Arlene George F32

阿琳·乔治 F32

• 批准号: 10722238
• 负责人: Arlene Joann George
• 金额: $ 7.36万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-01-02 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10722238
• 关键词: Acute; Acute Pain; Affect; Affective; American; Analgesics; Animal Model; Anterior; Anterolateral; Behavior; Behavioral; Brain region; Calcium; Cells; Central Nervous System; Chronic; Clinical; Code; Corpus striatum structure; Data; Decision Making; Dopamine; Dopamine Receptor; Electrophysiology (science); Esthesia; Exploratory Behavior; Fellowship; Fiber; Fostering; Goals; Grant; Health; Hyperactivity; Impairment; Injections; Injury; Interneurons; Knowledge; Lead; Learning; Life; Literature; Long-Term Potentiation; Machine Learning; Measures; Mechanics; Mediating; Mentors; Modeling; Monitor; Motivation; Motor; Movement; Mus; Neurologic; Neurons; Neurosciences; Nociception; Orofacial Pain; Outcome; Pain; Pain Measurement; Pathway interactions; Perception; Persistent pain; Photometry; Population; Postdoctoral Fellow; Process; Psychological reinforcement; Public Health; Punishment; Research; Research Personnel; Rewards; Role; Sensory; Sex Differences; Site; Slice; Somatosensory Cortex; Spinal Cord; Spinothalamic Tracts; Synapses; System; Techniques; Testing; Therapeutic Intervention; Time; Touch sensation; Training; Viral; Work; career; chronic neuropathic pain; chronic pain; chronic painful condition; cingulate cortex; clinical pain; design; dopamine system; experience; experimental analysis; in vivo; insight; nerve injury; nervous system disorder; neural; neural correlate; neuromechanism; neuronal circuitry; neurosurgery; optical imaging; optogenetics; pain behavior; pain chronification; pain model; pain perception; pain processing; painful neuropathy; post-doctoral training; programs; response; sensory feedback; sex; skill acquisition; spared nerve; tool

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.

项目概要 慢性疼痛（>3 个月）影响着超过 5000 万美国人，限制了他们的生活和日常活动，造成公众对疼痛的担忧。 尽管有针对急性疼痛的可用治疗方法，但缺乏治疗方法。 对患有慢性治疗性疼痛的人进行干预是纹状体的一个候选者。 以感觉运动整合和促进随意运动（尤其是相互作用）而闻名 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 纹状体可以通过激活纹状体 D2N 通路介导口面部疼痛的镇痛作用。 然而，慢性神经性疼痛背后的纹状体机制以及它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体感皮层（S1）的输入。 已知有助于疼痛处理的 S1 可以处理躯体感觉，包括伤害感受和触觉。 其活动在疼痛期间发生变化 除了脊髓丘脑束外，S1 还直接投射到脊髓。 该途径中的纹状体和可塑性变化可能指出一种参与从急性转变的机制。 慢性疼痛并影响持续的行为，包括动机和运动计划。 假设是，在从急性疼痛转变为慢性疼痛的过程中，过度活跃的纹状体 D2N 群体 S1过度活跃的驱动导致胃肠道疼痛相关行为的表达和抑制 具体目标 1 将检验从急性疼痛到慢性疼痛的转变这一假设。 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 与较高 D2N 活动相关的引导行为的训练潜力植根于尖端工具： 用于分析疼痛相关行为特征、体内慢性光学成像的机器学习应用 纤维光度测定、神经外科技术和病毒注射将检验这一假设。 皮质纹状体通路存在可塑性变化，其中 D2N 比 D1N 更强 在从急性疼痛到慢性疼痛的转变过程中，调节纹状体细胞活性将导致疼痛和疼痛的变化 目标 2 的训练潜力在于学习电生理技术、光遗传学。 这些实验的技术和数据编码分析将提供一个结果。 了解 (1) 疼痛的疼痛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；(2) D1N 和 D2N 活动在急性到急性发作的转变中的功能作用 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了解 这些目标的高潜力训练是为了填补我的知识空白而精心设计的。 这项奖学金的影响将促进我的成功、影响力和持久性。 神经系统疾病的独立研究生涯。