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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Simmons, Janine M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Cincinnati
Schools of Medicine
United States
Zip Code
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