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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

基本信息

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
项目类别：
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

项目摘要

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/文摘