Functional and Anatomical Diversity in Human VTA and Subtantia Nigra

人类 VTA 和黑质的功能和解剖多样性

• 批准号: 8224985
• 负责人: SAMUEL M MCCLURE
• 金额: $ 23.27万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8224985
• 关键词: Anatomy; Animal Experimentation; Animals; Area; Aversive Stimulus; Axon; Behavior; Behavioral; Biological Models; Brain; Brain Stem; Brain region; Cell Nucleus; Cell physiology; Characteristics; Corpus striatum structure; Cues; Data; Development; Diffusion Magnetic Resonance Imaging; Dopamine; Dorsal; Drug Addiction; Event; Fiber; Functional Magnetic Resonance Imaging; Human; Image; Ingestion; Investigation; Laboratories; Lateral; Link; Location; Magnetic Resonance Imaging; Maintenance; Measures; Medial; Methods; Midbrain structure; Modification; Molecular; Mus; Neurons; Nucleus Accumbens; Pattern; Pharmaceutical Preparations; Physiological; Physiology; Pigments; Population; Prefrontal Cortex; Primates; Property; Punishment; Rattus; Research; Resolution; Rest; Rewards; Rodent; Role; Route; Seeds; Signal Transduction; Stimulus; Structure; Subgroup; System; Techniques; Testing; Translations; Ventral Tegmental Area; Work; addiction; base; blood oxygen level dependent; dopamine system; dopaminergic neuron; drug of abuse; frontal lobe; imaging modality; motivated behavior; neural circuit; novel; parabrachial nucleus; pars compacta; reinforced behavior; relating to nervous system; response; theories; tool; water diffusion; white matter

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.

描述(申请人提供)：中脑多巴胺(DA)神经元在激励和强化行为方面的功能作用得到了大量数据的支持，导致了药物滥用导致成瘾的一条众所周知的途径。在这项工作中，通常假设所有DA神经元在奖赏预测中发出错误的信号时都有一个单一的函数。最近的发现挑战了这一假设，即以前未被识别的VTA内侧后部DA神经元亚群对厌恶和非奖赏刺激做出反应。这些发现在三个独立实验室的三个物种中得到了复制。除了在奖惩基础上的分化，这个群体的DA神经元也投射到与DA系统的其他部分不同的靶区。在这个项目中，我们的目标是使用脑干功能磁共振成像(FMRI)和扩散张量成像(DTI)来识别人类中脑功能和解剖的平行分化。近年来，fMRI在奖赏研究中得到了有益的应用。对VTA和SN内部反应的调查需要PI和合作者最近开发的方法学进步。最近的初步工作表明，我们能够区分VTA/SN内功能不同的亚区，这表明在当前项目中使用fMRI是可行的。此外，提案中描述的初步工作表明，我们能够执行从VTA/SN中脑种子区域到纹状体区域的白质纤维跟踪。拟议的研究结合了这些方法来识别人类中脑多巴胺能神经元中的平行系统。功能不同的DA神经元群体的潜在后果对成瘾研究具有深远意义。滥用药物会增强整个大脑中的DA；要完全理解药物摄入的行为后果，就需要了解DA在所有靶区的功能。动物研究是精确识别DA神经元亚群的极佳方法。然而，在人类中识别类似的系统是必要的，以将动物的工作与与成瘾相关的行为联系起来。 与公共健康相关：关于大脑中多巴胺功能的理论正在发生重大偏离，这对理解药物成瘾具有深远的影响。我们扩展了从人类中脑进行成像的方法，并开发了用于白质纤维追踪的新工具，以识别人类VTA/SN内的功能亚区。这些方法对于将动物研究的最新发现扩展到与成瘾相关的人类行为至关重要。