Stress has been implicated in diverse psychiatric diseases including post-traumatic stress disorder, depression, anxiety and substance abuse. One link between stress and these psychiatric disorders is corticotropin-releasing factor (CRF), the neuropeptide that orchestrates the stress response. In response to stress CRF regulates activity of the dorsal raphe (DR)-serotonin (5-HT) system, a system that has been implicated in stress-related psychiatric disorders. CRF has opposing inhibitory and excitatory effects on DR-5-HT neurons through CRF1 and CRF2 receptors, respectively. Low levels of CRF such as those released during acute stress initiate CRF1-mediated inhibition of 5-HT neuronal activity and this is associated with the promotion of escape from shock and active coping in response to swim stress. A history of stress causes a cellular redistribution of CRF receptors in the DR such that CRF2 is recruited to the plasma membrane. This switches regulation of the DR-5-HT system from CRF1-mediated inhibition to CRF2-mediated excitation and promotes learned helplessness and immobility. A working hypothesis of this research is that stress-induced redistribution of CRF receptors in DR neurons is a cellular mechanism that underlies stress-induced impairments in cognition and social behavior and that this is determined by sex and coping style. Stress-related psychiatric disorders are more prevalent in females, but our knowledge of CRF regulation of DR-5-HT function is based solely on studies using male rats. Therefore, both males and females will be used in these studies.
AIM 1 will characterize CRF effects on female DR-5-HT neuronal activity and determine whether the stress-induced CRF receptor redistribution that occurs in male DR also occurs in females.
Aim 2 will use resident-intruder stress as a social stress model that has a limited duration and causes CRF receptor redistribution in a subpopulation of vulnerable rats. Using this stressor, the role of CRF receptor redistribution in DR neurons in stress-induced cognitive and social impairments will be assessed in male and female rats.
Aim 3 will use male and female CRF-overexpressing mice as a genetic model of chronic stress and determine whether this condition causes CRF receptor redistribution in DR neurons that translates to changes in forebrain 5-HT and effects on behavior and cognitive function. Our past work characterized regulation of the male rat DR-5-HT system by CRF1 and CRF2 receptors and identified stress-induced CRF1/CRF2 redistribution as a cellular mechanism by which stress can impact this system to produce maladaptive psychopathology. Here we address the role of sex differences in this cellular mechanism, its impact on cognitive processes that are dysfunctional in mood disorders and the potential for genetic elevations of CRF, as have been proposed to occur in stress-related psychiatric disorders, to produce the same cellular and behavioral consequences.

Public Health Relevance

This research uses rodent models of stress to examine how the cellular process of protein trafficking in response to repeated or chronic stress is involved i maladaptive cognition or social behavior. An important component of this research is to determine whether there are sex differences in cellular, behavioral or cognitive responses to stress. The results will advance our knowledge of the causes of stress-related psychiatric diseases and guide future therapies for these diseases.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
High Priority, Short Term Project Award (R56)
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Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
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Winsky, Lois M
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Children's Hospital of Philadelphia
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