Delineating how Calca neurons in the parabrachial nucleus mediate chronic pain

描述臂旁核钙神经元如何介导慢性疼痛

• 批准号: 10605758
• 负责人: Logan Francis Condon
• 金额: $ 4.33万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605758
• 关键词: Absence of pain sensation; Acute; Animals; Automobile Driving; Behavior; Biological Assay; Calcium; Cell Nucleus; Cells; Central Nervous System; Chronic; Cre driver; Data; Disinhibition; Event; Exhibits; FOS gene; Face; Fibromyalgia; Frequencies; Functional disorder; Genes; Genetic Markers; Goals; Head; Image; Immediate-Early Genes; Implant; In Situ Hybridization; Injury; Investigation; Lead; Ligands; Ligation; Mediating; Methodology; Migraine; Modeling; Mus; Nerve; Neuronal Plasticity; Neurons; Nociceptors; Normal tissue morphology; Opioid; Opsin; Pain; Pain Measurement; Pain management; Persistent pain; Pharmaceutical Preparations; Play; Population; Proxy; Publications; Research; Role; Sensory; Spinal; Spinal Cord; Stimulus; Syndrome; Target Populations; Techniques; Tension Headache; Testing; Tetanus Toxin; Time; Tissue Fixation; Tissues; Trigeminal Nuclei; Vertebral column; Viral Vector; Work; addiction; allodynia; calcium indicator; chronic pain; chronic pain management; chronic painful condition; cohort; designer receptors exclusively activated by designer drugs; excitatory neuron; experience; experimental study; healing; in vivo calcium imaging; inflammatory pain; interest; lens; neural; neurotransmitter release; new therapeutic target; novel; pain behavior; pain model; pain perception; pain symptom; painful neuropathy; parabrachial nucleus; peptide hormone; prevent; response; sciatic nerve; side effect; tissue injury; two-photon

Project summary Chronic pain is a highly prevalent and impactful condition. It persists past the time expected for normal tissue healing from an acutely painful event, suggesting plasticity is occurring within the central nervous system to perpetuate the pain experience. Furthermore, there are several conditions known to occur in the absence of any tissue injury, such as fibromyalgia and tension-type headaches. Collectively, these conditions are referred to as nociplastic pain syndromes. The broad goal of this proposal is to identify regions within the central nervous system that exhibit plasticity in response to chronic pain. To model chronic pain, I will employ the partial sciatic nerve ligation (pSNL). I will focus my investigation on the parabrachial nucleus (PBN), a hub for the relay of aversive sensory information. My preliminary data suggests that the population of neurons expressing Calca within the PBN exhibits an increase in neuronal activity acutely following chronic pain induction, however this activity does not persist through the entire chronic pain experience. Additionally, silencing the PBN Calca population prevents pSNL driven pain and chronically stimulating this population produces pain that persists beyond stimulus cessation. Together this information informs my central hypothesis that PBN Calca neurons are involved in the initiation and perpetuation of chronic pain. To test this hypothesis, I will both manipulate Calca neurons and observe their activity during chronic pain. The experiments detailed in Aim 1 will probe whether PBN Calca neurons are involved in maintaining the chronic pain experience by assessing whether transient inhibition of PBN Calca neurons will ameliorate pSNL driven pain. Aim 2 will explore how much and what type of stimulation is required for the manifestation of persistent pain driven by PBN Calca neurons. This aim will also determine whether expression of the Calca gene is required for the manifestation of chronic pain. Finally, in Aim 3 I will observe the activity of PBN Calca neurons preceding and following the induction of chronic pain via calcium imaging. This will reveal when PBN Calca neurons exhibit increased activity during a chronic pain experience. Collectively, these experiments will delineate the role Calca neurons play in the manifestation and perpetuation of chronic pain. This work will further our understanding of how chronic pain conditions arise and persist in the absence of a driving injury and may suggest a target for novel pain therapies.

项目概要 慢性疼痛是一种非常普遍且影响深远的疾病。它的持续时间超过了正常组织的预期时间 从剧烈疼痛事件中恢复过来，表明中枢神经系统内正在发生可塑性 使痛苦经历永久化。此外，已知有几种情况会在没有 任何组织损伤，例如纤维肌痛和紧张型头痛。这些条件统称为 称为伤害性疼痛综合征。该提案的总体目标是确定中部地区 对慢性疼痛表现出可塑性的神经系统。为了模拟慢性疼痛，我将采用 部分坐骨神经结扎术（pSNL）。我将重点研究臂旁核 (PBN)，它是 厌恶性感官信息的传递。我的初步数据表明神经元的数量 在 PBN 中表达 Calca 表现出慢性疼痛后神经元活动急剧增加 然而，这种活动不会在整个慢性疼痛经历中持续存在。此外， 沉默 PBN Calca 群体可预防 pSNL 驱动的疼痛并长期刺激该群体 产生的疼痛在刺激停止后仍持续存在。这些信息共同构成了我的中心假设 PBN Calca 神经元参与慢性疼痛的发生和持续。为了检验这个假设，我 将操纵钙神经元并观察它们在慢性疼痛期间的活动。实验详述于 目标 1 将探讨 PBN Calca 神经元是否通过以下方式参与维持慢性疼痛体验： 评估 PBN Calca 神经元的短暂抑制是否会改善 pSNL 驱动的疼痛。目标2将 探索由以下原因引起的持续性疼痛的表现需要多少刺激和何种类型的刺激 PBN 钙神经元。这一目标还将确定 Calca 基因的表达是否是 慢性疼痛的表现。最后，在目标 3 中，我将观察 PBN Calca 神经元之前和之后的活动。 通过钙成像诱发慢性疼痛后。这将揭示 PBN Calca 神经元何时表现出 在慢性疼痛经历期间增加活动。总的来说，这些实验将描述角色 钙神经元在慢性疼痛的表现和持续中发挥作用。这项工作将进一步推动我们 了解在没有驾驶伤害的情况下慢性疼痛是如何产生和持续的，并且可能 提出新型疼痛疗法的目标。