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.

项目概要/摘要 亲密伴侣暴力 (IPV) 会增加创伤性脑损伤 (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、地区等方面，女性多于男性， 和其他人口统计变量在她们的一生中，特别是在怀孕期间，都会受到伤害。什么时候 如果伴侣之一怀孕，身体攻击的频率和强度就会增加，并且仍然集中在 头部、颈部和面部。但是，怀孕期间 TBI（妊娠 TBI；gTBI）对后代神经系统的影响 发展未知。孤立的 TBI 会加剧压力和炎症，众所周知，这会转移胎儿的神经 妊娠期暴露的发育。该提案的目标是提供 gTBI 可以干扰的概念验证 神经发育，从而将 gTBI 确立为发育障碍的环境危险因素。 这些研究不能在人体中进行，也不能从现有数据库中得出，因此有必要 实验室研究。该研究小组的初步数据显示，活产数、雄性断奶体重低、 皮质回路扭曲，焦虑和抑郁减少，免疫反应减弱（主要发生在男性） gTBI 后代。这些结果鼓励进一步研究 TBI 时机与怀孕、更广泛的影响 神经精神结果评估、增强神经回路分析和分子研究 细胞和突触的变化。神经发育破坏的程度与标准模型进行比较 母体免疫激活（MIA）和相应的控制。该提案的中心假设是 TBI 怀孕期间会导致后代的神经发育轨迹被破坏，包括改变 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，将在性交后 5 天和 12 天对定时怀孕的小鼠进行弥漫性 TBI 注射， 然后在以下方面跟踪男性和女性后代：[目标 1] 出生结果、后代生理学、神经行为 表型； [目标 2] 神经回路表型，以及 [目标 3] 突触蛋白表达和皮质细胞类型 - 特定基因表达（转录组学）。目标 1 将评估产后早期行为；认知、焦虑、 年轻人的抑郁样和感觉运动门控；和成年后代的社会行为。在目标 2 中，皮质 海马突触生理学和皮质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对齐。在目标 3 中，蛋白质印迹 突触蛋白的定量和细胞类型特异性转录组学为电路发育和分子生物学提供信息 轨迹。影响：成功完成拟议的研究将提供第一个概念验证： 怀孕期间 TBI 的后果（通常由 IPV 引起）可能会扭曲发育中的大脑回路， 确定神经发育障碍行为表型。