Role of Myeloid And CD4+ T Immune Cells in Post-Traumatic Plasticity

摘要 创伤性脑损伤（TBI）每年影响数百万美国人，并可能导致认知功能障碍， 感觉处理困难、睡眠中断和癫痫的发展。一个共同的神经 TBI的结果是电生理异常的发展，可导致创伤后癫痫 (PTE)或睡眠结构的破坏。然而，这些神经缺陷产生的机制 TBI的后果仍然知之甚少。 初步证据表明，炎症导致电生理异常， 在中度创伤性脑损伤小鼠模型中，事实上，TBI的特征在于 神经胶质细胞如星形胶质细胞和小胶质细胞的活化以及外周免疫细胞如 单核细胞衍生的巨噬细胞和T细胞。当神经炎症在皮层区域立即发生时 在急性损伤后，继发性神经炎症在同侧丘脑中缓慢发展，可能是由于 这是由于皮层和丘脑之间失去了密切的相互联系。因为皮质丘脑 皮层（CTC）回路在认知、睡眠和癫痫发作中起着关键作用，这些都受到TBI的影响， 这个回路中的延迟神经可塑性是一个很好的模型，可以用来区分免疫系统之间的相互作用。 细胞和神经回路。 外周免疫细胞的作用在TBI衍生的免疫缺陷的背景下尤其未被充分研究。 如PTE和睡眠中断等电生理缺陷。我们建议使用可控的皮质撞击 中度TBI小鼠模型，以确定单核细胞源性的延迟浸润的作用 巨噬细胞和CD 4 + T细胞在继发性神经元丢失（目的1），兴奋/抑制失衡， 皮质-丘脑回路（目标2），以及睡眠中断等电图异常的发展 目标3（Aim 3）为此，我们将结合联合收割机神经科学和免疫学的尖端工具， 包括基因操作、流式细胞术、免疫-神经相互作用的3D成像、突触生理学 以及慢性无线脑电图记录。 这项研究的资助将使我们能够更好地了解免疫系统如何与神经回路相互作用 导致神经功能缺损的发展。鉴于目前已有治疗方法， 临床阻断CD 4 + T细胞和巨噬细胞，这项研究有可能迅速影响TBI的治疗方式 在人类病人身上。

ABSTRACT Traumatic brain injury (TBI) impacts millions of Americans each year and can lead to cognitive dysfunction, difficulty with sensory processing, sleep disruption, and the development of epilepsy. One common neural outcome of TBI is the development of electrophysiological abnormalities that can lead to post-traumatic epilepsy (PTE) or disruptions in sleep architecture. However, the mechanisms by which these neurological deficits arise as a consequence of TBI remain poorly understood. Preliminary evidence indicates that inflammation contributes to the electrophysiological abnormalities that underlie PTE and sleep disruption in a mouse model of moderate TBI. Indeed, TBI is characterized by both the activation of glial cells like astrocytes and microglia and by the infiltration of peripheral immune cells like monocyte-derived macrophages and T-cells. While neuroinflammation occurs immediately in the cortical region of acute injury, secondary neuroinflammation develops slowly in the ipsilateral thalamus, presumably as a result of loss of intimate reciprocal connections between cortex and thalamus. Because the cortico-thalamo- cortical (CTC) circuit plays a key role in cognition, sleep, and seizures, which are all impacted by TBI, the delayed neural plasticity in this circuit is a good model for teasing apart the interaction between the immune cells and neural circuits after TBI. The role of peripheral immune cells is particularly understudied in the context of TBI-derived electrophysiological deficits like PTE and sleep disruption. We propose to use a controlled-cortical impact mouse model of moderate TBI to determine the role of delayed infiltration of monocyte-derived macrophages and CD4+ T cells in secondary neuronal loss (Aim 1), excitation/inhibition imbalance in the cortico-thalamic circuit (Aim 2), and the development of electrographic abnormalities such as sleep disruption and PTE (Aim 3). To do so, we will combine cutting-edge tools from both neuroscience and immunology, including genetic manipulations, flow cytometry, 3D imaging of immune-neural interactions, synaptic physiology in brain slices, and chronic wireless EEG recordings. Funding of this study will enable us to better understand how the immune system interacts with neural circuits after TBI to cause the development of neurological deficits. Given that there are treatments already available in clinic to block CD4+ T cells and macrophages, this study has the potential to rapidly impact how TBI is treated in human patients.