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 (SC) 的产生血清素 (5-HT) 的神经元与门控触摸有关 以及疼痛传递和调节从心肺控制到 尽管具有如此重要且具有临床意义的作用，但特定的血清素能细胞和 SC 回路 人们对其所涉及的知识知之甚少，受到令人敬畏的解剖学和缺乏分子遗传工具的挑战 我们使用了交叉遗传谱系追踪和适当的特异性和解析能力。 全基因组转录组学揭示 5-HT 神经元亚型，现在提供广受欢迎的绘图方法 并在功能上定义负责触觉、疼痛和稳态的特定脑干 SC 回路 我们提出了一个模型，其中转录和分子上不同的 5-HT 亚型形成独特的。 投射区域，选择性地支配脊髓并调节不同的组 下游细胞伙伴，创建电路，从而形成每个 5-HT 神经元亚型特有的功能。 通过 Tachykinin1 (Tac1-Pet1) 的共表达识别的 5-HT 神经元子集 (Pet1+) 的交叉标记 神经元）或早期生长反应 2（Egr2-Pet1 神经元）提供了两种主要尾部 5-HT 的遗传途径 神经元亚型，用于可视化其沿头尾和背腹脊髓的精确神经支配模式 轴——之前尚未探索过，因为神经调节剂的选择性共表达是有区别的。 不同的下降 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后处理。 5-HT 神经元亚型的突触伙伴，并将交叉光遗传学工具与急性 SC 切片相结合 电生理学探测 Egr2-Pet1 和 Tac1-Pet1 神经元下行的功能突触连接 结果将告知基因定义的 5-HT 神经元亚型如何进行功能组织。 参与感觉传递或自主调节的脊髓回路的调节。 可交付成果可能包括治疗疼痛、感觉过敏和心肺疾病的选择性治疗基质 损害。