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: 10220930
• 负责人: Anna Devor
• 金额: $ 38.82万
• 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/10220930
• 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 与认知功能相关的神经调节，例如唤醒，注意力，学习，记忆， 决策，评估奖励，在任何有意识的人类受试者中都活跃 氧合水平依赖性（BOLD）功能磁共振成像（fMRI）研究。但是，我们的 了解这些系统如何影响粗体信号仍然是基本的。实际上，我们的当前 基于BOLD信号的神经血管和神经痛量动物的知识已得出 几乎完全来自在麻醉动物的研究中，神经调节状态尚不确定。 最近，我们开发了多巴胺（DA），去甲肾上腺素（NE）和乙酰胆碱的光学报道。 （ACH）适用于在醒着的行为小鼠中对大脑功能的高分辨率成像。在拟议的项目中 我们将将这些记者与我们开发的大脑倡议工具的集成套件相结合 以及其他，研究“大脑状态”的微观构成及其在 宏观BOLD FMRI信号。这些工具（功能磁共振成像除外）仅适用于建模生物体。 因此，所有实验都将在醒着的行为小鼠中进行。 我们的中心假设是从一个或多个神经调节系统上升项目 批判性发作（“静止状态”）血液动力学波动的产生 作为任务引起的血液动力学反应。为了检验这一假设，我们将研究这种关系 在神经元，血管和代谢活性与（i）内在脑态的关系之间（目标1-2）和（ii）之间 接触可卡因 - 一种常见的滥用药物，通过影响神经调节而起作用（AIM 3）。大脑状态 将根据引用的DA，NE和ACH记者的读数进行操作定义 局部皮质动力学的电生理/成像测量。这些研究将在 静止状态血流动力学波动以及任务诱导的血流动力学反应的背景 主要体感和额叶皮层。 拟议的项目（i）将为静止状态和任务引起的fMRI提供更强的物理基础 在健康的个体中； （ii）在神经调节状态与能量消耗状态之间建立关系 （O2的脑代谢率，CMRO2）在定量基础上； （iii）检查可卡因对 神经元和血液动力学脑活动。这项研究还将提出有关方式的进一步假设 哪种物质暴露可能会影响fMRI读数。