It has been well established that early life adversity exposure (prior to puberty) is one of the strongest predictors of adult affective disorders such depression, anxiety, PTSD, and bipolar disorder, especially in women. The most common underlying feature in affective disorders is that of stress dysregulation. The goal of this proposal is to determine how the prepubertal adversity experience reprograms the brain toward stress dysregulation, or stress resilience, and how this is influenced during dynamic hormonal changes across the female life span, including pregnancy and aging. We are proposing to examine similar outcome measures proposed in the human subject studies in Projects I &II in a mouse model. The mouse model allows greater control over manipulations in the environment and dissection of potential mechanisms involved in programming of endpoints than what is possible in humans, and thus is an invaluable model for this SCOR proposal.
Aims for these studies include: 1) To examine the programming effects of prepubertal adversity on adult stress responsivity during the period of dynamic hormonal change, pregnancy, in a mouse model. Behavioral and physiological analyses during this period will include assessment of the HPA stress axis, and anxiety-like behaviors as well as stress responsivity in both male and female offspring;2) To examine the programming effects of prepubertal adversity on adult stress responsivity during the period of dynamic hormonal change, aging, in a mouse model. Sex differences in behavioral and physiological analyses in aged mice will include assessment of the HPA stress axis, cognitive flexibility and performance, and anxiety- like behaviors;and 3) To examine the potential molecular mechanisms by which prepubertal adversity may program changes in stress pathway maturation and thus altering long-term adult stress responses during dynamic hormonal periods, including examination of the sex-specific brain miRNA environment and epigenetic histone marks in relevant brain regions during the prepubertal window.

Public Health Relevance

Prepubertal trauma is one of the greatest predictors of affective disorder onset in women. The proposed studies in this Project will utilize a mouse model to examine how the brain responds during the stress insult, and which important genes are affected. As affective disorders tend to present during periods of dynamic hormonal shifts, mice will be studied during the important periods life, pregnancy &menopause, when the adult brain mav he more sensitive tn

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Specialized Center (P50)
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Special Emphasis Panel (ZRG1-EMNR-Q)
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University of Pennsylvania
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Morrison, Kathleen E; Narasimhan, Sneha; Fein, Ethan et al. (2016) Peripubertal Stress With Social Support Promotes Resilience in the Face of Aging. Endocrinology 157:2002-14
Jašarević, Eldin; Morrison, Kathleen E; Bale, Tracy L (2016) Sex differences in the gut microbiome-brain axis across the lifespan. Philos Trans R Soc Lond B Biol Sci 371:20150122
Smith, Ariana L; Hantsoo, Liisa; Malykhina, Anna P et al. (2016) Basal and stress-activated hypothalamic pituitary adrenal axis function in postmenopausal women with overactive bladder. Int Urogynecol J 27:1383-91
Bronson, Stefanie L; Bale, Tracy L (2016) The Placenta as a Mediator of Stress Effects on Neurodevelopmental Reprogramming. Neuropsychopharmacology 41:207-18
Morrison, Kathleen E; Epperson, C Neill; Sammel, Mary D et al. (2016) Preadolescent Adversity Programs a Disrupted Maternal Stress Reactivity in Humans and Mice. Biol Psychiatry :
Jašarević, Eldin; Howerton, Christopher L; Howard, Christopher D et al. (2015) Alterations in the Vaginal Microbiome by Maternal Stress Are Associated With Metabolic Reprogramming of the Offspring Gut and Brain. Endocrinology 156:3265-76
Kim, Deborah R; Bale, Tracy L; Epperson, C Neill (2015) Prenatal programming of mental illness: current understanding of relationship and mechanisms. Curr Psychiatry Rep 17:5
Hantsoo, Liisa; Epperson, C Neill (2015) Premenstrual Dysphoric Disorder: Epidemiology and Treatment. Curr Psychiatry Rep 17:87
Epperson, C Neill; Shanmugan, Sheila; Kim, Deborah R et al. (2015) New onset executive function difficulties at menopause: a possible role for lisdexamfetamine. Psychopharmacology (Berl) 232:3091-100
Nugent, Bridget M; Bale, Tracy L (2015) The omniscient placenta: Metabolic and epigenetic regulation of fetal programming. Front Neuroendocrinol 39:28-37

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