The contribution of cortical NK1R/nNOS interneurons in neurovascular coupling

皮质 NK1R/nNOS 中间神经元在神经血管耦合中的贡献

• 批准号: 10091379
• 负责人: Catherine Faber Ruff
• 金额: $ 4.55万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10091379
• 关键词: Address; Alleles; Alzheimer' s Disease; Anatomy; Area; Blood Vessels; Blood flow; Brain; Cells; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrum; Coupling; Electrophysiology (science); Genetic; Goals; Homeostasis; Immunohistochemistry; Impaired cognition; Interneurons; Knock-in Mouse; Knowledge; Label; Laser-Doppler Flowmetry; Measures; Mediating; Metabolic; Microcirculation; Mus; Neurokinin A; Neurons; Nitric Oxide; Nitric Oxide Synthase Type I; Pathogenesis; Perfusion; Population; Presynaptic Terminals; Pyramidal Cells; Research; Role; Slice; Stroke; Substance P Receptor; Synapses; Synaptophysin; Testing; Therapeutic; Time; Vascular blood supply; Vasodilation; Vasodilator Agents; Vertebral column; Visualization; base; cerebral hemodynamics; cerebral hypoperfusion; cerebrovascular; experimental study; hemodynamics; hippocampal pyramidal neuron; improved; in vivo; insight; neural circuit; neurovascular coupling; optogenetics; photoactivation; postsynaptic; relating to nervous system; response; stroke risk; tool

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.

项目总结/摘要 在脑血管疾病中，如阿尔茨海默病和中风，维持正常脑功能的能力， 血流受到影响神经血管耦合（NVC），神经活动之间的时间关系 和脑血流，被认为是在这些条件下中断，导致脑灌注不足， 认知功能障碍由于一氧化氮（NO）介导血管舒张，释放（NO）的神经元是好的 候选人作为脑血流（CBF）的主要调节剂。我们最近开发了一种新的基因工具- NK 1 R-creER敲入小鼠-允许我们靶向和操纵NO生成的特定子集 神经元（nNOS 1型神经元），并因此测试这些细胞参与神经血管偶联， 首次在这里，我们建议测试特定的假设，即nNOS 1型神经元接受兴奋性 锥体输入和介导血管舒张。目的1将研究NK 1 R-creER皮质中间神经元是否 使用免疫组织化学方法接收兴奋性锥体输入。目标2将调查是否 锥体神经元在NK 1 R-creER皮质中间神经元上形成功能性突触， 光遗传学方法和切片电生理学。最后，目标3将测试NK 1 R-creER中间神经元是否 使用激光多普勒血流测定法，活性对于增加体内脑血流量是必要的和足够的。 总之，这些实验将研究耦合神经活动和血液动力学的电路。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， 以脑灌注为靶点的药物治疗研究进展。