Uncovering the physiological role of functional hyperemia

揭示功能性充血的生理作用

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos 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

项目摘要

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.

自从 19 世纪发现以来，神经元激活导致该区域的血流量增加。这种现象——称为功能性充血——被认为可以为身体提供更多的能量营养。维持神经活动受损的功能性充血常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，这些疾病也表现出基线血流减少。水平，使得很难确定功能性充血本身在维持健康方面的重要性功能性充血也是许多成像技术（例如功能磁共振成像）的基础。利用空间局部血流增加来推断神经活动的位置尽管了解功能性充血对于血管/代谢测量具有广泛的重要性。神经科学，仅消除活动引起的血流量增加的影响——而不改变基线流量水平或神经元和其他皮质细胞的活动仍然未知。确定神经活动和神经代谢如何影响健康和阿尔茨海默病我们最近开发了一种模型系统来阻断功能性充血。令我们惊讶的是，我们发现感觉诱发的神经反应并非如此。在目标 1 中，我们将通过研究建立在这些初步数据的基础上。功能性充血的丧失会改变对感觉刺激的神经反应的哪些方面。光子钙成像将用于小鼠初级视觉皮层，以量化响应幅度兴奋性和抑制性神经元对刺激属性的选择性（方向选择性）受到影响。使用电生理学，我们将确定神经活动的时间精确方面，例如尖峰我们的工作假设是阻塞。功能性充血会损害参与产生动作电位的细胞机制（例如恢复然而，这些后果最初可能不会表现为响应水平降低，而是表现为响应水平降低。如尖峰时间、兴奋/抑制平衡、网络同步和信息编码的改变。还将确定健康的年轻大脑是否有能力以某种方式缓冲功能性充血的丧失患病的大脑无法阻止 AD 小鼠模型的功能性充血，这也将揭示这一点。 AD 病理学中减少功能性充血与基线血流水平的相对重要性。在目标 2 中，我们将研究阻断功能性充血如何影响神经元代谢，我们将记录。组织中氧气、葡萄糖、乳酸和 ATP 的浓度，以确定如何阻断功能充血会影响这些代谢物的水平以及是否会导致神经元的代谢过程。还将量化脉管系统对血流量暂时减少的反应。该提案将定义功能性充血在维持神经元即时代谢需求方面发挥着重要作用。