Mechanisms underlying neurovascular coupling:

当一个人在阅读、听音乐或做任何其他活动时，大脑的一个区域是活跃的。大脑的这个激活区域需要更多来自血液的营养和氧气。为了调节这种与神经元活动相关的血液供应增加，即所谓的神经血管耦合现象，大脑使用了复杂的机制。一个多世纪以来，神经血管耦合的机制一直是研究的主题，许多来自神经元和星形胶质细胞的血管活性因子都与神经血管耦合有关。星形胶质细胞是一种特殊类型的脑细胞，约占大脑的一半，但被认为在大脑活动中不起作用。最近的重要发现表明，星形胶质细胞通过在解剖学和功能上连接大脑神经元和血管，参与神经血管耦合。在本研究中，我们假设分别来自星形胶质细胞和神经元的两种气体一氧化碳（CO）和一氧化氮（NO）通过作用于星形胶质细胞诱导血管舒张。这个概念是非常创新的，因为通常认为这两种气体扩散到血管系统，直接引起血管舒张。然而，星形胶质细胞在解剖学上更接近NO和CO的释放位点，我们非常激动人心的初步结果表明，NO增加了星形胶质细胞中的钙，这是一种诱导血管舒张的机制。我们将利用分离细胞和组织以及活体动物研究NO和CO对神经血管偶联的影响。分离的细胞和组织将使我们能够理解分子水平上的机制，而活体动物将允许我们验证从分离的细胞或组织中得到的结果的功能意义。这种方法将提供从分子相互作用到整个动物的神经血管调节的综合理解。本提案的长期目标是加强我们对神经活动如何与血流相关的理解。

A sector of the brain is active when a person is reading, listening to music, or doing any other activity. This activated region of the brain needs more nutrients and oxygen that come from the blood. To regulate this increase in blood supply associated with neuronal activity, a phenomenon called NEUROVASCULAR COUPLING, the brain uses complex mechanims. These mechanisms underlying neurovascular coupling have been the subject of enquiry for more than a century, and numerous vasoactive factors derived from neurons and ASTROCYTES have been implicated in neurovascular coupling. Astrocytes are a specific type of brain cells which comprises about half the brain but were thought to play no role in brain processes. Recent important discoveries showed that astrocytes are involved in neurovascular coupling by linking, anatomically and functionally, the brain's neurons to blood vessels. In the present proposal, we HYPOTHETIZE that carbon monoxide (CO) and nitric oxide (NO), two gases derived from astrocytes and neurons respectively, induce vasodilation by acting on astrocytes. This concept is very innovative because it is generally assumed that these two gases diffuse to the vasculature to directly induce a vasodilation. However, astrocytes are anatomically closer to the sites of NO and CO release and our very exciting preliminary results showed that NO increases calcium in astrocytes, a mechanism that induces vasodilation. We will study the effect of NO and CO on neurovascular coupling using isolated cells and tissues as well as living animals. The isolated cells and tissues will allow the understanding of mechanisms at the molecular level and the living animals will permit to verify the functional significance of the results we get from isolated cells or tissues. This approach will give an integrated understanding of neurovascular regulation from molecular interactions to the whole animal.The LONG-TERM GOAL of the present proposal is to enhance our understanding of how neural activity is related to blood flow.