权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

摘要