Discovery of the Rostromedial Tegmental Nucleus in the Human Brain

人脑中被盖内侧核的发现

• 批准号: 10559693
• 负责人: Sabina Berretta
• 金额: $ 24.6万
• 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 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10559693
• 关键词: Address; Anatomy; Anxiety; Area; Autopsy; Behavioral; Benchmarking; Brain; Brain region; Cell Nucleus; Central Nervous System; 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; Neuroanatomy; Neurologic; Neurons; Nociception; ORL1 receptor; Opioid; Opioid Receptor; Output; Pain; Pattern; Performance; Play; Population; Property; Rest; Rewards; Rodent; Role; Sampling; Sensory; Signal Transduction; Stimulus; Stress; Structure; Substantia nigra structure; System; Techniques; Testing; Time; Ventral Tegmental Area; Work; addiction; 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; multimodality; neural circuit; neuroimaging; nigrostriatal pathway; nociceptin; nonhuman primate; novel; opioid use; pain processing; 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)是最近发现的一种中桥脑结构，代表着 价编码神经回路中的关键节点。RMTG已被证明在报酬厌恶中起到了作用 信号，涉及多模式感觉输入、运动和睡眠调节的厌恶学习。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实质 黑质多巴胺能神经元，从而发挥调节多巴胺能张力的门控机制。RMTg函数为 受高度富含在RMTg神经元中的µ-阿片受体(MOR)的有力调节。MOR激动症 抑制RMTg，进而释放RMTg中的边缘皮质和黑质纹状体多巴胺能神经元 刹车。值得注意的是，伤害素受体(NOPR)，也富含在啮齿动物的RMTg中，发挥着类似的作用，抑制 RMTg神经元，从而增加多巴胺能神经元的活性。 人类RMTG的细胞、分子和功能特性到目前为止还没有被研究过， 阻碍了我们对这个核团在精神障碍中的潜在作用的理解。要解决这一关键问题 知识鸿沟，我们建议，首次使用身体解剖相结合的方法研究人类的RMTG 技术和活体神经成像在7特斯拉进行。我们的主要假设是人类的RMTG 编码不同形态的刺激的价态属性(即，奖赏与厌恶)。我们还假设 阿片系统标志物(即MOR、NOPR和NOP)在人RMTg中的表达是 细胞核中的细胞和分子的独特性。卵巢癌组织中MOR、NOPR和NOP表达的特征 健康的人类捐献者，以及空间提供的区域特定的分子标记发现 转录学，将准确地描绘出人类RMTG相对于周围大脑区域和位置的情况 它位于可以通过成像研究检测到的解剖地标内。这项工作的目标是：(I)确定 人体RMTG的解剖标志(II.)评估新的RMTg标记和MOR、NOPR和NOP 在RMTgs神经元群体中的表达，以及(iii.)关于人类RMTg价编码功能的信息。 重要的是，拟议的研究将为小组的参与提供一个可测试和重要的实例 在人类中枢神经系统疾病中。我们的长远目标，是要令人信服地支持皇家运输小组在 精神障碍的病理生理学，开启了临床研究的新领域 这个回路中的核心与奖赏厌恶和情绪处理的中断有关。具体的 拟议研究的目的是：目标1：研究化学细胞构筑特征和 人类RMTG的转录图谱。目标2：表征官能团和价编码属性 人类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 人类组织、遗传学、阿片系统，以及精神和神经疾病的活体神经成像。