Early pregnancy stress programming of offspring emotionality

描述(申请人提供)：性别偏向的神经发育障碍，包括精神分裂症，与怀孕期间经历的母亲压力有关。我们最近发现了怀孕早期雄性后代对母体应激敏感的特定时期，成年后表现出行为和应激生理学提示大脑女性化。我们的假设将在这些拟议的研究中得到验证，即产前应激通过影响睾丸发育和睾酮产生的甲基化模式的变化，对发育中的男性大脑施加编程效应，在有性二态大脑发育的组织期。组织性和激活性睾丸素已被证明在男性应激神经回路的编程中起着重要作用。应激途径失调和敏感性是大多数神经精神障碍的特征。因此，这些研究的目的是：1)确定SRY基因甲基化和表达在早期产前应激雄性小鼠女性化应激敏感表型编程中的作用；2)检测第二代后代早期产前应激效应的遗传性，以确定可能在胚系中进行表观遗传修饰的PNS的可能基因靶点；3)利用产前睾酮治疗或DNMT1抑制来改善早期产前应激对雄性后代应激敏感性的影响。确定胎儿的先兆因素和这些回路的大脑发育发生变化的机制，以及识别这种表型的潜在可遗传方面，可能会为新的治疗靶点和疾病预防提供洞察。

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.