Though most individuals are capable of maintaining psychological integrity in the face of stress, stress-experiences are well known for instigating th onset and relapse of severe neuropsychiatric disorders including MDD and PTSD. Social stress is common to practically all mammalian species, and chronic subordination stress in rodents is most often followed by the expression of a long-lasting behavioral syndrome that includes social avoidance, anhedonia, impaired coping responses to other environmental stressors, and anxiety-like behaviors. Within the inbred strain of mouse C57BL/6J, the prominently expressed stress-induced syndrome does not occur in all individuals subjected to chronic social defeat stress, thereby allowing for measurements of resiliency. Presumably, these results suggest that individual differences across mice mediate the susceptibility or resistance to the deleterious effects of chronic stress. Nevertheless, unequivocal validation of this hypothesis is lacking since the majority of studies aimed at investigating susceptibility to chronic stress are based on experiments performed in mice that have been previously exposed to chronic stress, or mice that are subjected to molecular manipulations prior to stress exposure (ultimately altering normal brain function).Here were propose to use multi-circuit in vivo recording in conjunction with circuit selective modulation using designer receptors exclusively activated by designer drugs (DREADDs) to characterize the circuit based mechanisms that mediate resistance to stress in C57BL/6J mice. The rationale that underlies the proposed research is that variations in cortical-amygdala circuit function will be associated with stress responses, and that direct modulation of this circuit will alter stress resistance across mice. This strategy will provide an unprecedented circuit level of understanding of how stress exposure ultimately alters activity across neural circuits that regulate fear and reward processing and reveal new circuit based targets for therapeutic intervention for mood and anxiety disorders.

Public Health Relevance

Stress-experiences are well known for instigating the onset and relapse of severe neuropsychiatric disorders including major depressive disorder (MDD) and post traumatic stress disorder (PTSD). Here we intend to characterize the brain changes underlying the behavioral changes in a well established mouse model of MDD/PTSD symptoms using in vivo neurophysiological recording techniques. The resulting insights will lay the groundwork for a circuit-level understanding of behavioral pathologies observed in MDD and PTSD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH099192-02
Application #
8586562
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Simmons, Janine M
Project Start
2012-12-01
Project End
2017-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
2
Fiscal Year
2014
Total Cost
$353,250
Indirect Cost
$128,250
Name
Duke University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Kumar, Sunil; Hultman, Rainbo; Hughes, Dalton et al. (2014) Prefrontal cortex reactivity underlies trait vulnerability to chronic social defeat stress. Nat Commun 5:4537
Dzirasa, Kafui; Kumar, Sunil; Sachs, Benjamin D et al. (2013) Cortical-amygdalar circuit dysfunction in a genetic mouse model of serotonin deficiency. J Neurosci 33:4505-13