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

摘要 与认知功能相关的上行神经调节，例如觉醒、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。然而，我们的 对这些系统如何影响 BOLD 信号的了解仍然处于初级阶段。事实上，我们现在的 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）和乙酰胆碱的光学报告基因 (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， 我们将把这些报告器与我们开发的 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。这些工具（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。为了检验这个假设，我们将研究这种关系 神经元、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）。大脑状态 将根据参考的 DA、NE 和 ACh 报告基因的读数进行操作定义 局部皮质动力学的电生理学/成像测量。这些研究将在 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) 神经调节状态与能量消耗之间的关系 （O2 的脑代谢率、CMRO2）定量； (iii) 检查可卡因对 神经元和血流动力学脑活动。这项研究还将产生关于方法的进一步假设 哪些物质暴露可能会影响功能磁共振成像读数。

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.