Functional and Anatomical Diversity in Human VTA and Subtantia Nigra

描述（由申请人提供）：大量数据支持中脑多巴胺（DA）神经元在激励和强化行为中的功能作用，导致滥用药物导致成瘾的途径得到很好的描述。在这项工作中，通常认为所有DA神经元在奖励预测中的信号错误中都有一个单一的功能。最近的研究结果挑战了这一假设，即以前未被识别的内侧后VTA DA神经元亚群对厌恶和非奖励刺激有反应。这些发现已经在三个独立实验室的三个物种中得到了重复。除了基于奖励和惩罚的分化外，与DA系统的其他部分相比，这群DA神经元也投射到不同的目标区域。在这个项目中，我们的目标是利用脑干功能磁共振成像（fMRI）和扩散张量成像（DTI）识别人类中脑功能和解剖结构的平行分化。近年来，功能磁共振成像在奖励研究中得到了广泛的应用。调查VTA和SN内部的反应需要PI和合作者最近开发的方法进步。最近的初步工作表明，我们能够区分VTA/SN内功能不同的子区域，这表明在当前项目中使用fMRI的可行性。此外，提案中描述的初步工作表明，我们能够从VTA/SN的中脑种子区到纹状体区域进行白质纤维跟踪。拟议的研究将这些方法结合起来，以确定人类能量中脑中的平行系统。功能不同的DA神经元群对成瘾研究的潜在影响是深远的。滥用药物会增强整个大脑的DA；要完全了解药物摄入的行为后果，就需要了解DA在所有目标区域的功能。动物研究在精确识别DA神经元亚群方面非常出色。然而，识别人类的类似系统对于将动物工作与成瘾相关的行为联系起来是必要的。

DESCRIPTION (provided by applicant): The functional role of midbrain dopamine (DA) neurons in motivating and reinforcing behaviors is supported by a wealth of data, leading to a well described route by which drugs of abuse cause addiction. In this work, a single function is commonly supposed for all DA neurons in signaling errors in reward prediction. This supposition has been challenged by recent findings that previously unrecognized sub-population of DA neurons in the medial posterior VTA respond to aversive and not rewarding stimuli. These findings have been replicated in three species across three independent laboratories. In addition to differentiation on the basis of reward and punishment, this population of DA neurons also project to different target regions than the rest of the DA system. In this project, we aim to identify a parallel differentiation of function and anatomy in the human midbrain using brainstem functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI).fMRI has been used profitably in the study of reward in recent years. Investigation of responses within the VTA and SN has required methodological advances recently developed by the PI and collaborators. Recent preliminary work indicates that we are able to differentiate functionally distinct sub-regions within the VTA/SN indicating feasibility of using fMRI in the current project. Additionally, preliminary work described in the proposal indicates that we are able to perform white matter fiber tracking from midbrain seed regions in the VTA/SN to areas in the striatum. Proposed studies combine these methods to identify parallel systems in the human DAergic midbrain.The potential consequences of functionally distinct populations of DA neurons are profound for research into addiction. Drugs of abuse enhance DA throughout the brain; a complete understanding of behavioral consequences of drug ingestion requires understanding the function of DA in all target regions. Animal research is excellent for precisely identifying sub-populations of DA neurons. However, identification of similar systems in humans is necessary to link animal work to behaviors relevant for addiction. PUBLIC HEALTH RELEVANCE: A significant departure is underway regarding theories of dopamine function in the brain and this has profound consequences for understanding drug addiction. We extend methods developed for imaging from the human midbrain and develop novel tools for white matter fiber tracking to identify functional sub-regions within human VTA/SN. These methods are crucial for extending recent findings from animal research to human behaviors relevant to addiction.