Arlene George F32

项目总结 慢性疼痛(3个月)影响着5000多万美国人，限制了他们的生活和日常活动，创造了一个 健康危机。尽管有治疗急性疼痛的方法可用，但缺乏治疗方法 对那些遭受慢性疼痛的人进行治疗干预。参与疼痛的一个候选者是纹状体。 它以感觉运动整合和促进自愿运动而闻名，特别是在相互作用的情况下 GABA能多巴胺受体1(D1N)细胞和多巴胺受体2(D2N)表达主体之间的关系 神经元。纹状体可通过激活纹状体D2N通路来介导口面部疼痛的镇痛作用。 然而，慢性神经病理性疼痛背后的纹状体机制以及这种机制如何影响正在进行的感觉- 引导性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质(S1)的输入。 这有助于疼痛的处理。已知S1处理包括痛觉和触觉在内的躯体感觉 在疼痛过程中，它的活动会发生变化。除脊丘脑束外，S1还直接投射到 纹状体和可塑性的变化在这一途径中可能指向一种机制，参与从急性 导致慢性疼痛，并影响正在进行的行为，包括动力和运动规划。我最重要的是 假设是在从急性疼痛到慢性疼痛的过渡过程中，纹状体D2N人群过度活跃 由S1的过度活动驱动导致疼痛相关行为和抑制的表达增加 激励性行为。具体目标1将检验从急性疼痛到慢性疼痛的过渡 导致反射性和情感性疼痛特征的增加，这种神经性疼痛影响感官- 与较高的D2N活动相关的引导行为。目标1：S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，活体慢性光学成像 用纤维光度法、神经外科技术和病毒注射。《特定目标2》将检验这一假设 在皮质纹状体通路中存在可塑性变化，其中D2N比D1N更强 在从急性疼痛向慢性疼痛的转变中，调节纹状体细胞的活动将导致疼痛和 感官引导的行为。目标2：S的训练潜力在于学习电生理技术、光遗传学 技术，以及来自这些实验的数据编码分析。集体结果将提供一个 了解(1)疼痛的相关特征如何从急性疼痛转变为慢性疼痛，以及这种转变是如何发生的 影响感觉引导行为和(2)D1N和D2N活动在急性向 慢性疼痛我的研究将提供对不同时间活跃的纹状体通路的理解 阵痛期。这些目标的高培训潜力是精心设计的，以填补我基于空白的知识 在系统神经科学方面。这一奖学金的影响将培养我的成功、有影响力和持久的 神经疾病方面的独立研究生涯。

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.