Stress is a major determinant of vulnerability to debilitating psychiatric disorders including, depression, anxiety and substance abuse. The guiding goal of this research is to determine how neuromediators of the stress response interact with neural systems involved in emotion and behavior to produce mental and/or behavioral pathology. Towards this goal, we identified a critical link between stress and affective disorders by demonstrating that corticotropin-releasing factor (CRF), the neuropeptide that orchestrates the stress response, regulates activity of the dorsal raphe (DR)-serotonin (5-HT) system, a neurotransmitter system implicated in psychiatric disorders. Moreover, it was demonstrated that a history of stress changes the nature of CRF regulation of the DR-5-HT system from inhibition to excitation and that this is associated with a shift from active to passive coping behavior. Because passive behavior and inability to make decisions are characteristic and debilitating features of depression, understanding the mechanism of this stress-induced adaptation, the specific conditions that produce it and its sensitivity to pharmacological manipulation will advance our understanding of the pathophysiology of depression and our ability to design appropriate therapeutic strategies. This proposal for a competing renewal integrates diverse technical approaches (PCR, functional neuroanatomy, neurophysiology, microdialysis and behavior) and levels of analyses to achieve the following Specific Aims: 1) Identify molecular and cellular mechanisms underlying stress-induced changes in CRF regulation of the DR-5-HT system that promote a shift from active to passive behavior;2) Determine whether certain social stressors (e.g., neonatal maternal separation or adult social stress) produce a shift in CRF regulation of the DR and whether this is responsible for depressive-like behavior in these models;and 3) Determine whether the stress-induced adaptations can be reversed by classical or novel antidepressant agents and the mechanisms by which these agents do this. The manner in which individuals respond to stress is a major factor in determining physical and mental health. The proposed studies will advance our knowledge of 1) the biological determinants of different coping styles, 2) mechanisms by which stress results in the debilitating course of depression and 3) how this can be manipulated by pharmacological agents and thereby guide development of novel antidepressants.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH058250-15
Application #
8098697
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Winsky, Lois M
Project Start
1998-12-01
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
15
Fiscal Year
2011
Total Cost
$517,131
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Hwa, Lara S; Shimamoto, Akiko; Kayyali, Tala et al. (2016) Dissociation of ?-opioid receptor and CRF-R1 antagonist effects on escalated ethanol consumption and mPFC serotonin in C57BL/6J mice. Addict Biol 21:111-24
Wood, Susan K; Wood, Christopher S; Lombard, Calliandra M et al. (2015) Inflammatory Factors Mediate Vulnerability to a Social Stress-Induced Depressive-like Phenotype in Passive Coping Rats. Biol Psychiatry 78:38-48
Snyder, Kevin P; Hill-Smith, Tiffany E; Lucki, Irwin et al. (2015) Corticotropin-releasing Factor in the Rat Dorsal Raphe Nucleus Promotes Different Forms of Behavioral Flexibility Depending on Social Stress History. Neuropsychopharmacology 40:2517-25
Wood, Susan K; Zhang, Xiao-Yan; Reyes, Beverly A S et al. (2013) Cellular adaptations of dorsal raphe serotonin neurons associated with the development of active coping in response to social stress. Biol Psychiatry 73:1087-94
Wood, Susan K; McFadden, Kile V; Grigoriadis, Dimitri et al. (2012) Depressive and cardiovascular disease comorbidity in a rat model of social stress: a putative role for corticotropin-releasing factor. Psychopharmacology (Berl) 222:325-36
Bingham, Brian; McFadden, Kile; Zhang, Xiaoyan et al. (2011) Early adolescence as a critical window during which social stress distinctly alters behavior and brain norepinephrine activity. Neuropsychopharmacology 36:896-909
Waselus, Maria; Valentino, Rita J; Van Bockstaele, Elisabeth J (2011) Collateralized dorsal raphe nucleus projections: a mechanism for the integration of diverse functions during stress. J Chem Neuroanat 41:266-80
Nazzaro, Cristiano; Barbieri, Mario; Varani, Katia et al. (2010) Swim stress enhances nociceptin/orphanin FQ-induced inhibition of rat dorsal raphe nucleus activity in vivo and in vitro: role of corticotropin releasing factor. Neuropharmacology 58:457-64
Valentino, Rita J; Lucki, Irwin; Van Bockstaele, Elisabeth (2010) Corticotropin-releasing factor in the dorsal raphe nucleus: Linking stress coping and addiction. Brain Res 1314:29-37
Waselus, Maria; Nazzaro, Cristiano; Valentino, Rita J et al. (2009) Stress-induced redistribution of corticotropin-releasing factor receptor subtypes in the dorsal raphe nucleus. Biol Psychiatry 66:76-83

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