It is well established that childhood adversity is one of the most potent predictors of adult affective disorders, particularly among women. Further, an important dissociation has been reported for a subgroup of women who experience early life adversity but do not present with adult disease, suggesting that there may be resiliency factors important in disease protection or amelioration. In fact, the availability of a caring and stable parent or guardian has been shown to be one of the most important aspects that distinguish between positive and negative outcomes in abused individuals. We propose that one vital contributor to the increased risk for major depressive disorder (MOD) in women, and propensity for other affective disturbances at specific reproductive time points, is the programming effect of prepubertal adversity on dysregulation of hypothalamic pituitary adrenal (HPA) activity and ovarian steroid responsiveness across the lifespan. It is well documented that from puberty to the late perimenopause, MOD and several anxiety disorders are more common in females than males. Moreover, periods of hormonal flux across the female lifespan are associated with increased risk for affective disturbance: the premenstrum (premenstrual dysphoric disorder), the postpartum (onset/relapse bipolar disorder, MOD), and the perimenopause (depression symptoms and MDD. The goal of the scientific Projects in this SCOR proposal is to determine how the experience of prepubertal adversity reprograms the brain toward stress dysregulation, and how this intersects with periods of dynamic hormonal flux across the life span, including pregnancy (Projects I &III) and aging (Projects II &III). In addition, mechanistic epigenetic studies will examine sex differences in response to stress during this sensitive window of brain maturation (Project III). SCOR funding would harness the respective expertise of Drs. Epperson and Bale in behavioral and molecular models of stress and reproductive neuroendocrinology, psychophysiology, and neuroimaging, to create the Penn Center for the Study of Sex and Gender in Behavioral Health. The Center would provide an intellectual platform with important resources to encourage established investigators, and their mentees, to consider sex and gender as crucial factors in their research.

Public Health Relevance

Early life adversity is one of the greatest predictors of affective disorder onset in women. That gonadal steroids impact the initiation and maintenance of the stress response suggests that these systems are critical to the sex differences observed in neuropsychiatric and substance use disorders, as well as medical conditions such as autoimmune disorders, cardiovascular disease, obesity, and migraines to name a few.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Specialized Center (P50)
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Zehr, Julia L
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University of Pennsylvania
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Goel, Namni; Bale, Tracy L; Epperson, C Neill et al. (2014) Effects of sex and gender on adaptation to space: behavioral health. J Womens Health (Larchmt) 23:975-86
Howerton, Alexis R; Roland, Alison V; Bale, Tracy L (2014) Dorsal raphe neuroinflammation promotes dramatic behavioral stress dysregulation. J Neurosci 34:7113-23
Howerton, Christopher L; Bale, Tracy L (2014) Targeted placental deletion of OGT recapitulates the prenatal stress phenotype including hypothalamic mitochondrial dysfunction. Proc Natl Acad Sci U S A 111:9639-44
Altemus, Margaret; Sarvaiya, Nilofar; Neill Epperson, C (2014) Sex differences in anxiety and depression clinical perspectives. Front Neuroendocrinol 35:320-30
Morrison, K E; Rodgers, A B; Morgan, C P et al. (2014) Epigenetic mechanisms in pubertal brain maturation. Neuroscience 264:17-24
Kim, Deborah R; Hantsoo, Liisa; Thase, Michael E et al. (2014) Computer-assisted cognitive behavioral therapy for pregnant women with major depressive disorder. J Womens Health (Larchmt) 23:842-8
Hantsoo, Liisa; Ward-O'Brien, Deborah; Czarkowski, Kathryn A et al. (2014) A randomized, placebo-controlled, double-blind trial of sertraline for postpartum depression. Psychopharmacology (Berl) 231:939-48
Boersma, G J; Bale, T L; Casanello, P et al. (2014) Long-term impact of early life events on physiology and behaviour. J Neuroendocrinol 26:587-602
Epperson, C Neill; Kim, Deborah R; Bale, Tracy L (2014) Estradiol modulation of monoamine metabolism: one possible mechanism underlying sex differences in risk for depression and dementia. JAMA Psychiatry 71:869-70
Hantsoo, Liisa; Czarkowski, Kathryn A; Child, Josiah et al. (2014) Selective serotonin reuptake inhibitors and endothelial function in women. J Womens Health (Larchmt) 23:613-8

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