Start
1992-09-15
Project End
2019-06-30
Budget Start
2014-08-15
Budget End
2015-07-31
Support Year
21
Fiscal Year
2014
Total Cost
$498,385
Indirect Cost
$183,864
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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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

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