Mechanisms driving sex differences in cognitive outcomes following early life stress

早期生活压力后认知结果性别差异的驱动机制

基本信息

批准号：
9923470
负责人：
Kevin George Bath
金额：
$ 7.9万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9923470
关键词：
Achievement Address Adolescence Affect Affective Animals Attention Automobile Driving Behavior Behavioral Bilateral Biophysics Brain Caring Cells Cerebral cortex Child Cognitive Cognitive deficits Collaborations Complement Coupling Data Development Electrophysiology (science)Elements Environment Exposure to Female Genetic Goals Halorhodopsins Hippocampus (Brain)Histologic Homeless Youth Immunohistochemistry Impaired cognition Impairment Implant In Vitro Interneurons Lesion Life Mediating Mental Depression Modeling Morphology Motor Cortex Mus Neurobiology Neurons Outcome Parvalbumins Pathology Performance Phenocopy Physiology Population Post-Traumatic Stress Disorders Poverty Primates Process Resources Reversal Learning Risk Rodent Role Schools Sex Differences Slice Somatostatin Source Specificity Stress Synapses Techniques Testing Tissues Whole-Cell Recordings Woman Work awake calbindin calretinin cognitive control cognitive function cohort comorbidity density depressed patient depressive symptoms design early childhood early life adversity early life stress emerging adult emotion regulation flexibility high risk in vivo infancy lens male men mouse model neglect neurodevelopment novel optical fiber optogenetics postnatal relating to nervous system resilience stress reactivity

项目摘要

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.

抽象的' ！在美国，有 1600 万儿童生活在贫困线以下，其中有多达 250 万儿童处于贫困线以下。某一年无家可归者，以及超过 700,000 起已确认的虐待和/或忽视案件。贫困，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们。女性患压力相关疾病的风险特别高，其发生可能性是男性的两倍抑郁症或创伤后应激障碍（PTSD），这些疾病与认知障碍和缺乏灵活性高度共存。目标是该提案是使用早期生活压力（ELS）小鼠模型来确定性别差异的机制存在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而非雄性小鼠的眶额皮质（OFC）中小白蛋白阳性中间神经元的发育，这种效应是女性规则逆转学习中与压力相关的缺陷的基础。在 AIM 1 中，我们将确定 OFC 和两个控制区域的应激中间神经元发育的影响。选择皮质群体小清蛋白 (PV) 中间神经元与认知控制密切相关，并且受到显着影响通过压力。在 AIM 2 中，我们将测试以下假设：抑制 OFC 中 PV 中间神经元的活性将导致表型复制在 ELS 条件下饲养的雌性小鼠中观察到的认知缺陷。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进行研究，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 的镜头，这项工作的广泛学术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。问题这里讨论的内容与广大科学受众相关，并对发展产生直接影响旨在确定调节儿童和动物风险和复原力的因素的转化规划早年遭遇逆境。