Targeting a novel neural circuit to modulate trigeminal neuropathic pain

项目总结： 三叉神经病理性疼痛是一种使人虚弱的疾病，对临床医生来说是一种挑战，因为 这种疼痛通常对目前可用的治疗方法来说是难治的。这背后的脑神经回路机制 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。这样做的目的是 项目是解剖一种新的三叉神经病理性疼痛的调制神经回路。在我的初赛中 研究中，我使用了一种革命性的方法--“在活跃群体中进行靶向重组(TRAP)”--我发现 慢性应激对丘脑室旁核前核神经元的激活作用 眶下神经压迫性损伤(CCI-ION)。通过顺行和逆行追踪病毒，我发现 被捕获的aPVT神经元直接投射到前扣带回皮质(ACC)。此外，我发现光遗传 兴奋诱捕的aPVT神经元增强CCI-离子诱导的三叉神经病理性疼痛和 APVT神经元的光遗传沉默可以减轻这种疼痛。我的初步结果显示aPVT 神经元及其向ACC的投射可能参与三叉神经病理性疼痛的调制。在这 在此项目中，我将进一步探讨aPVT-ACC通路在三叉神经痛调制中的作用。我的假设是 对aPVT-ACC通路的特定操作可以调节三叉神经病理性疼痛的一种活动- 依赖方式：aPVT-ACC通路特异性激活通过增强三叉神经病理性疼痛 增强ACC内神经元的活性；相反，特异性抑制aPVT-ACC通路可以缓解疼痛 通过减少ACC中的神经元活动。为了解决这个中心假设，我将使用多学科 在两个具体目标下进行以下研究的方法。在目标1中，我将确定aPVT-Acc的作用 光基因操作对三叉神经痛调制通路的影响 CCI离子诱导的三叉神经病理性疼痛。将测量诱发的和自发的疼痛行为 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 微型化技术在三叉神经病理性疼痛中对ACC神经元活动的调节作用 基于显微镜的自由活动小鼠体内钙成像。总而言之，我希望展示aPVT- ACC通路在三叉神经痛觉调制中起关键作用。拟议的研究具有重要意义，因为它将推动 我们对痛觉调制的脑神经回路的理解。拟议的研究具有创新性，因为 研究将揭示三叉神经痛调制背后的一种以前未被识别的神经回路。

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.