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

基本信息

  • 批准号:
    10605758
  • 负责人:
  • 金额:
    $ 4.33万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
项目摘要 慢性疼痛是一种非常普遍和有影响的疾病。它持续超过正常组织预期的时间 从急性疼痛事件中愈合,表明中枢神经系统内正在发生可塑性, 让痛苦的体验永久化此外,有几种已知的情况发生在缺乏 任何组织损伤,如纤维肌痛和紧张型头痛。总的来说,这些条件是指 伤害性疼痛综合征该提案的总体目标是确定中央区域内的 对慢性疼痛表现出可塑性的神经系统。为了模拟慢性疼痛,我将使用 坐骨神经部分结扎(pSNL)。我将把我的调查重点放在臂旁核(PBN),一个枢纽, 传递令人厌恶的感觉信息。我的初步数据显示, 在PBN内表达Calca表现出慢性疼痛后神经元活性的急性增加 然而,这种活动并不持续通过整个慢性疼痛体验。此外,本发明还 沉默PBN Calca群体防止pSNL驱动的疼痛和长期刺激该群体 产生持续超过刺激停止的疼痛。这些信息共同构成了我的核心假设 PBN Calca神经元参与慢性疼痛的起始和持续。为了验证这个假设,我 将操纵Calca神经元并观察它们在慢性疼痛期间的活动。详细的实验在 目的1将探讨PBN Calca神经元是否参与维持慢性疼痛体验, 评估PBN Calca神经元的瞬时抑制是否将改善pSNL驱动的疼痛。目标2将 探索由以下原因驱动的持续性疼痛的表现需要多少和什么类型的刺激 PBN Calca神经元。这一目标还将确定Calca基因的表达是否是肿瘤发生所必需的。 慢性疼痛的表现。最后,在目的3中,我将观察PBN Calca神经元的活动, 在通过钙成像诱导慢性疼痛之后。这将揭示PBN Calca神经元何时表现出 在慢性疼痛体验期间增加活动。总的来说,这些实验将描绘出 Calca神经元在慢性疼痛的表现和延续中发挥作用。这项工作将进一步促进我们的 了解慢性疼痛状况如何出现,并在没有驾驶损伤的情况下持续存在, 为新型疼痛治疗提供了一个靶点。

项目成果

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