The contribution of cortical NK1R/nNOS interneurons in neurovascular coupling

项目摘要/摘要 在阿尔茨海默病和中风等脑血管疾病中，维持正常大脑的能力 血液流动受到影响。神经血管偶联(NVC)，神经活动之间的时间关系 和脑血流，被认为在这些情况下被扰乱，导致大脑低灌流和 认知功能障碍。由于一氧化氮(NO)介导血管扩张，所以释放NO的神经元是好的。 有望成为脑血流(CBF)的主要调节者。我们最近开发了一种新的遗传工具-- NK1R-Creer敲击鼠标-允许我们定位并操作特定的NO-生成子集 神经元(nNOS1型神经元)，从而测试这些细胞在神经血管偶联中的参与 第一次。在这里，我们建议检验nNOS1型神经元接受兴奋性的特定假设 锥体传入和介导血管扩张。目标1将研究NK1R-Creer皮层中间神经元 使用免疫组织化学方法接受兴奋性锥体输入。AIM 2将调查 锥体神经元在NK1R-Creer皮质间神经元上形成功能性突触 光遗传学方法和脑片电生理学。最后，Aim 3将测试NK1R-Creer中间神经元 使用激光多普勒血流计，活体活动是增加脑血流量的必要条件和充分条件。 总而言之，这些实验将研究神经活动和血流动力学的耦合回路。这种洞察力 NVC是我们了解常见脑血管疾病发病机制的基础 以脑血流为靶点的药物治疗进展。

Project Summary/Abstract In cerebrovascular disorders, such as Alzheimer’s Disease and stroke, the ability to maintain normal cerebral blood flow is compromised. Neurovascular coupling (NVC), the temporal relationship between neural activity and cerebral blood flow, is thought to be disrupted in these conditions resulting in cerebral hypoperfusion and cognitive dysfunction. As nitric oxide (NO) mediates vasodilation, the neurons that release (NO) are good candidates as a major regulator of cerebral blood flow (CBF). We recently developed a new genetic tool— NK1R-creER knockin mouse— that allows us to target and manipulate a specific subset of NO-generating neurons (nNOS Type 1 neurons), and thus test the involvement of these cells in neurovascular coupling for the first time. Here, we propose to test the specific hypothesis that nNOS Type 1 neurons receive excitatory pyramidal input and mediate vasodilation. Aim 1 will investigate whether NK1R-creER cortical interneurons receive excitatory pyramidal input using immunohistochemical approaches. Aim 2 will investigate whether pyramidal neurons form functional synapses onto NK1R-creER cortical interneurons using optogenetic approaches and slice electrophysiology. Lastly, Aim 3 will test whether NK1R-creER interneuron activity is necessary and sufficient to increase cerebral blood flow in vivo using laser Doppler flowmetry. Together, these experiments will investigate the circuits coupling neural activity and hemodynamics. This insight into NVC is fundamental to our understanding of the pathogenesis of common cerebrovascular diseases and the advancement of pharmacotherapeutics targeting cerebral perfusion.