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

摘要 与认知功能相关的提升神经调节，如唤醒、注意力、学习、记忆、 决策，奖励的评估，在任何有意识的人类受试者中都是活跃的，参与血液 氧合水平依赖(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粗体信号的理解仍处于初级阶段。事实上，我们目前 关于BOLD信号背后的神经血管和神经代谢机制的知识已经衍生出来 几乎完全来自麻醉动物的研究，在那里神经调节状态是不确定的。 最近，我们开发了多巴胺(DA)、去甲肾上腺素(NE)和乙酰胆碱的光学记录仪 (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， 我们将把这些记者与我们开发的一套集成的大脑倡议工具结合起来 和其他研究人员，来研究“大脑状态”的微观构成及其在 宏观上大胆的功能磁共振信号。这些工具(功能磁共振除外)只适用于模型生物。 因此，所有实验都将在清醒行为的小鼠身上进行。 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(“静息状态”)血流动力学波动的产生也有重要作用 作为任务诱导的血流动力学反应。为了检验这一假设，我们将研究 神经元、血管和代谢活动之间的关系是(I)大脑固有状态(目标1-2)的函数，以及(Ii) 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记者的读数在操作上进行定义 局部皮质动力学的电生理/成像测量。这些研究将在 静息状态血流动力学波动的背景以及任务诱导的血流动力学反应 初级躯体感觉和额叶皮质。 拟议的项目将(I)为静息状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)放置神经调节状态与能量消耗之间的关系 (3)研究可卡因对脑氧代谢的影响 神经和血液动力学脑活动。这项研究还将产生进一步的假设，关于在 接触哪种物质可能会影响功能磁共振读数。

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.