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

项目摘要 这些研究将确定早期生活逆境(ELA)是否影响创伤后的康复 发育中的大脑。ELA指的是一系列有压力的事件，包括母亲的忽视，还有 大量证据表明，ELA在晚年生活中精神和身体健康状况较差。当前模型链接ELA 到“生物嵌入”，即通过不同的神经生物学途径促进ELA的持久效应。 在这里，我将重点介绍其中的两个ELA途径，免疫系统和氧化还原状态，它们是恢复的修饰物 早年发生创伤性脑损伤(TBI)。我将研究ELA，这是由于在 大脑发育的关键时期[(出生后一天(P)2-9])，结合一个成熟的模型 出生后21天小鼠大脑皮层的局灶性损伤，这一年龄接近幼儿年龄 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，而且 表现出对炎性细胞因子的独特敏感性，对应于更明显的 血脑屏障(BBB)和白细胞募集，与受伤的成人脑比较。基于这些 综合研究结果，我假设ELA增强了神经炎症、血脑屏障破坏和氧化 在严重损伤的大脑中的压力，并促进长期的认知和社会缺陷。为了测试这一点 假设，特定的目标1将确定ELA在以下情况下对炎症具有相加或协同作用 与TBI相结合。流式细胞术将用于分析循环和脑内浸润性髓系细胞 促炎症细胞因子将通过ELISA在血清和脑匀浆中进行测定。具体目标2 将确定ELA是否支持脑外伤后的急性继发性发病。西方免疫印迹将被用来 检测氧化应激、血脑屏障破坏和细胞损伤。免费的组织学将评估细胞损伤， 小胶质细胞激活和FITC标记的右旋糖苷的屏障渗漏。具体目标3将决定ELA是否 破坏了脑外伤后的长期功能和结构恢复。我将评估焦虑样行为、学习和 记忆，以及成年后的社会行为。最后，将使用体视学来量化大脑皮层和 CA1、CA2和CA3的海马体体积和神经元。总而言之，这些研究提供了对 ELA如何影响早期颅脑损伤后的继发性损伤和恢复。这些发现提供了一个 为制定为那些患有脑损伤的儿童量身定做的独特战略而建立的基金会 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.