Investigation of neural ensembles driving pain chronification

项目总结 痛觉的不愉快或负面情感成分是一种截然不同的情感现象 从敏锐的感官品质。痛苦的这种情感层面构成了痛苦和激励的基础 慢性疼痛患者的缺陷。然而，在大脑网络中缺乏类似的细胞分辨机制 相对于外周和脊髓回路中复杂的伤害性细节。因此，加速发展的关键一步 有效的疼痛治疗的发展必须是发现大脑中特定的神经回路， 是痛觉中令人厌恶和令人不快的品质的原因。我们最近报道了这一发现 和基底外侧杏仁核(BLA)神经丛的特征，在单个神经元分辨率下， 在急性和慢性疼痛条件下，在情感动机行为中转换伤害性信息。 虽然这些研究提供了进入疼痛复杂情感回路的关键切入点，但尚不清楚如何 BLA伤害性感受器与更大的情感脑回路的其他部分相连。 我们在这里的目标是提供一个系统水平的了解伤害性大脑皮质网络参与 通过整合来自疼痛经验依赖转录组的多模式数据来感知疼痛， 基于活动的全脑电路跟踪和精确的化学发生控制--以激励为基础 基于行为的分类-在从急性疼痛到慢性疼痛的整个过渡过程中。因此，要发现这一点 伤害性大脑网络，在目标1中，我们将使用狂犬病病毒遗传策略结合立即早期 在干净、完整的脑组织中绘制基因图谱，以定位其活动被改变的关键神经元群体 慢性神经病理性疼痛。在AIM 2中，我们将使用单核RNA测序将转录鉴定联系起来 在确定的BLA Noci伤害性感觉输入细胞中，疼痛时序过程中细胞状态的变化。 合唱团。在AIM 3中，我们将通过化学遗传学操作投射到BLA的伤害性细胞类型来减轻 局部输注微球给药的疼痛情感激励行为。细胞和功能 识别这些基本的伤害性感觉回路应该会为发展精确度开辟新的途径 与疼痛体验的不同维度进行斗争的治疗方法，包括令人不快的情感部分。 这种电路靶向治疗可以选择性地减轻疼痛患者的痛苦，无论其病因如何。 并且不影响奖励，同时为保护性疼痛保留必要的感官辨别过程 轰动一时。

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.