Somatosensory and Autonomic Circuit Modulation by Brainstem Serotonergic Neurons

脑干血清素神经元的体感和自主回路调节

• 批准号: 10268955
• 负责人: Kathryn Michelle Lehigh
• 金额: $ 3.47万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10268955
• 关键词: Acute; Address; Agonist; Anatomy; Apnea; Axon; Behavioral; Biological Assay; Blood Pressure; Brain; Brain Stem; Breathing; Cell Lineage; Cell Nucleus; Cells; Coupled; Data; Dorsal; EGR2 gene; Electrophysiology (science); Eligibility Determination; Fiber; Functional disorder; Funding Opportunities; Genetic; Genetic Identity; Genetic Transcription; Goals; Growth; Guidelines; Health; Human; Hyperesthesia; Impairment; Label; Life; Maps; Mental Depression; Microscopy; Modeling; Molecular; Molecular Genetics; Moods; National Institute of Neurological Disorders and Stroke; Neuromodulator; Neurons; Neurotransmitters; Nomenclature; Output; Pain; Pattern; Physiologic Thermoregulation; Physiological Processes; Physiology; Presynaptic Terminals; Process; Property; Regulation; Resolution; Respiration; Role; Sensory; Serotonin; Signal Transduction; Slice; Slide; Specificity; Spinal Cord; Synapses; Tactile; Therapeutic; Touch sensation; Viral; cellular targeting; chronic pain; clinically significant; combat; experimental study; gamma-Aminobutyric Acid; genome-wide; in vivo; mouse genetics; nerve supply; neurobehavioral; neurochemistry; neuronal cell body; optogenetics; raphe nuclei; respiratory; response; sensory stimulus; serotonin receptor; somatosensory; therapeutic target; tool; transcription factor; transcriptomics; transmission process

Serotonin (5-HT)-producing neurons projecting from brainstem to spinal cord (SC) are implicated in gating touch and pain transmission and modulating physiological processes from cardiorespiratory control to thermoregulation. Despite such vital and clinically significant roles, the specific serotonergic cells and SC circuits involved are poorly understood, challenged by the formidable anatomy and lack of molecular genetic tools of suitable specificity and resolving capacity. We have used intersectional genetic lineage tracing and transcriptomics genome-wide to reveal subtypes of 5-HT neurons, now providing sought-after means to map and functionally define the specific brainstem-SC circuits responsible for touch, pain, and homeostatic modulation. We propose a model in which transcriptionally and molecularly distinct 5-HT subtypes form unique projection patterns, selectively innervating regions of the spinal cord and modulating distinguishing sets of downstream cellular partners, creating circuits, and thus, functions, unique to each 5-HT neuron subtype. Intersectional labeling of 5-HT neuron subsets (Pet1+) identified by co-expression of Tachykinin1 (Tac1-Pet1 neurons) or Early growth response 2 (Egr2-Pet1 neurons) provides genetic access to two major caudal 5-HT neuron subtypes for visualizing their precise innervation patterns along rostrocaudal and dorsoventral spinal cord axes—previously unexplored. Further, because selective co-expression of neuromodulators distinguishes different descending 5-HT neuron subtypes, I will explore the neurochemical composition of their axonal terminals within the SC. To follow, I will use recently generated trans-synaptic tracing tools to visualize post- synaptic partners of 5-HT neuron subtypes and combine intersectional optogenetic tools with acute SC slice electrophysiology to probe the functional synaptic connectivity of Egr2-Pet1 and Tac1-Pet1 neuron descending projections. Results will inform how genetically-defined 5-HT neuron subtypes are organized functionally in the modulation of spinal cord circuits involved in sensory transmission or autonomic regulation. Deliverables may include selective therapeutic substrates to treat pain, hyperesthesia, and cardiorespiratory impairment.

从脑干投射到脊髓的5-羟色胺（5-HT）产生神经元与门控触摸有关 和疼痛的传递和调节生理过程，从心肺控制到 体温调节尽管具有如此重要和临床意义的作用，但特异性多巴胺能细胞和SC回路 涉及的是知之甚少，挑战的强大解剖和缺乏分子遗传工具， 合适的特异性和分辨能力。我们使用交叉遗传谱系追踪， 全基因组转录组学揭示5-HT神经元的亚型，现在提供了抢手的手段来映射 并在功能上定义了负责触摸，疼痛和自我平衡的特定脑干-SC回路 调变我们提出了一个模型，其中转录和分子不同的5-HT亚型形成独特的 投射模式，选择性地支配脊髓的区域，并调节 下游的细胞伙伴，创造电路，因此，功能，独特的每一个5-HT神经元亚型。 5-HT神经元亚群（Pet 1+）的交叉标记通过速激肽1（Tac 1-Pet 1）的共表达来鉴定 神经元）或早期生长反应2（Egr 2-Pet 1神经元）提供了两个主要的尾部5-HT的遗传途径 神经元亚型，用于显示它们沿沿着喙尾和背腹脊髓的精确神经支配模式 斧头-以前未探索。此外，由于神经调质的选择性共表达区分了 不同的下行5-HT神经元亚型，我将探讨其轴突的神经化学成分， 接下来，我将使用最近生成的跨突触追踪工具来可视化SC内的后 5-HT神经元亚型突触伴侣和联合收割机交叉光遗传学工具与急性SC切片 Egr 2-Pet 1和Tac 1-Pet 1下行神经元功能性突触连接的电生理学研究 预测。结果将告知遗传定义的5-HT神经元亚型在功能上是如何组织的 在涉及感觉传递或自主调节的脊髓回路的调制中。 赋形剂可包括选择性治疗底物以治疗疼痛、感觉过敏和心肺功能障碍。 损伤