Stress-related psychiatric disorders, like depression and post-traumatic stress disorder, are debilitating mental illnesses that affect twice as many women as men. Although the etiology of this disparity remains unknown, it is thought to be due to sex differences in stress responses. Corticotropin-releasing factor (CRF) orchestrates stress responses, in part, by regulating norepinephrine (NE) and serotonin (5-HT) transmission, and CRF is dysregulated in stress-related disorders. The goal of my current research is to identify sex differences in a receptor for CRF (CRF1 subtype) that may account for sex differences in stress responsivity. To date, I found that CRF1 signals and is trafficked differently in female rats in a manner that can account for elevated responses to acute stress and decreased adaptation to chronic stress. In females, CRF1 immunoprecipitation revealed a greater coupling to Gs, the GTP-binding protein that mediates most cellular responses. Additionally, stress-induced CRF1 association with 2-arrestin2, an integral step in receptor internalization, was apparent in males but not females. Immunoelectron microscopy confirmed stress-induced CRF1 internalization in male rats only, suggesting that this adaptive process to compensate for large amounts of CRF, as may be released in depression, is compromised in females. Importantly, sex differences in CRF1 function rendered NE neurons in the locus coeruleus of female rats more sensitive to low levels of CRF and less adaptable to high levels of CRF. However, because this is the first report of sex differences in stress- related neuropeptide receptor, many questions remain unanswered.
Aim 1 of this proposal, which will be completed during the mentored phase (K99), investigates why CRF1 binds proteins differently in males vs. females. There are no sex differences in CRF1 structure, so I will learn proteomic approaches to identify whether sex differences in post-translational modifications of CRF1 account for these effects.
Aims 2 and 3 will be completed during the independent phase.
Aim 2 will identify the hormones that contribute to the sex difference in CRF1. To this end, I will combine previously acquired endocrine techniques with the skills learned during the K99 phase to determine whether ovarian or testicular hormones establish the sex differences.
Aim 3 will evaluate whether sex differences extend to the other receptor subtype, CRF2, in the dorsal raphe nucleus. Because CRF1 and CRF2 share a high degree of sequence identity, proteomic approaches are expected to reveal sex differences in the CRF2. CRF2 activation of the dorsal raphe-5-HT system promotes a passive behavioral response strategy to stress that is a risk factor for depression. Thus, sex differences in CRF2 may contribute to the increased vulnerability of females this disorder. By addressing these questions, this proposal will help elucidate the etiology of sex differences in stress-related disorders. Moreover, because CRF antagonists are being developed to treat these illnesses, considering sex differences in CRF receptors may increase the efficacy of these compounds in women.

Public Health Relevance

Women are twice as likely as men to suffer from stress-related psychiatric disorders, such as depression and post-traumatic stress disorder, however the biological basis of this sex difference remains unknown. The proposed research will identify molecular and hormonal changes that increase the function of a critical stress-related neuropeptide in female rats. This project will not only help us understand why women are more vulnerable to stress-related mental illnesses, but it will identify new pharmaceutical targets which can lead to treatments that are efficacious in both men and women.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Career Transition Award (K99)
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Special Emphasis Panel (ZMH1-ERB-L (05))
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Desmond, Nancy L
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Children's Hospital of Philadelphia
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Bangasser, D A; Dong, H; Carroll, J et al. (2017) Corticotropin-releasing factor overexpression gives rise to sex differences in Alzheimer's disease-related signaling. Mol Psychiatry 22:1126-1133
Valentino, Rita J; Bangasser, Debra A (2016) Sex-biased cellular signaling: molecular basis for sex differences in neuropsychiatric diseases. Dialogues Clin Neurosci 18:385-393
Bangasser, Debra A; Wiersielis, Kimberly R; Khantsis, Sabina (2016) Sex differences in the locus coeruleus-norepinephrine system and its regulation by stress. Brain Res 1641:177-88
Cole, Robert D; Kawasumi, Yushi; Parikh, Vinay et al. (2016) Corticotropin releasing factor impairs sustained attention in male and female rats. Behav Brain Res 296:30-34
Bangasser, Debra A; Kawasumi, Yushi (2015) Cognitive disruptions in stress-related psychiatric disorders: A role for corticotropin releasing factor (CRF). Horm Behav 76:125-35
Reyes, B A S; Bangasser, D A; Valentino, R J et al. (2014) Using high resolution imaging to determine trafficking of corticotropin-releasing factor receptors in noradrenergic neurons of the rat locus coeruleus. Life Sci 112:2-9
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
Valentino, Rita J; Van Bockstaele, Elisabeth; Bangasser, Debra (2013) Sex-specific cell signaling: the corticotropin-releasing factor receptor model. Trends Pharmacol Sci 34:437-44
Bangasser, Debra A; Valentino, Rita J (2012) Sex differences in molecular and cellular substrates of stress. Cell Mol Neurobiol 32:709-23
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

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