Sex-biased neurodevelopmental disorders, including schizophrenia, have been associated with maternal stress experienced during pregnancy. We have recently identified a specific period of early pregnancy where male offspring were sensitive to the effects of maternal stress, displaying as adults behaviors and stress physiology suggestive of brain feminization. Our hypothesis to be examined in these proposed studies is that prenatal stress exerts programming effects on the developing male brain via changes in methylation patterns affecting testis development and testosterone production during the organizational period of sexually dimorphic brain development. Organizational and activational testosterone has been shown to be important in programming of male stress neurocircuitry. Stress pathway dysregulation and sensitivity is a hallmark of most neuropsychiatric disorders. Therefore, these studies are designed: 1) To determine the contribution of SRY gene methylation and expression in the programming of a feminized stress-sensitive phenotype of early prenatal stress male mice, 2) To examine the heritability of early prenatal stress effects in second generation offspring to identify possible gene targets of PNS that may be epigenetically modified in the germline, and 3) To utilize prenatal testosterone treatment or DNMT1 inhibition to ameliorate the effects of early prenatal stress on male offspring stress sensitivity. Determination of the fetal antecedents and mechanisms by which alterations in brain development of these circuits occur, and identification of potential heritable aspects of this phenotype may provide insight into novel therapeutic targets and disease prevention.

Public Health Relevance

Sex-biased neurodevelopmental disorders, including schizophrenia, have been associated with maternal stress experienced during pregnancy. We have recently identified a specific period of early pregnancy where male offspring were sensitive to the effects of maternal stress, displaying as adults behaviors and stress physiology suggestive of brain feminization. Our hypothesis to be examined in these proposed studies is that prenatal stress exerts programming effects on the developing male brain via changes in methylation patterns affecting testis development and testosterone production during the organizational period of sexually dimorphic brain development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH087597-02
Application #
8120977
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Desmond, Nancy L
Project Start
2010-08-05
Project End
2015-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
2
Fiscal Year
2011
Total Cost
$396,000
Indirect Cost
Name
University of Pennsylvania
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Bronson, Stefanie L; Chan, Jennifer C; Bale, Tracy L (2017) Sex-Specific Neurodevelopmental Programming by Placental Insulin Receptors on Stress Reactivity and Sensorimotor Gating. Biol Psychiatry 82:127-138
Bale, Tracy L; Epperson, C Neill (2017) Sex as a Biological Variable: Who, What, When, Why, and How. Neuropsychopharmacology 42:386-396
Morrison, Kathleen E; Epperson, C Neill; Sammel, Mary D et al. (2017) Preadolescent Adversity Programs a Disrupted Maternal Stress Reactivity in Humans and Mice. Biol Psychiatry 81:693-701
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
Bale, Tracy L (2016) The placenta and neurodevelopment: sex differences in prenatal vulnerability. Dialogues Clin Neurosci 18:459-464
Bronson, Stefanie L; Bale, Tracy L (2016) The Placenta as a Mediator of Stress Effects on Neurodevelopmental Reprogramming. Neuropsychopharmacology 41:207-18
Jašarevi?, 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
Bale, Tracy L; Epperson, C Neill (2015) Sex differences and stress across the lifespan. Nat Neurosci 18:1413-20
Jašarevi?, 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
Jašarevi?, Eldin; Rodgers, Ali B; Bale, Tracy L (2015) A novel role for maternal stress and microbial transmission in early life programming and neurodevelopment. Neurobiol Stress 1:81-88

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