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.

项目摘要/摘要 功能磁共振成像（fMRI）具有血液氧合水平依赖性（粗体）对比度 间接通过其局部血液动力学反应来测量神经元活性。大胆的回应 通常显示出持续增加的持续增加以上（即积极的大胆反应，PBR），但有时 显示持续下降的下降低于其基线（即负粗体反应，NBR）。虽然PBR很好 与神经元活性增加有关，NBR与神经元活性降低或 被认为具有非神经元的起源，例如“偷血”，从而使血液从较小的活性中转移 由于局部压力变化而与局部神经元活性无关的区域变化。所以， NBR的物理起源仍然难以捉摸。我们的长期目标是确定 神经血管耦合的变化随不同基因座（LC）活性而变化，相关的变化 在行为动物中，去甲肾上腺素（NA）释放。本应用程序的总体目标是确定和 表征LC活性参与NBR在啮齿动物体感皮层中的产生。 我们的中心假设是，感官刺激引起的LC活性的调节直接改变了这两个 血管张力和神经元活性，影响NBR和PBR。这个项目的理由是 在正常生理条件下确定LC活性如何参与fMRI信号将有助于 更深入地了解患病状态中LC活性的功能改变，例如 精神分裂症和阿尔茨海默氏病可能导致非侵入性fMRI信号变化。中央 假设将通过追求特定目的来确定直接LC调制对 NBR，特别是Na对NBR的影响。在此目标下，LC-NA活性将通过 LC的电刺激和在不同的实验中，通过LC的光遗传学抑制作用抑制 评估它如何调节NBR。另外，nbrs在体感中被感觉刺激引起 通过阻止Na的突触前释放来评估Na是否调节NBR，将抑制皮层。这 本应用程序中提出的研究具有创新性，因为它专注于直接和瞬态调制 LC活性测试其对NBR的影响并检查LC对模态特异性大脑的作用 区域，这与现状背道而驰。拟议的研究很重要，因为它将整合 NBR的双重血管和神经元起源，通过证明了感官刺激驱动的作用 LC-NA系统有关神经调节和血液动力学反应。没有这样的信息，神经元 fMRI地图的解释可能会保持限制，尤其是静止状态fMRI研究的推论和 不同LC依赖性皮质状态的血液动力学反应。