Noradrenergic modulations of fMRI signal

fMRI 信号的去甲肾上腺素能调制

• 批准号: 10373198
• 负责人: MITSUHIRO FUKUDA
• 金额: $ 42.72万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-29 至 2024-03-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373198
• 关键词: Adrenergic Agonists; Affect; Alzheimer' s Disease; Animals; Arousal; Behavior; Biological Models; Blood; Blood Vessels; Blood flow; Brain; Brain Stem; Brain region; Cell Nucleus; Data; Detection; Disease; Electric Stimulation; Etiology; Functional Magnetic Resonance Imaging; Generations; Goals; Health; Human; Image; Knowledge; Literature; Location; Maps; Measures; Mission; Modality; Nature; Neocortex; Neurons; Norepinephrine; Optics; Outcome; Physiological; Play; Property; Public Health; Research; Rest; Rodent; Role; Schizophrenia; Sensory; Signal Transduction; Sleep Wake Cycle; Somatosensory Cortex; Source; System; Testing; Theft; Time; Topical application; Translating; United States National Institutes of Health; awake; base; blood oxygen level dependent; blood oxygenation level dependent response; cerebral blood volume; disability; experimental study; hemodynamics; human subject; imaging study; innovation; locus ceruleus structure; neuronal excitability; neurophysiology; neuroregulation; neurovascular coupling; noradrenergic; optogenetics; pressure; presynaptic; relating to nervous system; response; sensory stimulus; somatosensory; vasoconstriction

PROJECT SUMMARY/ABSTRACT Functional magnetic resonance imaging (fMRI) with blood oxygenation level-dependent (BOLD) contrast indirectly measures neuronal activity by way of their localized hemodynamic responses. BOLD responses typically show sustained increases above their baseline (i.e., positive BOLD responses, PBR), but sometimes show sustained decreases below their baseline (i.e., negative BOLD responses, NBR). While the PBR is well associated with increased neuronal activity, the NBR has been associated with decreased neuronal activity or is thought to have non-neuronal origins, such as “blood stealing”, whereby blood is diverted from lesser active regions to more active regions due to local pressure changes independent of local neuronal activity. Therefore, the physiological origin of the NBR remains elusive. Our long-term goal is to determine how properties of neurovascular coupling change with varying locus coeruleus (LC) activity, and the associated changes in noradrenaline (NA) release, in behaving animals. The overall objective in this application is to determine and characterize the involvement of LC activity in the generation of the NBR in the rodent somatosensory cortex. Our central hypothesis is that modulations of LC activity evoked by sensory stimulation directly alters both vascular tone and neuronal activity, which affect the NBR as well as the PBR. The rationale for this project is that determining how LC activity is involved in fMRI signals in normal physiological conditions will facilitate a deeper understanding of how functional alterations of LC activity in diseased states, such as with schizophrenia and Alzheimer's disease, may contribute to noninvasive fMRI signal changes. The central hypothesis will be tested by pursuing the specific aim to identify the effects of direct LC modulations on the NBR and, specifically, the effect of NA on the NBR. Under this aim, LC-NA activity will be enhanced by electrical stimulation of LC and, in different experiments, suppressed by optogenetic inhibition of LC to evaluate how it modulates the NBR. In addition, NBRs evoked by sensory stimulation in the somatosensory cortex will be suppressed by blocking presynaptic release of NA to evaluate if NA modulates the NBR. The research proposed in this application is innovative because it focuses on the direct and transient modulations of LC activity to test their effects on the NBR and examines the actions of LC on modality-specific brain regions, which is a departure from the status quo. The proposed research is significant because it will integrate the dual vascular and neuronal origins of the NBR by demonstrating a sensory-stimulation driven role of the LC-NA system on neuromodulation and hemodynamic responses. Without such information, the neural interpretation of fMRI maps will likely remain limited, especially inferences from resting-state fMRI studies and hemodynamic responses of different LC-dependent cortical states.

项目总结/摘要 功能磁共振成像（fMRI）与血氧水平依赖（BOLD）对比 通过局部血液动力学反应间接测量神经元活动。BOLD反应 通常显示出持续增加超过其基线（即，正面粗体回答，PBR），但有时 显示出低于其基线的持续下降（即，阴性粗体响应，NBR）。虽然PBR很好 与神经元活动增加相关，NBR与神经元活动减少相关，或 被认为具有非神经元起源，例如“偷血”，由此血液从较不活跃的 由于局部压力的变化独立于局部神经元活动，因此从局部区域到更活跃的区域。因此，我们认为， NBR的生理学来源仍然难以捉摸。我们的长期目标是确定 随着蓝斑（LC）活动的变化，神经血管偶联发生变化， 去甲肾上腺素（NA）释放，在行为动物。本申请的总体目标是确定和 表征LC活性参与啮齿动物躯体感觉皮层中NBR的产生。 我们的中心假设是，由感觉刺激引起的LC活动的调制直接改变了两者 血管紧张度和神经元活动，影响NBR和PBR。该项目的基本原理是 在正常生理条件下，确定LC活动如何参与功能磁共振成像信号将有助于 更深入地了解LC活性在疾病状态下的功能改变，例如 精神分裂症和阿尔茨海默病，可能有助于非侵入性fMRI信号的变化。中央 将通过追求特定目标来验证假设，以确定直接LC调制对 NBR，特别是NA对NBR的影响。在这一目标下，LC-NA活动将通过以下方式得到加强： 在不同的实验中，通过LC的光遗传学抑制来抑制LC的电刺激， 评估它如何调节NBR。此外，在躯体感觉中，感觉刺激诱发的NBR 通过阻断NA的突触前释放来抑制皮质，以评估NA是否调节NBR。的 在本申请中提出的研究是创新的，因为它集中于直接和瞬态调制 的LC活动，以测试它们对NBR的影响，并检查LC对特定模式的脑的作用 地区，这是对现状的背离。这项研究具有重要意义，因为它将整合 NBR的双重血管和神经元起源，通过证明感觉刺激驱动的作用， LC-NA系统对神经调节和血流动力学反应的影响。如果没有这些信息，神经 对fMRI图的解释可能仍然有限，特别是从静息状态fMRI研究中得出的推论， 不同LC依赖性皮质状态的血流动力学反应。