Investigation of neural ensembles driving pain chronification

驱动疼痛慢性化的神经系统的研究

基本信息

批准号：
10567552
负责人：
KEVIN T BEIER
金额：
$ 28.85万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-15 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10567552
关键词：
Acceleration Acute Acute Pain Affective Amygdaloid structure Anatomy Animals Anterior Area Automobile Driving Behavior Brain Brain imaging Cells Chromosome Mapping Chronic intense pain Classification Color Complex Data Development Dimensions Disease Drug Delivery Systems Emotional Emotions Etiology Evolution Female Functional Magnetic Resonance Imaging Future Genetic Genetic Recombination Glutamates Goals Healthcare Human Image Immediate-Early Genes In Situ Hybridization Insula of Reil Intervention Investigation Light Link Literature Maps Mediating Mental Health Methods Microscopy Microspheres Molecular Profiling Motivation Mus Negative Valence Nervous System Neurons Nociception Nociceptors Opioid Pain Pain Map Pain management Pain quality Pathway interactions Patients Peripheral Peripheral nerve injury Pharmacological Treatment Pharmacology Play Population Positive Valence Precision therapeutics Presynaptic Terminals Process Rabies Rabies virus Reporting Resolution Rewards Role Sensory Signal Transduction Site Spinal Structure System Testing Time Vertebral column Virus Work adaptive learning brain circuitry brain tissue cell type chronic neuropathic pain chronic pain chronic pain management chronic pain patient chronic painful condition combat experience genetic approach genetic manipulation genetic technology healing human imaging imaging modality imaging study innovation interest invention male motivated behavior multimodal data negative affect nerve injury nervous system disorder neural neural circuit novel opioid mortality pain behavior pain chronification pain patient pain perception pain reduction pain relief pain sensation preservation prevent rabies label receptor side effect single cell sequencing single nucleus RNA-sequencing spatiotemporal targeted treatment transcriptomics virus genetics

项目摘要

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.

项目概要疼痛感知的不愉快或负面情感成分是一种独特的情感现象疼痛的这种情感维度是痛苦和动机的基础。然而，慢性疼痛患者的大脑网络中缺乏类似的细胞解决机制。相对于外周和脊髓回路中复杂的伤害性细节，这是加速的关键一步。有效疼痛治疗的发展必须是发现大脑中特定的神经回路我们最近报道了这一发现。以及在单一神经分辨率下基底外侧杏仁核 (BLA) 神经系统的表征，在急性和慢性疼痛情况下，转化情感动机行为中的伤害性信息。虽然这些研究提供了进入疼痛复杂情感回路的关键点，但尚不清楚如何 BLA 伤害感受整体与更大的情感大脑回路的其他部分相连。我们的目标是提供对涉及伤害性皮质脑网络的系统级理解通过整合来自疼痛体验依赖性转录组学的多模态数据来对疼痛进行情感感知，基于活动的全脑回路追踪和精确的化学遗传学控制——以动机为基础基于行为的分类——贯穿从急性疼痛到慢性疼痛的转变，从而发现这一点。伤害感受大脑网络，在 AIM 1 中，我们将使用狂犬病病毒遗传策略与立即早期相结合在清除的、完整的脑组织中进行基因定位，以定位其活动的关键神经群体在 AIM 2 中，我们将采用单核 RNA 测序来关联转录组同一性。以及在疼痛慢性化期间细胞状态的变化，在确定的伤害性输入细胞中对 BLA 伤害在 AIM 3 中，我们将通过化学遗传学方法操纵投射到 BLA 的伤害感受细胞类型以减轻伤害。局部注射微球药物递送的疼痛情感动机行为。这些基本伤害感受回路的识别应该为开发精确度开辟新途径对抗不同方面的疼痛体验的疗法，包括不愉快的情感成分。无论病因如何，这种回路靶向疗法都可以选择性地减轻疼痛患者的痛苦并且在不影响奖励的情况下，同时保留保护性疼痛所需的感觉辨别过程感觉。