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.

抽象的 roust骨换膜核（RMTG）是一种最近发现的中桥结构，代表了一个 编码神经回路的价值内的关键节点。 RMTG已被证明在奖励规避中发挥作用 信号传导，涉及多模式感觉输入，运动和睡眠调节的厌恶性学习。在啮齿动物中 和非人类隐私，RMTG Gabaergic项目有力抑制腹侧对接区域和底座 NIGRA多巴胺能神经元，从而发挥门控机制调节多巴胺能张力。 RMTG函数是 受µ-阿片受体（MOR）的强度调节，这些受体高度富含RMTG神经元。 mor激动剂 抑制RMTG，反过 制动。值得注意的是，也富含啮齿动物RMTG的Nocteptin受体（NOPR）起着相似的作用，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 阻碍了我们对该核在精神疾病中的潜在作用的理解。解决这个关键 知识差距，我们首次提出研究人类RMTG的研究差距 在7特斯拉进行的技术和体内神经影像学。我们的总体假设是人类RMTG 编码刺激（即奖励与厌恶）的价性能。我们也假设 人类RMTG中Ooid系统标记物（即MOR，NOPR和NOP）的表达是 该核中的细胞和分子唯一性。 MOR，NOPR和NOP表达的表征 健康的人类捐助者，以及空间可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RMTG相对于周围的大脑区域和位置 它在通过成像研究中可检测到的解剖标记中。这项工作的目标是（i）定义 人类RMTG的解剖学地标，（ii。评估）新颖的RMTG标记和MOR，NOPR和NOP RMTGS的神经元种群中的表达，（iii。）在人类中编码功能的RMTG价值。 重要的是，拟议的研究将为RMTG的参与提供可测试的重要实例 在人类中枢神经系统疾病中。我们的长期目标是为RMTG在 精神疾病的病理生理学，为整合临床研究的新领域打开了大门 电路中的该核在破坏奖励避免和情感处理时实现。具体 拟议的研究的目的是：目标1：研究化学量表结构特征和 人RMTG的转录曲线。 AIM 2：表征功能和价值编码的属性 人类RMTG。为了研究人类RMTG，我们将利用我们的专业知识 人体组织，遗传学，阿片类药物系统以及精神病和神经系统疾病的体内神经影像学。