Gravida traumatic brain injury (TBI) impacts neurodevelopment of the offspring

项目摘要/摘要 亲密伴侣暴力(IPV)增加了创伤性脑损伤(TBI)的风险，因为身体攻击 瞄准头部、颈部和面部。在社会经济、种族、教育、地区、 而其他人口统计变量在她们的一生中都处于危险之中，特别是在怀孕期间。什么时候 其中一人怀孕，身体攻击的频率和强度增加，并保持专注于 头部、颈部和面部。但是，妊娠期脑损伤对子代神经的影响 发展是未知的。孤立的脑损伤会增加压力和炎症，众所周知，这会转移胎儿的神经- 孕期暴露的发育。提案目标是提供gTBI可以干扰的概念验证 神经发育，从而将gTBI确立为发育障碍的环境风险因素。 这些研究不能在人身上进行，也不能从现有的数据库中得出，因此有理由 实验室研究。来自这个研究小组的初步数据显示，活产仔，低雄性断奶体重， 扭曲的皮质环路，焦虑和抑郁减轻，免疫反应减弱，主要发生在男性 GTBI子代。这些结果鼓励进一步研究与怀孕有关的TBI时机，范围更广 神经精神病学结果的评估、增强的神经回路分析和分子研究 细胞和突触的变化。神经发育中断的程度与标准模型进行比较 母体免疫激活(MIA)和各自的对照。这一提议的中心假设是，TBI 在怀孕期间导致后代神经发育轨迹中断，包括改变 神经行为表现、神经回路组织和特定细胞类型的分子紊乱。 为了验证这一假设，将弥漫性脑损伤分别在产后5天和12天交付给计时怀孕的小鼠，并 然后从以下方面跟踪男性和女性后代：[目标1]出生结果、后代生理、神经行为 [目标2]神经回路表型，[目标3]突触蛋白表达和皮质细胞类型- 特定的基因表达(转录组学)。目标1将评估早期产后行为；认知、焦虑、 青壮年的抑郁样和感觉运动门控；成年后代的社会行为。在Aim 2中，皮质 并将通过电生理学和激光来评估海马区突触生理学和皮质连通性 扫描光刺激，并与定量神经元形态一致。在目标3中，西方印迹 突触蛋白的定量和细胞类型特异的转录切分为电路发育和分子提供信息 轨迹。影响：拟议研究的成功完成将提供第一个概念证明 妊娠期间脑外伤的后果，通常是由IPV引起的，可以扭曲发育中的大脑回路和 确定神经发育障碍的行为表型。

PROJECT SUMMARY/ABSTRACT Intimate partner violence (IPV) increases the risk of traumatic brain injury (TBI), because the physical assaults target the head, neck, and face. Women, more than men, across socioeconomic, racial, educational, regional, and other demographic variables are in harm’s way throughout their life and particularly during pregnancy. When one partner is pregnant, the frequency and intensity of physical assaults increase and remain focused on the head, neck, and face. But, the consequences of a TBI during pregnancy (gravida TBI; gTBI) on offspring neuro- development are unknown. Isolated TBI elevates stress and inflammation, which are known to divert fetal neuro- development with gestational exposure. The proposal goal is to provide proof-of-concept that gTBI can disturb neurodevelopment, thereby establishing gTBI as an environmental risk factor for developmental disorders. These studies cannot be performed in people or be derived from existing databases, thereby warranting laboratory studies. Preliminary data from this research team showed live births, low male weaning weight, distorted cortical circuity, reduced anxiety and depression, and a muted immune response principally in male gTBI offspring. These results encourage further investigation of TBI timing with respect to pregnancy, broader assessment of neuropsychiatric outcomes, enhanced neural circuit analyses, and molecular investigations of cell and synaptic change. The extent of neurodevelopment disruption is compared to a standard model of maternal immune activation (MIA) and respective controls. The central hypothesis of this proposal is that TBI during pregnancy leads to disrupted neurodevelopmental trajectory in the offspring that includes altered neurobehavioral performance, neurocircuit organization, and cell type-specific molecular disturbances. To test this hypothesis, a diffuse TBI will be delivered to timed-pregnant mice at 5 and 12 days post-coitum and then follow male and female offspring in terms of: [Aim 1] birth outcomes, offspring physiology, neurobehavioral phenotype; [Aim 2] neurocircuitry phenotype, and [Aim 3] synaptic protein expression and cortical cell type- specific gene expression (transcriptomics). Aim 1 will evaluate early post-natal behaviors; cognition, anxiety, depressive-like, and sensorimotor gating in young adult; and social behaviors in adult offspring. In Aim 2, cortical and hippocampal synaptic physiology and cortical connectivity will be evaluated by electrophysiology and laser scanning photostimulation, and aligned with quantitative neuronal morphology. In Aim 3, western blot quantification of synaptic proteins and cell type-specific transcriptomics inform circuit development and molecular trajectories. Impact: Successful completion of the proposed studies will provide the first proof-of-concept that consequences of TBI during pregnancy, often resulting from IPV, can distort developing brain circuity and determine a neurodevelopmental disorder behavioral phenotype.