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，如唤醒、注意力、学习、记忆， 决策，奖励的评估，在任何参与血液的有意识的人类主体中都是活跃的 氧合水平依赖性（BOLD）功能性磁共振成像（fMRI）研究。然而，我们的 对这些系统如何影响BOLD信号的理解仍然是基本的。事实上，我们目前 BOLD信号背后的神经血管和神经代谢机制的知识已经被推导出来 几乎完全来自麻醉动物的研究，其中神经调节的状态是不确定的。 最近，我们开发了多巴胺（DA）、去甲肾上腺素（NE）和乙酰胆碱的光学报告分子 (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， 我们将联合收割机与由我们开发的一套集成的“大脑倡议”工具相结合 和其他人，研究“大脑状态”的微观构成及其在大脑中的反映。 宏观粗体fMRI信号。这些工具（功能磁共振成像除外）仅适用于模型生物。 因此，所有实验将在清醒行为小鼠中进行。 我们的中心假设是来自一个或多个神经调节系统的上行投射 也对自发（“静息状态”）血流动力学波动的产生起关键作用 任务诱发的血液动力学反应。为了验证这一假设，我们将研究 神经元、血管和代谢活动之间的关系，作为（i）内在脑状态（目的1-2）和（ii） 接触可卡因-一种通过影响神经调节而起作用的常见滥用药物（目标3）。大脑状态 将根据DA、NE和ACh报告子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 静息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下， 初级躯体感觉皮层和额叶皮层 该项目将（i）为静息态和任务诱导的功能磁共振成像提供更强的生理基础 在健康个体中;（ii）将神经调节状态与能量消耗之间的关系置于 （脑代谢率的O2，CMRO 2）的定量基础上;和（iii）检查可卡因的影响， 神经元和血液动力学脑活动。这项研究还将产生进一步的假设， 哪种物质会影响功能磁共振成像的读数

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.