Glial regulation of neurovascular coupling in CNS disorders

项目总结 中枢神经系统(CNS)中神经元活动的增加导致局部 脑部血流量。这种反应被称为神经血管偶联，在几个中枢神经系统中丢失或减弱 疾病，包括中风、阿尔茨海默病(AD)、肌萎缩侧索硬化症(ALS)、多发性硬化症 (Ms)和创伤性脑损伤(TBI)。由此导致的血糖和氧气水平的下降 神经元的放电和恢复可能会加剧神经元的损伤，并对神经学做出贡献。 恶化。因此，在这些情况下的治疗管理的一个关键目标包括恢复 血液流动。然而，疾病中神经血管偶联减弱的潜在机制是 未知，使临床上使用的有效疗法的开发复杂化。我们之前已经 证明星形胶质细胞是从代谢活动中传递信号的必要中间体 神经元到微血管的毛细血管，而不是小动脉。与这一提议相关的是，星形胶质细胞也 对环境的变化非常敏感，并对中枢神经系统的侮辱做出反应。这 反应包括星形胶质细胞形态和基因表达模式的剧烈变化，但 这些变化对神经血管偶联的影响尚不清楚。我们假设这一反常现象 来自反应性星形胶质细胞的信号负责损伤或损伤中神经血管偶联的减弱 疾病。我们的初步数据支持这一假设：在中风的实验模型中，星形胶质细胞 反应性被诱导，依赖活动的扩张在毛细血管、血管 由星形胶质细胞调节的隔室。因此，我们的目标是确定反应的机制(S) 星形胶质细胞可能抑制毛细血管扩张。具体地说，我们将测试神经血管的假设 卒中后有选择地抑制毛细血管的偶联，但不抑制微动脉(目标1)，确定是否 反应性星形胶质细胞的活性诱发反应在终止于 毛细血管而不是微动脉(目标2)，并确定负责抑制血管紧张素转换酶的信号通路。 活动诱发的毛细血管扩张(目标3)。

PROJECT SUMMARY Increased neuronal activity in the central nervous system (CNS) elicits corresponding increases in local cerebral blood flow. This response, termed neurovascular coupling, is lost or attenuated in several CNS disorders, including stroke, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and traumatic brain injury (TBI). The resulting decrease in blood glucose and oxygen available to actively firing and recovering neurons is likely to exacerbate neuronal damage and contribute to neurological deterioration. Therefore, a key goal of therapeutic management in these conditions includes restoration of blood flow. However, the mechanisms underlying the attenuation of neurovascular coupling in disease are unknown, complicating the development of effective therapeutics for use in the clinic. We have previously demonstrated that astrocytes are necessary intermediates that convey signals from metabolically active neurons to microvascular capillaries but not arterioles. Of relevance to this proposal, astrocytes are also exquisitely sensitive to changes in their environment and become reactive in response to CNS insults. This response encompasses drastic changes in astrocyte morphology and gene expression patterns, but the consequence of these changes on neurovascular coupling remain undefined. We hypothesize that aberrant signals from reactive astrocytes are responsible for the attenuation of neurovascular coupling in injury or disease. Our preliminary data support this hypothesis: after an experimental model of stroke wherein astrocyte reactivity is induced, activity-dependent dilation is significantly attenuated at capillaries, the vascular compartment regulated by astrocytes. Therefore, our goal is to determine the mechanism(s) by which reactive astrocytes might suppress capillary dilation. Specifically, we will test the hypothesis that neurovascular coupling is suppressed selectively at capillaries but not arterioles following stroke (Aim 1), determine whether activity-evoked responses of reactive astrocytes are selectively altered in astrocyte endfeet terminating on capillaries but not on arterioles (Aim 2), and identify the signaling pathways responsible for the suppression of activity-evoked capillary dilation (Aim 3).