Investigation of neural ensembles driving pain chronification

项目摘要 疼痛感知的不愉快或消极情感成分是一种情绪现象， from the perceptive知觉sensory感官qualities质量.这种痛苦的情感维度是痛苦和动机的基础。 慢性疼痛患者的缺点。然而，大脑网络中缺乏类似的细胞解析机制 相对于外周和脊髓回路中复杂的伤害感受细节。因此，加快发展的关键一步 有效的疼痛治疗的发展必须是发现大脑中的特定神经回路， 是造成疼痛感知的厌恶和不愉快的原因。我们最近报道了 和表征的基底外侧杏仁（BLA）神经合奏，在单神经元分辨率， 在急性和慢性疼痛条件下将伤害性信息转化为情感动机行为。 虽然这些研究提供了一个进入复杂的疼痛情感回路的关键点， BLA伤害感受整体与更大的情感脑回路的其它部分连接。 我们的目标是提供一个系统水平的理解伤害性皮层脑网络参与 通过整合来自疼痛经验依赖性转录组学的多模态数据， 基于活动的全脑回路追踪，以及精确的化学发生控制-锚定在动机上 基于行为的分类-从急性疼痛到慢性疼痛的整个过渡期。因此，为了发现这一点 伤害性脑网络，在AIM 1中，我们将使用狂犬病病毒遗传策略结合立即早期 在清除的、完整的脑组织中进行基因定位，以定位其活性被改变的关键神经元群体。 慢性神经性疼痛。在AIM 2中，我们将使用单核RNA测序来连接转录组身份， 以及在BLA伤害性疼痛的确定的伤害性输入细胞中疼痛慢性化过程中细胞状态的变化， 合奏。在AIM 3中，我们将化学遗传学地操纵投射到BLA的伤害感受细胞类型， 疼痛的情感动机行为与局部注入微球药物输送。细胞和功能 这些基本伤害感受回路的识别应该为开发精确性开辟新的途径 治疗，以打击不同层面的疼痛经验，包括不愉快的情感成分。 这种回路靶向疗法可以选择性地减轻疼痛患者的痛苦，而不管病因如何 而不影响奖赏，同时保留了保护性疼痛的必要感觉辨别过程 感觉。

PROJECT SUMMARY The unpleasantness, or negative affective component, of pain perception is an emotional phenomenon distinct from the perceptive sensory qualities. This affective dimension of pain underlies the suffering and motivational deficits of chronic pain patients. However, similar cellular-resolution mechanisms within brain networks is lacking relative to the intricate nociceptive detail in the peripheral and spinal circuits. Thus, a key step toward accelerating the development of effective pain treatments must be the discovery of the specific neural circuits in the brain that are responsible for the aversive and unpleasant quality of pain perception. We recently reported the discovery and characterization of a basolateral amygdalar (BLA) neural ensemble, at single neuron resolution, that transforms nociceptive information in affective-motivational behavior in both acute and chronic pain conditions. While these studies provide a critical point of entry into the complex affective circuits of pain, it is not clear how the BLA nociceptive ensemble connects with other parts of the larger affective brain circuitry. Our goal here is to provide a systems-level understanding of the nociceptive cortical brain networks involved in the affective perception of pain by integrating multimodal data from pain-experience-dependent transcriptomics, activity based whole-brain circuit tracing, and precision chemogenetic control—anchored in motivational behavior-based classifications—throughout the transition from acute to chronic pain. Thus, to discover this nociceptive brain network, in AIM 1 we will use a rabies viral-genetic strategy combined with immediate early gene mapping in cleared, intact brain tissue to locate key neuronal populations whose activity is altered by chronic neuropathic pain. In AIM 2, we will employ single-nuclei RNA sequencing to link transcriptomic identity and change in cellular states during pain chronification in defined nociceptive input cells to the BLA noci- ensemble. In AIM 3, we will chemogenetically manipulate nociceptive cell-types projecting to the BLA to mitigate pain affective-motivational behaviors with locally infused microsphere drug-delivery. The cellular and functional identification of these fundamental nociceptive circuits should open new avenues for developing precision therapeutics to combat different dimensions of pain experiences, including the unpleasant affective component. Such circuit-targeted therapies could selectively diminish the suffering of pain patients, regardless of etiology and without influencing reward, while preserving necessary sensory discriminative processes for protective pain sensation.