Spatiotemporal Coding in the Pain Circuit Along the Spine-brain Continuum

总结/摘要 疼痛是一项全国性的健康挑战，每年使我们的经济损失超过6000亿美元。面对 无效的治疗，数以百万计的患者被过度处方阿片类药物，这是 导致上瘾和过量致死 本申请是对RFA-NS-18-009“BRAIN计划：目标BRAIN电路项目”的回应 (R01)它呼吁“创新的方法和新的范式， 在中枢神经系统回路机制的背景下的伤害感受和疼痛”。 我们提出AIM 1）工具开发来测试PV II/III层神经元抑制PV II/III层神经元的假设。 伤害感受中继神经元在体内，目的2）行为发展，以验证快速报告的新模型 3）结合实时神经记录从脊髓-大脑连续体， 生态行为，以测试这一假设，不同的节奏在感觉丘脑和新皮层是 与触觉和伤害性刺激在时间上相关。此外，PV神经元的兴奋抑制丘脑 神经元和调节丘脑皮质节律。 这些目标将使用疼痛的实验室动物模型和最先进的技术进行研究， 从脊髓和大脑的多个区域同时记录，结合细胞特异性刺激 在清醒的啮齿类动物中使用光学方法在外围进行。因此，这种应用将提高我们的科学性， 了解中枢神经系统的疼痛机制，并可能导致新的诊断和 治疗方法。

Summary/Abstract Pain is a national health challenge costing our economy more than $600 Billions per year. Faced with ineffective therapies, millions of patients are being over-prescribed opioid-based medications, which is contributing to addiction and lethal overdose. This application is in response to RFA-NS-18-009 “BRAIN Initiative: Targeted BRAIN Circuits Projects (R01)” which calls for “Innovative approaches and new paradigms for identifying and understanding nociception and pain in the context of circuit mechanisms of the central nervous system”. We propose AIM 1) tool development to test the hypothesis that Laminae II/III PV neurons inhibit nociceptive relay neurons in vivo, AIM 2) behavioral development to validate a novel model for rapid reporting of sensory stimuli, and AIM 3) combination of real-time neural recording from the spine-brain continuum and ecological behavior to test the hypothesis that distinct rhythms in sensory thalamus and neocortex are temporally correlated with tactile and noxious stimuli. Moreover, excitation of PV neurons inhibits thalamic neurons and modulates thalamocortical rhythms. These aims will be investigated using laboratory animal models of pain and state-of-the-art techniques for simultaneous recording from multiple areas in the spine cord and brain, combined with cell-specific stimulation in the periphery using optical methods in awake rodents. Therefore, this application will enhance our scientific understanding of pain mechanisms in the central nervous system and potentially lead to novel diagnostic and therapeutic approaches.