Discovery of the Rostromedial Tegmental Nucleus in the Human Brain

人脑中被盖内侧核的发现

基本信息

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
项目类别：
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

项目摘要

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.

抽象的喙内侧被盖核（RMTg）是最近发现的中脑桥结构，代表了 RMTg 已被证明在奖赏厌恶中发挥作用。信号传导、涉及多模式感觉输入、运动和睡眠调节的厌恶学习。和非人类灵长类动物，RMTg GABA能投射强烈抑制腹侧被盖区和实质黑质多巴胺能神经元，从而发挥调节多巴胺能音调功能的门控机制。受到μ-阿片受体 (MOR) 的强有力调节，该受体在 RMTg 神经元中高度丰富。抑制 RMTg，进而从 RMTg 中释放中皮质边缘和黑质纹状体多巴胺能神经元值得注意的是，啮齿动物 RMTg 中也富含伤害感受素受体 (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，人类 RMTg 的细胞、分子和功能特性尚未得到研究，阻碍我们理解该核在精神疾病中的潜在作用。知识差距，我们建议首次结合事后分析来研究人类 RMTg 技术和在 7 特斯拉下进行的体内神经成像我们的总体假设是人类 RMTg。编码不同形式的刺激的价属性（即奖励与厌恶）。人类 RMTg 中阿片类系统标记物（即 MOR、NOPR 和 NOP）的表达是该细胞核中 MOR、NOPR 和 NOP 表达的特征。健康的人类捐赠者，以及空间提供的区域特异性分子标记发现转录组学，将准确描述人类 RMTg 相对于周围大脑区域和位置的情况它位于可通过成像研究检测的解剖标志内。这项工作的目标是 (i) 定义。人类 RMTg 的解剖标志，(ii.) 评估新的 RMTg 标记以及 MOR、NOPR 和 NOP RMTg 神经群体中的表达，以及 (iii.) 提供人类 RMTg 价编码功能的信息。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我们的长期目标是为 RMTg 在人类中枢神经系统疾病中的作用提供令人信服的支持。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这个核心与奖赏厌恶和情绪处理的破坏有关。本研究的目的是：目标 1：研究化学细胞结构特征和人类 RMTg 的转录谱目标 2：表征 RMTg 的功能和价态编码特性。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、阿片类药物系统以及精神和神经疾病的体内神经影像学。