Stress-related mental illnesses, such as depression and anxiety disorders, are more prevalent in women than men. Dysfunctions in corticotropin-releasing factor (CRF), the neuropeptide that orchestrates the stress response, have been linked to depression and anxiety disorders. However, sex differences in the CRF system are not well characterized. Recent work from our laboratory identified sex differences in neuronal responses to CRF. Specifically, postsynaptic sensitivity of locus coeruleus (LC) neurons to CRF was greater in female vs. male rats. Moreover, swim stress sensitized LC neurons to CRF in male rats only. The following proposal will expand on these finding to determine the underlying cellular mechanism of these differences.
The specific aims are as follows: 1) Identify sex differences in the coupling and signaling of the CRF receptor. CRF receptor immunoprecipitation will be used to determine whether there are sex differences in coupling of different G-proteins to the CRF receptor under stressed and unstressed conditions. Additionally, sex differences in CRF receptor signaling will be evaluated by using PKA and PKC assays. Preliminary data indicate that the CRF receptor is coupled more strongly to the Gs protein in unstressed females compared to unstressed males. Following swim stress, Gs coupling to the CRF receptor increases in males only. These are the first data to suggest sex differences in the coupling of a receptor to different G-proteins. Sex differences in CRF receptor structure and function may contribute to increased stress-susceptibility in women. 2) Identify sex differences in CRF receptor trafficking following stress. Here we will use immunoprecipitation of the CRF receptor, along with immunoelectron microscopy to determine whether the CRF receptor is trafficked differently in male vs. female rats after stress. Preliminary data suggest that following stress, CRF receptor internalization in females may be comprimised. If supported, this would suggest that female rats lack this compensatory stress response.

Public Health Relevance

Women are twice as likely to suffer from stress-related psychiatric disorders, like depression and anxiety disorders, as men. The proposed experiments will identify sex differences in the receptor for CRF, an important neuromodulator of stress, which may underlie the increased vulnerability of females to stress and stress-related pathology. Importantly, because CRF antagonists are being developed to treat depression and anxiety disorders, sex differences in the CRFr could impact the efficacy of these compounds in women.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32MH084423-02
Application #
7690400
Study Section
Special Emphasis Panel (ZRG1-F02A-H (20))
Program Officer
Desmond, Nancy L
Project Start
2008-09-30
Project End
2011-06-29
Budget Start
2009-09-30
Budget End
2010-09-29
Support Year
2
Fiscal Year
2009
Total Cost
$50,054
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Valentino, Rita J; Reyes, Beverly; Van Bockstaele, Elisabeth et al. (2012) Molecular and cellular sex differences at the intersection of stress and arousal. Neuropharmacology 62:13-20
Bangasser, Debra A; Zhang, Xiaoyan; Garachh, Veraaj et al. (2011) Sexual dimorphism in locus coeruleus dendritic morphology: a structural basis for sex differences in emotional arousal. Physiol Behav 103:342-51
Carr, Gregory V; Bangasser, Debra A; Bethea, Thelma et al. (2010) Antidepressant-like effects of kappa-opioid receptor antagonists in Wistar Kyoto rats. Neuropsychopharmacology 35:752-63
Bangasser, D A; Curtis, A; Reyes, B A S et al. (2010) Sex differences in corticotropin-releasing factor receptor signaling and trafficking: potential role in female vulnerability to stress-related psychopathology. Mol Psychiatry 15:877, 896-904
Bangasser, Debra A; Shors, Tracey J (2010) Critical brain circuits at the intersection between stress and learning. Neurosci Biobehav Rev 34:1223-33