Early pregnancy stress programming of offspring emotionality

描述（由申请人提供）：性别偏见的神经发育障碍，包括精神分裂症，与怀孕期间经历的母亲压力有关。我们最近发现了一个特定的怀孕早期时期，男性后代对母亲压力的影响很敏感，表现为成年人的行为和压力生理暗示大脑女性化。我们的假设是检查这些拟议的研究是，产前压力施加编程的影响，通过改变甲基化模式影响睾丸发育和睾酮的生产过程中的组织期的性二态性大脑发育的男性大脑。组织和激活睾酮已被证明是重要的编程男性压力神经回路。应激通路失调和敏感性是大多数神经精神障碍的标志。因此，这些研究设计为：1）确定SRY基因甲基化和表达在早期产前应激雄性小鼠的雌性化应激敏感表型的编程中的贡献，2）检查第二代后代中早期产前应激效应的遗传性以鉴定可能在生殖系中表观遗传修饰的PNS的可能基因靶标，（3）利用产前睾酮治疗或DNMT 1抑制来改善产前早期应激对雄性后代应激敏感性的影响。确定这些回路的大脑发育发生改变的胎儿前因和机制，并确定这种表型的潜在遗传方面，可能会提供新的治疗靶点和疾病预防的见解。

DESCRIPTION (provided by applicant): 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.