Mechanisms driving sex differences in cognitive outcomes following early life stress

《摘要》 好了！ 在美国，1600万儿童生活在贫困线或以下，多达250万儿童生活在贫困线以下 在某一年内无家可归，以及超过700,000个确认的虐待和/或疏忽案件。贫穷， 移位和父母的压力是年轻人最常见和最有力的压力源。 孩子们。女性患与压力相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，这些疾病高度并存于认知障碍和僵化。的目标是 这项建议是使用早期生活应激(ELS)的小鼠模型来识别潜在的性别差异的机制 有早期生活压力引起的认知功能障碍的风险。我们将测试ELS驱动改变的新假设 雌性而不是雄性小鼠眼眶前额叶皮质小白蛋白阳性中间神经元的发育 这是规则颠倒学习女性压力相关缺陷的基础。在目标1中，我们将确定 应激对OFC和两个控制区中间神经元发育的影响。精选的皮质种群 小白蛋白(PV)中间神经元与认知控制密切相关，并受到显著影响。 因为压力。在AIM 2中，我们将检验这样的假设，即OFC中PV-中间神经元的抑制活性将表现为表型 在ELS条件下饲养的雌性小鼠观察到认知缺陷。在AIM 3中，我们将测试ELS的影响 对照和ELS饲养雌雄小鼠OFC内PV阳性中间神经元的生理学研究 如果ELS改变了这些细胞的功能发展或整合到OFC中。通过ELS的镜头， 这项工作的广泛的智力意义在于它有望揭示驱动性别差异的机制 病理风险以及环境对大脑和行为发育的影响。这些问题 这里讨论的问题与广泛的科学受众相关，并对发展产生直接影响 旨在确定影响儿童和动物风险和复原力的因素的翻译规划 暴露在早期的逆境中。

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.