Mechanisms driving sex differences in cognitive outcomes following early life stress

摘要 ! 在美国，有1600万儿童生活在贫困线或贫困线以下，其中多达250万儿童生活在贫困线以下。 在某一年内，无家可归者人数超过70万，经证实的虐待和/或忽视案件超过70万。贫穷， 流离失所和父母的压力是年轻人最常见和最有力的压力来源。 孩子女性患上与压力有关的疾病的风险特别高，患上这种疾病的可能性是男性的两倍。 抑郁症或创伤后应激障碍，与认知障碍和易发性高度共病的病症。的目标 这项计划是利用一个早期生活压力（ELS）的小鼠模型来确定性别差异的潜在机制 早期生活压力引起的认知功能障碍的风险。我们将测试ELS驱动器改变的新假设， 雌性小鼠而非雄性小鼠眶额皮质（OFC）中小清蛋白阳性中间神经元的发育， 影响的基础压力相关的赤字规则逆转学习女性。在AIM 1中，我们将确定 OFC和两个对照区域中应激中间神经元发育的影响。选择皮质人群， 小清蛋白（PV）中间神经元在认知控制中有很大的牵连，并受到显着影响， 压力。在AIM 2中，我们将检验抑制OFC中PV-中间神经元的活性将复制表型的假设。 在ELS条件下饲养的雌性小鼠中观察到认知缺陷。在AIM 3中，我们将测试ELS的影响 对对照组和ELS饲养的雄性和雌性小鼠OFC中PV阳性中间神经元的生理学影响，以确定 如果ELS改变了这些细胞的功能发育或整合到OFC中。通过ELS的透镜， 这项工作的广泛学术意义在于它有望为推动性别差异的机制提供信息 病理学风险以及环境对大脑和行为发育的影响。的问题 这里讨论的问题与广泛的科学受众有关，也对发展产生直接影响。 旨在确定儿童和动物风险和恢复力的介导因素的翻译编程 早期的逆境。

ABSTRACT' ! In the U.S. 16 million children live at or below the poverty line, with as many as 2.5 million children that are homeless during a given year, and over 700,000 confirmed cases of abuse and/or neglect. Poverty, displacement, and parental stress, represent some of the most common and potent sources of stress for young children. Females are at particularly high risk for stress-related pathology, and twice as likely as men to develop depression or PTSD, conditions that are highly comorbid with cognitive impairments and inflexibility. The goal of this proposal is to use a mouse model of early life stress (ELS) to identify mechanism underlying sex differences in risk for early life stress-induced cognitive dysfunction. We will test the novel hypothesis that ELS drives altered development of parvalbumin-positive interneurons in orbitofrontal cortex (OFC) of female but not male mice, an effect that underlies stress-associated deficits in rule-reversal learning females. In AIM 1, we will determine the effects of stress interneuron development in OFC and two control regions. Select cortical populations of Parvalbumin (PV) interneurons have been heavily implicated in cognitive control, and are significantly affected by stress. In AIM 2 we will test the hypothesis that inhibiting activity of PV-interneurons in OFC will phenocopy cognitive deficits observed in female mice reared under ELS conditions. In AIM 3, we will test the impact of ELS on physiology of PV-positive interneurons in OFC of control and ELS reared male and female mice to determine if ELS alters the functional development or integration of these cells into the OFC. Through the lens of ELS, the broad intellectual significance of this work is in its promise for informing the mechanisms driving sex differences in risk for pathology and the impact of the environment on brain and behavioral development. The questions addressed here are relevant to a broad scientific audience and also have immediate impact on the development of translational programming aimed at identifying factors mediating risk and resilience in children and animals exposed to early adversity.