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

妊娠创伤性脑损伤（TBI）影响后代的神经发育

• 批准号: 10734284
• 负责人: JONATHAN LIFSHITZ
• 金额: $ 40.98万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734284
• 关键词: Address; Adopted; Adult; Adult Children; Advocacy; Affect; Anxiety; Behavior; Birth; Brain; Cells; Child; Cognition; Darkness; Data; Databases; Development; Diffuse; Disease; Education; Electrophysiology (science); Environmental Risk Factor; Epidemiology; Face; Female; Frequencies; Gene Expression; Glutamates; Goals; Head; Health; Hippocampus; Immune; Immune response; Infection; Inflammation; Intervention; Investigation; Knowledge; Laboratory Study; Lasers; Life; Light; Liquid substance; Live Birth; Maps; Marble; Measures; Mental Depression; Molecular; Morphology; Mus; Neck; Neurodevelopmental Disorder; Neuroimmune; Neurons; Neurotransmitter Receptor; Outcome; Outcome Measure; Pathology; Percussion; Performance; Persons; Pharmaceutical Preparations; Phenotype; Physiology; Policy Making; Post-Concussion Syndrome; Prefrontal Cortex; Pregnancy; Prevalence; Proteins; Race; Reciprocal Social Interaction; Reporting; Research; Risk; Scanning; Schizophrenia; Science; Sex Bias; Sleep; Social Behavior; Standard Model; Stress; Survivors; Symptoms; Synapses; Tail Suspension; Testing; Traumatic Brain Injury; Ultrasonics; Vulnerable Populations; Weaning; Weight; Western Blotting; Woman; anxiety reduction; assault; autism spectrum disorder; behavioral outcome; behavioral phenotyping; brain circuitry; cell cortex; cell type; comparison control; density; depressive symptoms; developmental disease; experimental study; fetal; immune activation; intimate partner violence; male; men; molecular marker; molecular phenotype; morphometry; mouse model; neural circuit; neurobehavioral; neurodevelopment; neuropsychiatry; offspring; patch clamp; physical assault; postnatal; postsynaptic; pregnant; prepulse inhibition; presynaptic; protein expression; response; single-cell RNA sequencing; social; socioeconomics; synaptic pruning; transcriptome; transcriptomics; vocalization; young adult

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.

项目总结/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、 和其他人口统计变量在她们的一生中，特别是在怀孕期间，都处于危险之中。当 一方怀孕，身体攻击的频率和强度增加，并继续集中在 头、颈和脸。但是，妊娠期间TBI（妊娠TBI; gTBI）对后代神经系统的影响， 发展未知。孤立的TBI会增加应激和炎症，这是众所周知的转移胎儿神经- 妊娠期暴露的发展。该提案的目标是提供gTBI可以干扰的概念验证 神经发育，从而确立gTBI作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获得，因此， 实验室研究来自这个研究小组的初步数据显示，活产，低雄性断奶体重， 扭曲的皮质回路，减少焦虑和抑郁，以及主要在男性中的免疫反应减弱 gTBI后代。这些结果鼓励进一步调查TBI与妊娠的时间关系， 神经精神病学结果的评估，增强的神经回路分析，以及 细胞和突触变化。将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。这一建议的核心假设是，TBI 导致后代神经发育轨迹中断， 神经行为表现、神经回路组织和细胞类型特异性分子紊乱。 为了检验这一假设，将在妊娠后5天和12天向定时妊娠小鼠递送弥漫性TBI， 然后根据以下方面跟踪雄性和雌性后代：[目的1]出生结果，后代生理学，神经行为， 表型; [目的2]神经回路表型，和[目的3]突触蛋白表达和皮质细胞类型- 特异性基因表达（转录组学）。目标1将评估出生后早期的行为，认知，焦虑， 抑郁样，感觉运动门控在年轻的成年人;和社会行为的成年后代。在Aim 2中，皮质 海马突触生理学和皮层连接将通过电生理学和激光进行评估 扫描光刺激，并与定量神经元形态学对齐。在Aim 3中，蛋白质印迹法 突触蛋白质和细胞类型特异性转录组学的定量为电路开发和分子生物学提供了信息。 轨迹影响：成功完成拟议的研究将提供第一个概念验证， 妊娠期间TBI的后果，通常由IPV引起，可能会扭曲发育中的脑回路， 确定神经发育障碍行为表型。