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

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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.