Effects of intrinsic and drug-induced neuromodulation on functional brain imaging

内在和药物诱导的神经调节对功能性脑成像的影响

• 批准号: 10413059
• 负责人: Anna Devor
• 金额: $ 38.25万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10413059
• 关键词: Acetylcholine; Acute; Affect; Animal Model; Animals; Arousal; Attention; BRAIN initiative; Blood Vessels; Brain; Brain imaging; Brain region; Cerebrovascular Circulation; Cerebrum; Chronic; Cocaine; Conscious; Consumption; Decision Making; Dilator; Dopamine; Electrophysiology (science); Energy Metabolism; Evaluation; Exposure to; Foundations; Functional Magnetic Resonance Imaging; Generations; Human; Image; Imaging technology; Individual; Intoxication; Knowledge; Learning; Measurable; Measurement; Measures; Mediating; Memory; Metabolic; Microscope; Microscopic; Modality; Mus; Neuromodulator; Neurons; Neurotransmitters; Nitric Oxide; Norepinephrine; Optical reporter; Optics; Partial Pressure; Pharmaceutical Preparations; Pharmacology; Physiological; Property; Prostaglandins; Psychiatrist; Psychologist; Pyramidal Cells; Reporter; Research; Rest; Rewards; Signal Transduction; Somatosensory Cortex; Substance of Abuse; System; Testing; Time; Vasodilation; awake; base; blood oxygen level dependent; cocaine exposure; cognitive function; constriction; drug of abuse; experimental study; foot; frontal lobe; hemodynamics; high resolution imaging; human subject; imaging study; inhibitory neuron; metabolic rate; neuropeptide Y; neuroregulation; neurotransmission; neurovascular; non-invasive imaging; optogenetics; response; tool; two photon microscopy; two-photon; vasoconstriction

Abstract Ascending neuromodulation associated with cognitive functions, such as arousal, attention, learning, memory, decision making, evaluation of reward, are active in any conscious human subject participating in a Blood Oxygenation Level Dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) study. And yet, our understanding of how these systems affect the BOLD signal remains rudimentary. In fact, our current knowledge of neurovascular and neurometaboic mechanisms that underlie the BOLD signal has been derived almost exclusively from studies in anesthetized animals where the state of neuromodulation was uncertain. Recently, we have developed optical reporters for dopamine (DA), norepinephrine (NE), and acetylcholine (ACh) applicable for high-resolution imaging of brain function in awake behaving mice. In the proposed project, we will combine these reporters with an integrated suite of the BRAIN Initiative tools, developed by us and others, to investigate the microscopic makeup of “brain states” and their reflection in macroscopic BOLD fMRI signals. These tools (except fMRI) are only applicable to model organisms. Therefore, all experiments will be performed in awake behaving mice. Our Central Hypothesis is that ascending projections from one or more neuromodulatory systems contribute critically to generation of spontaneous (“resting-state”) hemodynamic fluctuations as well as task-induced hemodynamic responses. To test this hypothesis, we will investigate the relationship between neuronal, vascular and metabolic activity as a function of (i) intrinsic brain states (Aims 1-2), and (ii) exposure to cocaine – a common drug of abuse that acts by affecting neuromodulation (Aim 3). Brain states will be operationally defined based on the readout of DA, NE, and ACh reporters referenced to electrophysiological/imaging measures of local cortical dynamics. These studies will be performed in the context of resting-state hemodynamic fluctuations as well as task-induced hemodynamic responses in the primary somatosensory and frontal cortices. The proposed project will (i) provide a stronger physiological foundation for resting-state and task-induced fMRI in healthy individuals; (ii) place the relationship between the state of neuromodulation and energy expenditure (cerebral metabolic rate of O2, CMRO2) on a quantitative footing; and (iii) examine the effects of cocaine on neuronal and hemodynamic brain activity. This study will also generate further hypotheses about the ways in which substance exposure may affect fMRI readouts.

抽象的 与认知功能相关的上行神经调节，例如唤醒、注意力、学习、记忆、 决策制定、奖励评估，在参与血液活动的任何有意识的人类受试者中都是活跃的 氧合水平依赖性（BOLD）功能磁共振成像（fMRI）研究。 事实上，我们目前对这些系统如何影响 BOLD 信号的了解还很初级。 已经得出了 BOLD 信号背后的神经血管和神经代谢机制的知识 几乎完全来自对神经调节状态不确定的麻醉动物的研究。 最近，我们开发了多巴胺（DA）、去甲肾上腺素（NE）和乙酰胆碱的光学产生器 (ACh) 适用于清醒行为小鼠脑功能的高分辨率成像 在拟议的项目中， 我们将把这些生产者与我们开发的 BRAIN Initiative 工具集成套件结合起来 等人，研究“大脑状态”的微观构成及其在 宏观 BOLD fMRI 信号（fMRI 除外）仅适用于模型生物。 因此，所有实验都将在清醒行为的小鼠中进行。 我们的中心假设是来自一个或多个神经调节系统的上升投射 对自发（“静息态”）血流动力学波动的产生也有重要贡献 作为任务引起的血流动力学反应，为了检验这一假设，我们将研究这种关系。 神经、血管和代谢活动之间作为 (i) 大脑内在状态（目标 1-2）和 (ii) 的函数 接触可卡因——一种常见的滥用药物，通过影响神经调节发挥作用（目标 3）。 将根据参考的 DA、NE 和 ACh 生产者的读数进行操作定义 这些研究将在局部皮质动力学中进行。 静息态血流动力学波动以及任务引起的血流动力学反应的背景 初级体感皮质和额叶皮质。 拟议的项目将 (i) 为静息态和任务诱导的功能磁共振成像提供更强大的生理基础 在健康个体中；（ii）确定神经调节状态与能量消耗之间的关系 （O2、CMRO2 的脑代谢率）定量基础；以及 (iii) 检查可卡因对 这项研究还将产生关于大脑神经和血液动力学活动的进一步假设。 哪些物质暴露可能会影响功能磁共振成像读数。