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

项目概要 这些研究将确定早期生活逆境 (ELA) 是否会影响创伤性损伤后的恢复。 正在发育的大脑。 ELA 指的是一系列广泛的压力事件，包括母亲的忽视，并且有 大量证据表明 ELA 会导致晚年心理和身体健康状况较差。当前模型链接 ELA 到“生物嵌入”，即变态神经生物学途径促进 ELA 的持久作用。 在这里，我将重点关注其中两个 ELA 途径，即免疫系统和氧化还原状态，作为恢复的调节剂 早期创伤性脑损伤 (TBI) 后。我将研究 ELA，这是由于期间支离破碎的孕产妇护理造成的 大脑发育的关键时期 [（出生后 (P) 2-9]），结合完善的模型 小鼠出生后第 21 天大脑皮层局灶性损伤，该年龄接近幼儿年龄 孩子。我们和其他人已经证明 p21 的大脑特别容易受到氧化应激的影响 显示出对炎症细胞因子的独特敏感性，对应于更明显的破坏 与受伤的成人大脑相比，血脑屏障（BBB）和白细胞募集。基于这些 集体发现，我假设 ELA 会增强神经炎症、BBB 破坏和氧化 严重受伤的大脑会承受压力，并导致长期的认知和社交缺陷。为了测试这个 假设，特定目标 1 将确定 ELA 在以下情况下是否对炎症具有累加或协同作用： 与 TBI 结合。流式细胞术将用于分析循环和脑浸润的骨髓谱系细胞 促炎细胞因子将通过 ELISA 检测血清和脑匀浆中的值。具体目标2 将确定 ELA 是否支持 TBI 后的急性继发性发病机制。西方免疫印迹将用于 检测氧化应激、血脑屏障破坏和细胞损伤。免费组织学将评估细胞损伤， 小胶质细胞激活，以及 FITC 标记的葡聚糖的屏障渗漏。具体目标 3 将确定 ELA 是否 破坏 TBI 后的长期功能和结构恢复。我将评估类似焦虑的行为、学习和 成年后的记忆力和社会行为。最后，体视学将用于量化皮质和 CA1、CA2 和 CA3 中的海马体积和神经元。这些研究共同提供了对以下问题的初步见解： ELA 如何影响早期 TBI 后的继发性损伤和恢复。这些发现提供了一个 为制定针对脑损伤儿童的独特策略奠定了基础 经验丰富的ELA。

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.