Discovery of the Rostromedial Tegmental Nucleus in the Human Brain

人脑中被盖内侧核的发现

• 批准号: 10452303
• 负责人: Sabina Berretta
• 金额: $ 20.5万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10452303
• 关键词: Address; Agonist; Anatomy; Anxiety; Area; Autopsy; Behavioral; Benchmarking; Brain; Brain region; Cell Nucleus; Central Nervous System Diseases; Characteristics; Confocal Microscopy; Emotional; Female; Foundations; Fright; Functional Magnetic Resonance Imaging; Functional disorder; Gene Expression; Gene Expression Profile; Genetic; Goals; Human; Impairment; Knowledge; Learning; Locomotion; Marker Discovery; Mental Depression; Mental disorders; Modality; Molecular; Neuraxis; Neurologic; Neurons; Nociception; ORL1 receptor; Opioid; Output; Pain; Pattern; Performance; Play; Population; Property; Rest; Rewards; Rodent; Role; Sampling; Sensory; Signal Transduction; Sleep; Stimulus; Stress; Structure; Substantia nigra structure; System; Techniques; Testing; Time; Ventral Tegmental Area; Work; blood oxygen level dependent; clinical investigation; dopaminergic neuron; experimental study; financial incentive; human tissue; imaging study; immunocytochemistry; in vivo; inhibitory neuron; mRNA Expression; male; member; molecular marker; mu opioid receptors; multimodality; neural circuit; neuroimaging; nociceptin; nonhuman primate; novel; opioid use; post-traumatic stress; preclinical study; protein expression; response; schizophrenia-spectrum disorder; sensory input; sex; sleep regulation; transcriptomics

ABSTRACT The rostromedial tegmental nucleus (RMTg), a recently discovered mesopontine structure, represents a key node within valence encoding neural circuitry. The RMTg has been shown to play a role in reward-aversion signaling, aversive learning involving multimodal sensory inputs, locomotion, and sleep regulation. In rodents and non-human primates, RMTg GABAergic projections powerfully inhibit ventral tegmental area and substantia nigra dopaminergic neurons, thus exerting a gating mechanism regulating dopaminergic tone. RMTg function is robustly regulated by µ -opioid receptors (MOR), which are highly enriched in RMTg neurons. MOR agonism inhibits the RMTg, in turn releasing mesocorticolimbic and nigrostriatal dopaminergic neurons from the RMTg brake. Notably, nociceptin receptors (NOPR), also enriched in the rodent RMTg, play a similar role, inhibiting RMTg neurons and thus increasing the activity of dopaminergic neurons. The cellular, molecular, and functional properties of the human RMTg have not been investigated to date, hampering our understanding of the potential role of this nucleus in psychiatric disorders. To address this critical knowledge gap, we propose studying, for the first time, the human RMTg using a combination of postmortem techniques and in vivo neuroimaging performed at 7 Tesla. Our overarching hypothesis is that the human RMTg encodes valence properties of stimuli (i.e., rewarding vs. aversive) of varying modalities. We also hypothesize that the expression of opioid system markers (i.e., MOR, NOPR, and NOP) in the human RMTg underlies the cellular and molecular uniqueness in this nucleus. A characterization of MOR, NOPR, and NOP expression in healthy human donors, together with region-specific molecular marker discovery afforded by spatial transcriptomics, will accurately delineate the human RMTg with respect to surrounding brain regions and place it within anatomical landmarks detectable by imaging studies. The objectives of this work are to (i) define anatomical landmarks of the human RMTg, (ii.) assess novel RMTg markers and MOR, NOPR, and NOP expression in RMTgs’ neuronal populations, and (iii.) inform on RMTg valence encoding functions in humans. Importantly, the proposed study will provide a testable and significant instance for the involvement of the RMTg in human CNS disorders. Our long-term goal is to provide compelling support for the role of the RMTg in the pathophysiology of psychiatric disorders, opening the doors to a new domain of clinical investigations integrating this nucleus in circuitry implicated in the disruption of reward-aversion and emotional processing. The specific aims of the proposed study are: Aim 1: To investigate the chemocytoarchitectonic characteristics and transcriptional profile of the human RMTg. Aim 2: Characterize functionality and valence encoding properties of the human RMTg. To study the human RMTg, we will leverage our expertise in neuroanatomical analysis of human tissue, genetics, the opioid system, and in vivo neuroimaging of psychiatric and neurological illnesses.

摘要 头内侧被盖核（RMTg）是最近发现的一种脑桥结构， 价编码神经回路中的关键节点。研究表明，RMTg在奖励厌恶中发挥作用 信号传导、涉及多模态感觉输入的厌恶学习、运动和睡眠调节。在啮齿动物中 和非人灵长类动物，RMTg GABA能投射强烈抑制腹侧被盖区和腹侧被盖区， 黑质多巴胺能神经元，从而发挥调节多巴胺能紧张的门控机制。RMTg函数为 受μ -阿片受体（莫尔）的强烈调节，该受体在RMTg神经元中高度富集。莫尔激动作用 抑制RMTg，进而从RMTg释放中皮质边缘和黑质纹状体多巴胺能神经元 制动装置.值得注意的是，也在啮齿动物RMTg中富集的伤害感受素受体（NOPR）发挥类似的作用，抑制 RMTg神经元，从而增加多巴胺能神经元的活性。 迄今为止尚未研究人RMTg的细胞、分子和功能特性， 阻碍了我们对这个核在精神疾病中的潜在作用的理解。处理这个关键 知识的差距，我们建议研究，第一次，人类RMTg使用死后相结合， 技术和在7特斯拉下进行的体内神经成像。我们的首要假设是，人类的RMTg 编码刺激的价属性（即，奖励与厌恶）的不同形式。我们还假设 阿片样物质系统标记物（即，莫尔、NOPR和NOP）是RMTg的基础。 细胞和分子的独特性一个表征的莫尔，NOPR，和NOP表达在 健康的人类供体，连同空间定位提供的区域特异性分子标记发现， 转录组学，将准确地描绘人类RMTg相对于周围的大脑区域和位置 它在通过成像研究可检测到的解剖标志内。这项工作的目标是：（一）确定 人RMTg的解剖标志，（ii.）评估新的RMTg标志物和莫尔、NOPR和NOP 在RMTgs神经元群体中的表达，和（iii.）告知RMTg在人类中的价编码功能。 重要的是，拟议的研究将提供一个可测试的和重要的情况下，参与的RMTg 在人类中枢神经系统疾病中。我们的长期目标是为RMTg在以下方面的作用提供强有力的支持： 精神疾病的病理生理学，打开了一个新的临床研究领域的大门， 这个神经回路中的核心与奖赏厌恶和情绪处理的中断有关。具体 本研究的主要目的是：目的1：研究细胞的化学结构特征， 人RMTg的转录谱。目标2：表征化合物的官能度和价编码性质 人RMTg。为了研究人类RMTg，我们将利用我们在神经解剖学分析方面的专业知识， 人体组织、遗传学、阿片系统以及精神和神经疾病的体内神经成像。