Importance of Brain Temperature on the Inflammatory and Microvascular Consequences of Mild TBI

脑震荡或轻度创伤性脑损伤（mTBI）的潜在有害影响是一个主要的公共卫生问题， 问题.虽然大多数mTBI患者在1-2周内恢复，但亚群需要数周才能恢复。 几个月完全恢复，有些报告症状持续数年后，最初的创伤。因此， mTBI后改变大脑恢复的临床相关因素尚未得到充分研究，但急需研究 区临床研究报告称，剧烈活动和运动可导致核心代谢物轻度升高， 和大脑温度我们现在表明，相对温和的脑温升高只有39摄氏度， 在两种不同的mTBI模型中， 常温mTBI。这些观察结果表明，大脑温度的微小变化或周围的时间， 可能影响mTBI的急性和长期创伤后果。新的初步结果 证明mTBI时的高温对炎症、微血管和 血流动力学紊乱这项提案的目标是调查温度之间的因果关系- 敏感的炎症和脑血管反应以及结构和行为变化的出现 这可能是高温mTBI后结果恶化的基础。目的1将表征炎性 在常温或高温条件下对mTBI的反应。流式细胞术将用于表征 巨噬细胞/小胶质细胞表型和生物标志物分析，包括细胞因子和趋化因子信号传导 与慢性认知结果相关。补充大鼠和转基因模型，包括CCL 2和 caspase 1基因敲除小鼠将阐明炎症细胞浸润在触发细胞毒性炎症中的作用 在高温mTBI之后。目的2将集中在常温或低温下微血管通透性模式， 高温mTBI与紧密连接蛋白和内皮粘附分子变化一致。的 巨噬细胞起源对脑血管通透性和完整性的细胞鉴定将与 用光片荧光显微镜观察ICAM-1和MMP-9转基因模型的炎症反应 以及3D图像可视化和定量。因为创伤后大脑的血流动力学状态 影响mTBI后的继发性损伤机制，目标3将评估局部脑血流的改变， 血管反应性使用放射自显影和双光子激光扫描显微镜。底层 将使用eNOS和iNOS敲除小鼠测试这些血液动力学反应的机制。临床 相关治疗包括靶向小胶质细胞和巨噬细胞/内皮细胞的米诺环素和孕酮 将在这些高热mTBI和脑震荡模型中测试相互作用。这些研究将 阐明高温mTBI后的温度敏感性炎症和脑血管事件，确定 高热和继发性损伤机制的因果关系和临床相关干预试验 已经在临床上使用，以减少这种常见的脑损伤的破坏性后果。

The potentially detrimental effects of concussion or mild traumatic brain injury (mTBI) are a major public health problem. Although the majority of mTBI patients recover within 1-2 weeks, a subpopulation takes weeks to months for full recovery and some report symptoms lasting years after the initial trauma. Thus, identification of clinically relevant factors that alter the brain's recovery after mTBI is an understudied, but much needed research area. Clinical investigations have reported that strenuous activity and exercise can lead to mild elevations in core and brain temperature. We now show that a relatively mild brain temperature elevation of only 39oC significantly aggravates neuropathological and cognitive outcome in two distinct models of mTBI as compared to normothermic mTBI. These observations suggest that small variations in brain temperature at or around the time of injury may influence the acute and long term traumatic consequences of mTBI. Novel preliminary results demonstrate that hyperthermia at the time of mTBI has profound effects on inflammatory, microvascular and hemodynamic perturbations. The goal of this proposal is to investigate the causal links between temperature- sensitive inflammatory and cerebrovascular responses and the emergence of structural and behavioral changes that may underlie the exacerbation of outcome after hyperthermic mTBI. Aim 1 will characterize the inflammatory responses to mTBI during normothermic or hyperthermic conditions. Flow cytometry will be used to characterize macrophage/microglia phenotypes and biomarker analysis including cytokine and chemokine signaling correlated with chronic cognitive outcomes. Complementary rat and transgenic models including CCL2 and caspase 1 knockout mice will clarify the role of inflammatory cell infiltration on triggering cytotoxic inflammation after hyperthermic mTBI. Aim 2 will focus on the microvascular permeability patterns following normothermic or hyperthermic mTBI in concert with tight junctional protein and endothelial adhesion molecule changes. The cellular identification of macrophage origins on cerebrovascular permeability and integrity will be correlated with inflammatory responses using ICAM-1 and MMP-9 transgenic models with light sheet fluorescence microscopy and 3D image visualization and quantitation. Because the hemodynamic state of the posttraumatic brain can influence secondary injury mechanisms after mTBI, Aim 3 will assess alterations in local cerebral blood flow and vascular reactivity using autoradiography and two-photon laser scanning microscopy. The underlying mechanisms of these hemodynamic responses will be tested using eNOS and iNOS knockout mice. Clinically relevant treatments including minocycline and progesterone targeting microglia and macrophage/endothelial interactions will be tested in these models of hyperthermic mTBI and concussion. Together, these studies will clarify the temperature-sensitive inflammatory and cerebrovascular events after hyperthermic mTBI, determine causal relationships of hyperthermia and secondary injury mechanisms and test clinically relevant interventions that are already in use in the clinic to reduce the devastating consequences of this common type of brain injury.