Elucidating Structural and Functional Alterations of CNS Pericytes on Chronic Brain Implants

项目总结 穿透微电极显著提高了我们对大脑功能的了解，并使我们能够 恢复因神经疾病而失去的运动和感觉控制。然而，皮质内注射的疗效 用于临床治疗的微电极受限于不能随着时间的推移检测或调节神经元，并且 推测是由于身体对异物的严重反应所致。而生物机制调节 人们对设备故障知之甚少，新出现的假说表明，神经血管功能障碍在 在装置植入后导致进行性神经元丢失和组织衰竭方面发挥重要作用。神经血管 健康和功能在一定程度上是由血管周围周细胞控制的，血管周细胞是直接结合的特殊壁细胞。 有脑血管。周细胞在调节血管张力、血脑屏障等方面发挥重要作用 正直和神经免疫功能，并越来越多地被认为是 脑部炎症和疾病的发病机制。设备植入如何扰乱大脑的结构和功能 周细胞及其对神经健康、神经胶质活性和血管完整性的后续影响目前 未知。初步数据表明，装置插入改变了周细胞的分布和形态， 这与神经细胞钙功能障碍、神经胶质细胞激活和血管恶化同步发生。 对于F99期，我将确定电极植入如何影响体内功能性周细胞的活动 用基因编码的钙指示剂GCaMP6s表征钙信号动力学 仅存在于PDGFRβ+周细胞内。此外，我将培训如何使用光遗传学来瞄准和 在植入期间和植入过程中调节周细胞特异性反应，以达到预期的结果 促进脑损伤后周细胞健康、神经保护和血管功能。腺相关病毒 (AAV)转导将被用于观察周细胞刺激后的神经元钙动力学。 最后，大量的研究金工作将集中在预期的职业生涯发展活动上。 在K00阶段获得博士后培训。 在K00阶段，我将利用我在神经接口技术和神经免疫方面的专业知识 对继续识别和表征脑损伤和脑损伤中神经退行性变机制的反应 使用先进的神经调节技术治疗或逆转阿尔茨海默氏症等脑部疾病的病理 疾病和相关痴呆(ADRD)。这一阶段的活动将涉及更有针对性的职业生涯 发展培训，旨在成为一名完全实现的、独立的ADRD调查员。在……里面 总结、完成上述研究目标和专业培训的慷慨后盾 对NIH D-SPAN奖的支持将使我能够在 神经接口生物学、神经调节和神经退行性疾病的交叉学科。

PROJECT SUMMARY Penetrating microelectrodes significantly advance our understanding of brain function and enable us to restore motor and sensory control lost from neurological disorders. However, the efficacy of intracortical microelectrodes for clinical therapy is limited by an inability to detect or modulate neurons over time and is presumed to be due to severe bodily reactions to a foreign body. While the biological mechanisms regulating device failure are poorly understood, emerging hypotheses suggests that neurovascular dysfunction plays a significant role in enabling progressive neuron loss and tissue failure after device implantation. Neurovascular health and function are governed in part by perivascular pericytes, specialized mural cells in direct apposition with cerebral blood vessels. Pericytes demonstrate important roles regulating vascular tone, blood-brain barrier integrity, and neuroimmune functions and have become increasingly recognized as prominent figures in the pathogenesis of brain inflammation and disease. How device implantation disrupts the structure and function of pericytes and the subsequent ramifications on neural health, glial activity, and vascular integrity are currently unknown. Preliminary data suggests that device insertion alters the distribution and morphology of pericytes, which occurs in tandem with neuronal calcium dysfunction, glial activation, and vascular deterioration. For the F99 phase, I will determine how electrode implantation affects functional pericyte activity in vivo using a genetically encoded calcium indicator GCaMP6s to characterize calcium signaling dynamics exclusively within PDGFRβ+ pericyte cells. Additionally, I will train in the use of optogenetics to target and modulate pericyte-specific responses during insertion and throughout implantation with the expected outcome of promoting pericyte health, neuroprotection, and vascular function after brain injury. Adeno-associated viral (AAV) transduction will be performed to visualize neuronal calcium dynamics following pericyte stimulation. Finally, substantial fellowship efforts will focus on activities in professional career development in anticipation of securing postdoctoral training during the K00 phase. For the K00 phase, I will leverage my expertise of neural interface technology and neuroimmune responses to continue identifying and characterizing mechanisms of neurodegeneration during brain injury and use advanced neuromodulating techniques to treat or reverse pathology in brain diseases such as Alzheimer’s disease and related dementia (ADRD). Activities during this phase will involve more directed career development training that is tailored toward becoming a fully realized, independent ADRD investigator. In summary, completion of the above-mentioned research aims and professional training backed by the generous support of an NIH D-SPAN award will enable me to carve out a novel and innovative area of research at the intersect of neural interface biology, neuromodulation, and neurodegenerative disease.