Defining the Logic of Neurovascular Signaling in the Brain

摘要 血液是大脑中一种重要而有限的资源：神经元活动需要氧气和 葡萄糖，甚至限制区域的流动被剥夺，都不可避免地导致细胞死亡。你还好吗？ 受控血液的分布与皮质需求的变化有关？答案直接关系到 皮质功能。从发展的角度来看，它们产生了血管结构的“设计规则”。从 从生理学的角度来看，答案定义了将神经元活动与变化联系起来的状态变量 在血液流动中。这对神经成像有影响，因为从血液中提取氧气是 BOLD功能磁共振成像的对比基础。最后，对于神经学来说，答案决定了 对血管创伤和疾病的认知过程。 目前关于神经元和小动脉之间的分子信号转导的文献主要基于切片 准备工作表明，扩张小动脉的血管活性信号分子之间存在竞争 平滑的肌肉和引起收缩的肌肉。这种信号分子的混合物被释放出来 由直接接触肌肉的抑制性中间神经元和通过 包裹血管的星形胶质细胞的兴奋。这幅图画令人信服，但又不完整，很自然。 刺激在亚秒的水平上改变流量，而文献指出的是几十秒的变化。 主要的挑战是分析信号分子和体内流动。我们会满足这一点的 通过将我们在体内电生理学和成像方面的优势与我们的方法相结合来应对挑战 精确量化血流和新设计的信号分子指示器。 我们设想了一种神经血管控制模型，它将不同神经元亚型的活动映射到 血管张力的变化。基础信号分子的动力学形成了状态 变量，就像通道动力学一样，形成了单神经元动力学的状态变量。这样的一个 模型将阐明神经血管疾病模型和神经成像研究。

Abstract Blood is a vital and limited resource in the brain: neuronal activity requires supplies of oxygen and glucose, and deprivation of flow to even restricted regions leads inevitably to cell death. How is the distribution of blood controlled relative to the changing needs of cortex? The answers bear directly on cortical function. Developmentally, they yield "design rules" for vascular architecture. From the perspective of physiology, the answers define state variables that relate neuronal activity to changes in blood flow. This has implications for neuroimaging, as the extraction of oxygen from blood is the basis of contrast in BOLD fMRI. Lastly, for neurology, the answers determine the resistance of cognitive processes to vascular trauma and disease. The current literature on molecular signaling between neurons and arterioles, based mainly on slice preparations, points to a competition between vasoactive signaling molecules that dilate arteriole smooth muscle and those that cause constriction. Mixtures of such signaling molecules are released by inhibitory interneurons, which directly contact muscle, and by excitatory neurons, which act via the excitation of astrocytes that encapsulate vessels. This picture is compelling yet incomplete, as natural stimuli change flow on the subsecond level while the literature points to changes on tens of seconds. The main challenge is to assay both signaling molecules and flow in vivo. We will meet this challenge by combining our strengths in in vivo electrophysiology and imaging with our methods for precise quantification of blood flow and newly engineered indicators for signaling molecules. We envision a model of neurovascular control that maps the activity of different neuronal subtypes to changes in vascular tone. The dynamics of the underlying signaling molecules form the state variables, much as channel dynamics form the state variables in single neuron dynamics. Such a model will clarify neurovascular disease models and neuroimaging studies.