Glial regulation of neurovascular coupling in CNS disorders

项目摘要 中枢神经系统（CNS）中神经元活动的增加导致局部神经元活动的相应增加。 脑血流量这种反应称为神经血管偶联，在几种CNS中丧失或减弱。 疾病，包括中风、阿尔茨海默病（AD）、肌萎缩侧索硬化（ALS）、多发性硬化 (MS)和创伤性脑损伤（TBI）。由此导致的血糖和氧气的减少， 放电和恢复神经元可能会加剧神经元损伤，并有助于神经系统疾病的发生。 恶化因此，在这些条件下治疗管理的关键目标包括恢复 血流然而，疾病中神经血管耦合减弱的潜在机制是 未知的，复杂的开发有效的治疗方法用于临床。我们先前已经 表明星形胶质细胞是传递代谢活性信号的必要中间体， 神经元到微血管毛细血管，但不是小动脉。与此相关的是，星形胶质细胞也是 对环境的变化非常敏感，对中枢神经系统的损伤有反应。这 反应包括星形胶质细胞形态和基因表达模式的急剧变化，但 这些变化对神经血管偶联的影响尚不清楚。我们假设 来自反应性星形胶质细胞的信号负责损伤中神经血管偶联的衰减， 疾病我们的初步数据支持这一假设：在中风的实验模型中， 反应性被诱导，活性依赖性扩张在毛细血管显著减弱， 由星形胶质细胞调节的隔室。因此，我们的目标是确定反应性 星形胶质细胞可能抑制毛细血管扩张。具体来说，我们将检验神经血管 偶联在中风后毛细血管而不是小动脉被选择性抑制（目的1），确定是否 反应性星形胶质细胞的活性诱发反应在星形胶质细胞终足中选择性改变， 毛细血管，但不是在小动脉（目的2），并确定信号通路负责抑制 活动诱发的毛细血管扩张（目的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).