Targeting a novel neural circuit to modulate trigeminal neuropathic pain

靶向新型神经回路来调节三叉神经病理性疼痛

• 批准号: 10588645
• 负责人: SUFANG LIU
• 金额: $ 15.15万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10588645
• 关键词: Address; Affective; Animal Model; Anterior; Anterior Nuclear Group; Attenuated; Biological Assay; Brain; Chickenpox; Development; Devices; Distal; Dorsal; Electrical Engineering; Emotional; Future; Genetic Recombination; Goals; Herpes zoster disease; Human; Knowledge; Measures; Mediating; Microscope; Molecular; Mus; Nerve; Neurons; Pain; Pain management; Pathway interactions; Patients; Population; Refractory; Regulation; Research; Role; Sensory; Structure; Structure of paraventricular nucleus of thalamus; Testing; Thalamic structure; Time; Trigeminal Pain; Trigeminal System; Trigeminal nerve structure; Viral; base; behavior measurement; chronic constriction injury; chronic pain; chronic pain management; cingulate cortex; excitatory neuron; in vivo calcium imaging; innovation; interdisciplinary approach; nerve injury; neural circuit; neuroimaging; neuroregulation; non-opioid analgesic; novel; optogenetics; orofacial; pain behavior; pain model; pain relief; painful neuropathy; preference; spontaneous pain; wireless

Project Summary: Trigeminal neuropathic pain is a debilitating condition and represents a challenge to clinicians because such pain is often refractory to currently available therapies. The brain neural circuit mechanism underlying this type of pain remains poorly understood. We will address the knowledge gap in this project. The objective of this project is to dissect a novel neural circuit for the modulation of trigeminal neuropathic pain. In my preliminary study, using a revolutionary approach called “Targeted Recombination in Active Populations (TRAP)”, I identify that neurons in the anterior paraventricular thalamic nucleus (aPVT) are markedly activated by chronic constriction injury of the infraorbital nerve (CCI-ION). By anterograde and retrograde viral tracing, I show that the TRAPed aPVT neurons directly project to anterior cingulate cortex (ACC). Moreover, I found that optogenetic excitation of the TRAPed aPVT neurons enhances CCI-ION-induced trigeminal neuropathic pain and optogenetic silencing of the aPVT neurons attenuates such pain. My preliminary results suggest that aPVT neurons and their projection to ACC could be involved in the modulation of trigeminal neuropathic pain. In this project, I will further interrogate the role of aPVT-ACC pathway in trigeminal pain modulation. My hypothesis is that specific manipulation of aPVT-ACC pathway can modulate trigeminal neuropathic pain in an activity- dependent manner: Specific activation of aPVT-ACC pathway enhances trigeminal neuropathic pain through increasing neuronal activity in the ACC; oppositely, specific inhibition of aPVT-ACC pathway produces pain relief by decreasing neuronal activity in the ACC. To address this central hypothesis, I will use multidisciplinary approaches to conduct the following studies in two specific aims. In Aim 1, I will determine the role of aPVT-ACC pathway in trigeminal pain modulation by investigating the effect of optogenetic manipulation of this pathway on CCI-ION-induced trigeminal neuropathic pain. Both evoked and spontaneous pain behaviors will be measured with von Frey test and real-time place preference assay, respectively. In Aim 2, I will characterize aPVT-ACC pathway-mediated regulation of neuronal activity in the ACC during trigeminal neuropathic pain using miniatured microscope-based in vivo calcium imaging in freely moving mice. Collectively, I expect to show that the aPVT- ACC pathway is critical for trigeminal pain modulation. The proposed research is significant since it will advance our understanding of brain neural circuitry for pain modulation. The proposed studies are innovative since these studies will reveal a previously unrecognized neural circuit that underlies trigeminal pain modulation.

项目概要： 三叉神经性疼痛是一种使人衰弱的疾病，对临床医生来说是一个挑战，因为 这种疼痛通常对目前可用的疗法是难治的。这背后的大脑神经回路机制 疼痛的类型仍然知之甚少。我们将解决这个项目中的知识差距。的目的 本计画旨在剖析一种新的神经回路，以调节三叉神经病理性疼痛。在我的初步调查中， 研究，使用一种革命性的方法，称为“有针对性的消除活跃人群（TRAP）"，我确定 丘脑室旁前核（aPVT）神经元在慢性脑缺血后明显激活， 眶下神经缩窄性损伤（CCI-ION）。通过顺行和逆行病毒追踪，我表明， TRAPed的aPVT神经元直接投射到前扣带皮层（ACC）。此外，我发现光遗传学 被诱捕的aPVT神经元的兴奋增强CCI-ION诱导的三叉神经病理性疼痛， aPVT神经元的光遗传学沉默减弱了这种疼痛。我的初步结果显示aPVT 三叉神经痛的调制可能与三叉神经痛的神经元及其投射有关。在这 本课题将进一步探讨aPVT-ACC通路在三叉神经痛调制中的作用。我的假设是 aPVT-ACC通路的特异性操作可以调节三叉神经病理性疼痛的活性- 依赖性方式：aPVT-ACC通路的特异性激活通过以下途径增强三叉神经病理性疼痛： 增加ACC中的神经元活性;相反，特异性抑制aPVT-ACC通路产生疼痛缓解 为了解决这一中心假设，我将使用多学科 方法进行以下两个具体目标的研究。在目标1中，我将确定aPVT-ACC的作用 通过研究光遗传学操纵这一通路对三叉神经痛调制的影响， CCI-ION诱导的三叉神经痛。将测量诱发性和自发性疼痛行为 分别采用von Frey检验和实时位置偏爱分析。在目标2中，我将描述aPVT-ACC 三叉神经病理性疼痛时ACC神经元活动的通路介导调节 在自由活动的小鼠中进行基于显微镜的体内钙成像。总的来说，我希望能证明- ACC通路在三叉神经痛调制中起着重要作用。这项研究具有重要意义，因为它将推动 我们对疼痛调节的大脑神经回路的理解。这些研究是创新的，因为 研究将揭示一种以前未被认识的神经回路，它是三叉神经疼痛调制的基础。