In response to PA-09-137 """"""""Basic and Translational Research in Emotion"""""""", this project will use murine models to elucidate the mechanisms underlying the effects of stress and the neuropeptide corticotropin releasing factor (CRF) on anxiety-like behavior related to post-traumatic stress disorder (PTSD). PTSD patients exhibit increases in startle reactivity, exaggerated contextual fear expression, and deficits in information processing. These patients also appear to exhibit pathology in the CRF system, specifically increased CRF concentrations in the cerebrospinal fluid. CRF is a neuropeptide that coordinates many behavioral and neuroendocrine responses to stress via activation of two known receptor subtypes, CRF1 and CRF2. Work funded by this grant has used mouse models to demonstrate that acute activation of both CRF receptor subtypes modulates anxiety-disorder related behaviors, such as exaggerated startle reactivity, increases in context fear-induced startle, and reductions in information processing. Although increased CRF signaling is seen in PTSD patients, it is not known if increased CRF is a pre-exisiting vulnerability factor for development of PTSD after exposure to trauma, or if CRF hypersecretion only manifests as a response to trauma. The overarching hypothesis is that CRF receptor activation is required for enduring effects of trauma on anxiety-like behavior, and that CRF hypersecretion increases the efficacy of predator stress to induce long term anxiety-like responses. To model CRF hypersecretion reported in PTSD subjects, these studies will use a genetic model of increased CRF signaling involving temporal control of CRF over-expression (CRFOE) in the forebrain via doxycycline administration. To model trauma exposure, the feline predator stress model in mice will be used. In this model, single exposure to a feline induces enduring anxiety-like behaviors up to 3 weeks post exposure. This predator stress model has face and predictive validity for PTSD.
Aim 1 will examine the relative potency of predator stress to induce PTSD-like symptoms in mice with CRFOE. To test the hypothesis that CRF hypersignaling increases vulnerability to long-term effects of stress we will examine the effects of CRFOE after predator stress across 3 groups: those with CRFOE throughout life, modeling heritable CRF hyper-secretion, CRFOE only in development, modeling effects of childhood trauma on later vulnerability to stress in adulthood, and finally CRFOE only during adulthood to determine if CRFOE for a relatively brief period before and during trauma is sufficient to increase vulnerability to trauma.
Aim 2 will identify the contributions of CRF1 and CRF2 signaling to the post-trauma consolidation of predator stress effects on long term anxiety-like behavior in wild- type mice. These studies will provide critical information on two fronts: (1) the verification of CRF hypersignaling as a potential vulnerability factor for development of PTSD-like symptoms after trauma;and (2) the efficacy of CRF receptor ligands to block consolidation of trauma effects. These data will inform clinical studies of possible risk factors for PTSD and help identify novel prophylactic treatment strategies.

Public Health Relevance

Post-traumatic stress disorder (PTSD) is a debilitating anxiety disorder that occurs in 10- 15% of individuals exposed to a life threatening trauma. Using a mouse model of PTSD, this proposal examines the contribution of abnormalities in corticotropin releasing factor, a neurohormone released during stress, to vulnerability for development of PTSD-like symptoms and examines the efficacy of drugs that block this hormone to prevent development of PTSD-like symptoms. These studies will increase our understanding of risk factors and potential prophylactic treatments for PTSD.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
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Winsky, Lois M
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University of California San Diego
Schools of Medicine
La Jolla
United States
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Toth, Mate; Flandreau, Elizabeth I; Deslauriers, Jessica et al. (2016) Overexpression of Forebrain CRH During Early Life Increases Trauma Susceptibility in Adulthood. Neuropsychopharmacology 41:1681-90
Flandreau, Elizabeth; Risbrough, Victoria; Lu, Ailing et al. (2015) Cell type-specific modifications of corticotropin-releasing factor (CRF) and its type 1 receptor (CRF1) on startle behavior and sensorimotor gating. Psychoneuroendocrinology 53:16-28
Park, Hyo-Jin; Ran, Yong; Jung, Joo In et al. (2015) The stress response neuropeptide CRF increases amyloid-? production by regulating ?-secretase activity. EMBO J 34:1674-86
Inslicht, Sabra S; Richards, Anne; Madden, Erin et al. (2014) Sex differences in neurosteroid and hormonal responses to metyrapone in posttraumatic stress disorder. Psychopharmacology (Berl) 231:3581-95
Toth, Mate; Gresack, Jodi E; Bangasser, Debra A et al. (2014) Forebrain-specific CRF overproduction during development is sufficient to induce enduring anxiety and startle abnormalities in adult mice. Neuropsychopharmacology 39:1409-19
Toth, Mate; Ziegler, Michael; Sun, Ping et al. (2013) Impaired conditioned fear response and startle reactivity in epinephrine-deficient mice. Behav Pharmacol 24:1-9
Hauger, Richard L; Olivares-Reyes, J Alberto; Braun, Sandra et al. (2013) Desensitization of human CRF2(a) receptor signaling governed by agonist potency and ?arrestin2 recruitment. Regul Pept 186:62-76
Tatro, Erick T; Risbrough, Victoria; Soontornniyomkij, Benchawanna et al. (2013) Short-term recognition memory correlates with regional CNS expression of microRNA-138 in mice. Am J Geriatr Psychiatry 21:461-73
Li, Xia; Risbrough, Victoria B; Cates-Gatto, Chelsea et al. (2013) Comparison of the effects of the GABAB receptor positive modulator BHF177 and the GABAB receptor agonist baclofen on anxiety-like behavior, learning, and memory in mice. Neuropharmacology 70:156-67
Toth, M; Gresack, J E; Hauger, R L et al. (2013) The role of PKC signaling in CRF-induced modulation of startle. Psychopharmacology (Berl) 229:579-89

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