Early life adversity as a modifier of recovery after traumatic brain injury to the developing brain.

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Project Summary These studies will determine if early life adversity (ELA) impacts recovery after traumatic injury to the developing brain. ELA refers to a broad spectrum of stressful events, including maternal neglect, and there is substantial evidence implicating ELA in later life poorer mental and physical health. A current model links ELA to “biological embedding”, whereby allostatic neurobiological pathways promote the enduring effects of ELA. Here I will focus on two of these ELA pathways, the immune system and redox state, as modifiers of recovery after an early age traumatic brain injury (TBI). I will study ELA, resulting from fragmented maternal care during a critical period of brain development [(postnatal day (P) 2-9], in combination with a well-established model of focal injury to the cerebral cortex in mice at postnatal day p21, an age that approximates the toddler-aged child. We and others have demonstrated that the brain at p21 is particularly vulnerable to oxidative stress and shows a unique sensitivity to inflammatory cytokines, corresponding to a more pronounced disruption of the blood-brain barrier (BBB) and leukocyte recruitment, compared to the injured adult brain. Based on these collective findings, I hypothesize that ELA enhances neuroinflammation, BBB disruption, and oxidative stress in the acutely injured brain and promotes long-term cognitive and social deficits. To test this hypothesis, Specific Aim 1 will determine if ELA has an additive or synergistic effect on inflammation when combined with TBI. Flow cytometry will be used to profile circulating and brain-infiltrated myeloid lineage cells and pro-inflammatory cytokines will be measured by ELISAs in serum and brain homogenates. Specific Aim 2 will determine if ELA supports acute secondary pathogenesis after TBI. Western immunoblots will be used to detect oxidative stress, BBB disruption, and cell damage. Complimentary histology will assess cell injury, microglial activation, and barrier leakage to FITC-tagged dextrans. Specific Aim 3 will determine if ELA disrupts long-term functional and structural recovery after TBI. I will assess anxiety-like behaviors, learning and memory, and social behaviors at adulthood. Lastly, stereology will be used to quantify cortical and hippocampal volumes and neurons in CA1, CA2, and CA3. Together, these studies offer the first insights into how ELA may influence secondary damage and recovery after an early age TBI. Such findings offer a foundation for developing strategies that are uniquely tailored to those brain-injured children who have experienced ELA.