毛细血管与神经微环路的相互影响及其在阿尔兹海默病中的表现

The circulation system is vital for physiological functions of the brain, and in return that the cerebral blood flow is tightly controlled by neuronal activity. Healthy neurovascular coupling is required for normal activity of the brain; the deficits of such underlie many neurological diseases, such as Alzheimer’s disease. It has been well known that the cerebral blood flow is precisely controlled by neural activity, but its effects on surrounding neural circuits in both physiological and pathological conditions remain unknown. Furthermore, how neurons coordinate with each other to efficiently influence the blood flow in nearby capillary also remains uncertain. We will take advantage of multiple whole-cell patch clamp recordings technique, two-photon microscopy and other state-of-the-art methods to analyze the effects of blood vessels on the formation and maintenance of local neural microcircuits, and to evaluate whether neurons will form functional groups to control local blood flow. We will also further explore the cellular mechanism underlying the deficits of neurovascular coupling in neurological disease with corresponding mouse model systems. The execution of this project will help us to understand how the brain responses precisely to sensory stimuli, and to discover new etiological mechanisms for cognitive deficits in the neurological diseases with defective neurovascular coupling, therefore to facilitate the discovery of methods for early diagnosis and brand-new treatments for those diseases.

脑内的血液循环系统对脑行使正常功能至关重要，反之也受到神经元活动的紧密调控。这种严密的神经血管耦合是正常大脑活动所必需的，众多神经性疾病的发生发展与其异常有关，如阿尔兹海默病。神经元活动能够精密调节血流量已被人们熟知，但在生理及病理情况下，毛细血管对周边神经组织中的神经环路有何影响以及神经元之间又是如何相互协调影响其间血流量之前却从未被探索过。我们将结合多通道全细胞膜片钳记录和在体双光子显微成像分析等主要手段，在体外和体内两个系统下分析血管对周边神经微环路形成和维持的影响，以及神经元是否是通过形成功能小群体的方式来调节相邻毛细血管管径的大小；并将应用相应的疾病模型小鼠探讨神经性疾病中神经血管耦合缺陷的细胞机制。该项目的成功实施将促进人们理解大脑是如何能够精密地对外界做出适当的反应，也将从全新的角度阐述神经性疾病出现认知功能障碍的病理机制，从而为这类疾病的早期诊断和及时防治提供新的科学依据。