Uncovering the physiological role of functional hyperemia

揭示功能性充血的生理作用

• 批准号: 10587764
• 负责人: Philip O'Herron
• 金额: $ 48.98万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587764
• 关键词: APP-PS1; Action Potentials; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Astrocytes; Biological Models; Biosensor; Blood Vessels; Blood flow; Brain; Brain Diseases; Brain region; Buffers; Calcium; Cells; Cerebrovascular Circulation; Cognition Disorders; Data; Dilator; Disease; Disease Progression; Electrodes; Electrophysiology (science); Equilibrium; Fire - disasters; Functional Imaging; Functional Magnetic Resonance Imaging; Glucose; Glycolysis; Health; Hyperemia; Image; Imaging Techniques; Impairment; Ions; Knock-out; Light; Literature; Location; Measures; Metabolic; Metabolism; Monitor; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurophysiology - biologic function; Neurosciences; Nutrient; Opsin; Oxidative Phosphorylation; Oxygen; Pathology; Phenotype; Physiological; Play; Property; Proxy; Reaction; Regulation; Role; Running; Sensory; Signal Transduction; Smooth Muscle Myocytes; Stimulus; Techniques; Temperature; Testing; Tissues; Vasodilation; area striata; arteriole; cell cortex; excitatory neuron; extracellular; fluorescence imaging; functional disability; functional loss; imaging study; improved; information processing; inhibitory neuron; insight; mouse model; neural; neuronal metabolism; neurovascular; neurovascular unit; novel; optogenetics; orientation selectivity; pharmacologic; reactive hyperemia; response; sensory stimulus; two-photon; vasoconstriction; visual stimulus; wasting

Neuronal activation leads to increases in blood flow to the region. Since its discovery in the 19th century, this phenomenon – termed functional hyperemia – has been thought to provide increased energy nutrients to sustain the increased neural activity. Impaired functional hyperemia is seen in many neurodegenerative diseases including Alzheimer's disease (AD). However, these diseases also manifest reduced baseline flow levels, making it difficult to determine the importance of functional hyperemia per se in sustaining healthy neuronal function. Functional hyperemia also forms the basis of many imaging techniques (such as fMRI), that take advantage of the spatially localized blood flow increase to infer the location of neural activity from vascular/metabolic measures. Despite the widespread importance of understanding functional hyperemia for neuroscience, the impacts of eliminating only the activity-induced increase in blood flow – without altering baseline flow levels or the activity of neurons and other cortical cells – are still unknown. This proposal will determine how neuronal activity and neuro-metabolism are affected in health and in Alzheimer's disease when functional hyperemia is blocked. We recently developed a model system to block functional hyperemia using optogenetics. To our surprise, we found that sensory-evoked neuronal responses were not diminished when functional hyperemia was blocked. In Aim 1 we will build on this preliminary data by studying what aspects of neural responses to sensory stimuli are altered by the loss of functional hyperemia. Two- photon calcium imaging will be used in mouse primary visual cortex to quantify how the response amplitude and selectivity to stimulus attributes (orientation selectivity) of excitatory and inhibitory neurons are affected. Using electrophysiology, we will determine if temporally precise aspects of neuronal activity, such as spike timing and network synchrony (i.e. gamma oscillations) are altered. Our working hypothesis is that blocking functional hyperemia impairs the cellular machinery involved in generating action potentials (such as restoring ion gradients). However, these consequences may not initially appear as reduced response levels, but rather as alterations in spike timing, excitatory/inhibitory balance, network synchrony, and information encoding. We will also determine if healthy young brains have the capacity to buffer the loss of functional hyperemia in ways that a diseased brain cannot by blocking functional hyperemia in a mouse model of AD. This will also shed light on the relative importance of reduced functional hyperemia versus baseline flow levels in AD pathology. In Aim 2 we will study how neuronal metabolism is affected by blocking functional hyperemia. We will record the concentrations of oxygen, glucose, lactate and ATP in the tissue to determine how blocking functional hyperemia affects the levels of these metabolites and if it leads to altered metabolic processing in neurons. We will also quantify how the vasculature reacts to temporary reductions in blood flow. This proposal will define the role functional hyperemia plays in maintaining the moment-to-moment metabolic needs of neurons.

神经元的激活导致流向该区域的血流量增加。自从它在19世纪被发现以来，这 这一现象被称为功能性充血，一直被认为能为 维持增加的神经活动。损伤性功能性充血见于许多神经退行性疾病 包括阿尔茨海默病(AD)在内的疾病。然而，这些疾病也表现为基线流量减少。 水平，这使得很难确定功能性充血本身对维持健康的重要性 神经功能。功能性充血也是许多成像技术(如功能磁共振成像)的基础， 利用空间局部血流量增加来推断神经活动的位置 血管/新陈代谢指标。尽管了解功能性充血对 神经科学：只消除活动引起的血流增加而不改变的影响 基线血流水平或神经元和其他皮质细胞的活动仍是未知的。这项提议将 确定神经活动和神经代谢在健康和阿尔茨海默病中是如何受到影响的 功能性充血受阻时的疾病。我们最近开发了一个模型系统来阻止功能 利用光遗传学来治疗充血。令我们惊讶的是，我们发现感官诱发的神经元反应并不是 当功能性充血被阻断时，其功能减弱。在目标1中，我们将以这些初步数据为基础，通过研究 功能性充血的丧失改变了神经对感觉刺激的反应的哪些方面。两个- 光子钙成像将用于量化小鼠初级视皮层的反应幅度 兴奋性和抑制性神经元对刺激属性的选择性(定向选择性)受到影响。 利用电生理学，我们将确定神经元活动的时间上的精确方面，如棘波 定时和网络同步(即伽马振荡)被改变。我们的工作假设是阻止 功能性充血损害了参与产生动作电位的细胞器(如恢复 离子梯度)。然而，这些后果最初可能不会表现为反应水平降低，而是相反 作为棘波时序、兴奋/抑制平衡、网络同步性和信息编码的改变。我们 也将确定健康的年轻大脑是否有能力缓冲功能性充血的丧失 通过阻断阿尔茨海默病小鼠模型中的功能性充血，患病的大脑无法做到这一点。这也会让我们明白 关于减少功能性充血与基础血流水平在AD病理中的相对重要性。 在目标2中，我们将研究阻断功能性充血对神经元代谢的影响。我们将录制 组织中氧、葡萄糖、乳酸和三磷酸腺苷的浓度来确定阻断功能 充血会影响这些代谢物的水平，如果它导致神经元代谢过程改变的话。我们 还将量化血管系统对暂时性血流量减少的反应。这项提案将定义 功能性充血在维持神经元每时每刻的代谢需求方面起着重要作用。