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，从而得出了一个良好描述的药物滥用导致成瘾的途径。在这项工作中，一个单一的功能，通常假设所有的DA神经元的信号错误的奖励预测。这一假设受到了挑战，最近的研究结果，以前未被识别的亚群DA神经元的内侧后腹侧被盖区的反应厌恶，而不是奖励刺激。这些发现在三个独立实验室的三个物种中得到了复制。除了基于奖励和惩罚的分化之外，这个DA神经元群体还投射到与DA系统的其余部分不同的目标区域。在这个项目中，我们的目标是确定一个平行的分化的功能和解剖在人类中脑使用脑干功能磁共振成像（fMRI）和扩散张量成像（DTI）。对VTA和SN内的反应进行调查需要PI和合作者最近开发的方法进步。最近的初步工作表明，我们能够区分功能不同的子区域内的VTA/SN表明在当前项目中使用功能磁共振成像的可行性。此外，提案中描述的初步工作表明，我们能够执行从VTA/SN中脑种子区到纹状体区域的白色纤维跟踪。拟议的研究联合收割机，这些方法来确定在人类DA能midbrain.The功能不同的DA神经元群体的潜在后果是深刻的成瘾研究的平行系统。滥用药物会增强整个大脑中的DA;要全面了解药物摄入的行为后果，需要了解DA在所有目标区域的功能。动物研究对于精确识别DA神经元的亚群是非常好的。然而，在人类中识别类似的系统是必要的，以将动物的工作与成瘾相关的行为联系起来。 公共卫生相关性：关于多巴胺在大脑中功能的理论正在发生重大变化，这对理解药物成瘾具有深远的影响。我们扩展了人类中脑成像的方法，并开发了白色纤维跟踪的新工具，以识别人类VTA/SN内的功能子区域。这些方法对于将最近的研究结果从动物研究扩展到与成瘾相关的人类行为至关重要。

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.