Arlene George F32

项目摘要 慢性疼痛（>3个月）影响了超过5000万美国人，限制了他们的生活和日常活动， 健康危机。虽然对于那些经历急性疼痛的人有可用的治疗方法，但缺乏有效的治疗方法。 对慢性疼痛患者的治疗干预。其中一个参与疼痛的候选者是纹状体 它以感觉运动整合和促进自主运动而闻名， GABA能多巴胺受体1（D1 N）细胞和多巴胺受体2（D2 N）表达主要 神经元纹状体可以通过激活纹状体D2 N通路介导口面疼痛的镇痛作用。 然而，慢性神经病理性疼痛的纹状体机制以及这种机制如何影响持续的感觉- 引导行为在很大程度上是未知的。纹状体也有来自初级躯体感觉皮层（S1）的输入。 有助于疼痛处理。已知S1处理包括伤害感受和触摸的躯体感觉 它的活动会随着疼痛而改变除脊髓丘脑束外，S1也有直接投射到脊髓背角。 纹状体和可塑性的变化，这一途径可能指向一个机制，参与过渡到急性 慢性疼痛和影响持续的行为，包括动机和运动规划。我的首要任务 一种假设是，在从急性疼痛向慢性疼痛的过渡期间，过度活跃的纹状体D2 N群体 由S1过度活跃驱动的疼痛相关行为和抑制的表达增强 动机行为。具体目标1将检验从急性疼痛到慢性疼痛的转变 导致反射性和情感性疼痛特征的增加，并且这种神经性疼痛影响感觉- 与更高的D2 N活性相关的指导行为。Aim 1的培训潜力植根于尖端工具： 用于分析疼痛相关行为特征的机器学习应用，体内慢性光学成像 用光纤光度法，神经外科技术和病毒注射。具体目标2将检验假设 皮质纹状体通路存在可塑性变化，其中D2 N比D1 N更增强 在从急性疼痛向慢性疼痛的过渡中，调节纹状体细胞活性将导致疼痛的变化， 感官引导的行为目标2的训练潜力在于学习电生理技术、光遗传学 技术，并从这些实验中的数据编码分析。集体成果将提供一个 了解（1）疼痛相关的疼痛特征如何从急性疼痛转变为慢性疼痛，以及这种转变如何发生 影响感觉引导的行为和（2）D1 N和D2 N活性在急性向急性过渡中的功能作用。 慢性疼痛我的研究将提供对纹状体通路在不同时间活跃的理解 疼痛的时期。这些目标的高培训潜力是精心设计的，以填补我的差距为基础的知识 在系统神经科学中。这个奖学金的影响将促进我的成功，有影响力，持久 神经系统疾病的独立研究生涯

PROJECT SUMMARY Chronic pain (>3 months) affects over 50 million Americans, limiting their life and daily activities, creating a public health crisis. Although there are available treatments for those experiencing acute pain, there is a lack of therapeutic intervention for those suffering from chronic pain. One candidate involved in pain is the striatum which is known for sensorimotor integration and facilitating voluntary movement particularly with the interplay between the GABAergic dopamine receptor 1 (D1N) cells and dopamine receptor 2 (D2N) -expressing principal neurons. The striatum can mediate analgesic action in orofacial pain through activation of striatal D2N pathways. However, the striatal mechanisms underlying chronic neuropathic pain and how this affects ongoing, sensory- guided behaviors is largely unknown. The striatum also has inputs from the primary somatosensory cortex (S1) that contribute to pain processing. S1 is known to process somatic sensations including nociception and touch and its activity changes during pain. In addition to the spinothalamic tract, S1 also has direct projections to the striatum and plasticity changes in this pathway could point to a mechanism involved in the transition from acute to chronic pain and affect ongoing behaviors including motivation and motor planning. My overarching hypothesis is that during the transition from acute to chronic pain, overactive striatal D2N populations driven by hyperactivity of S1 lead to the heightened expression of pain-related behaviors and inhibition of motivational behavior. Specific Aim 1 will test the hypothesis that the transition from acute to chronic pain leads to an increase in reflexive and affective pain features and that this neuropathic pain influences sensory- guided behavior associated with higher D2N activity. Aim 1’s training potential is rooted in cutting-edge tools: machine-learning applications for analyzing pain-related behavioral signatures, in vivo chronic optical imaging with fiber photometry, and neurosurgical techniques and viral injections. Specific Aim 2 will test the hypothesis that there are plasticity changes in corticostriatal pathways in which D2N are more potentiated compared to D1N in the transition from acute to chronic pain and modulating striatal cell activity will lead to changes in pain and sensory-guided behavior. Aim 2’s training potential lies in learning electrophysiological techniques, optogenetic techniques, and data coding analysis from these experiments. The collective results will provide an understanding of (1) how pain-related features of pain change from acute to chronic pain and how this transition affects sensory-guided behavior and (2) the functional role of D1N and D2N activity in the transition of acute to chronic pain My research will provide an understanding of striatal pathways that are active in different time periods of pain. The high training potential for these aims is carefully designed to fill my gap-based knowledge in systems neuroscience. The impact of this fellowship will foster my successful, impactful, and enduring independent research career in neurological disorders.