Excitatory neurotransmission in the ventral tegmental area following neuropathic injury

神经性损伤后腹侧被盖区的兴奋性神经传递

• 批准号: 10475635
• 负责人: Claire Manning
• 金额: $ 4.07万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-24 至 2023-03-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10475635
• 关键词: Absence of pain sensation; Acute; Address; Affect; Affective; Amygdaloid structure; Animal Behavior; Animals; Anterior; Area; Automobile Driving; Behavior; Behavioral; Brain; Brain region; Cell physiology; Cells; Complex; Coupled; Cues; Depressed mood; Development; Disease; Distant; Dopamine; Dopamine Receptor; Electrophysiology (science); Emotional; Esthesia; Excitatory Synapse; Glutamates; Goals; Injury; Interneurons; Knowledge; Label; Laboratory Research; Lead; Leadership; Learning; Lesion; Measures; Mental Depression; Modeling; Modification; Molecular; Moods; Mus; Nervous system structure; Neuraxis; Neurobiology; Neuronal Plasticity; Neurons; Neuropathy; Nociception; Nucleus Accumbens; Pain; Pain management; Peripheral; Peripheral Nervous System; Persons; Play; Population; Pre-Clinical Model; Procedures; Property; Psychological reinforcement; Role; Running; Science; Signal Transduction; Site; Slice; Source; Substance Use Disorder; Synapses; Testing; Training; United States; Ventral Tegmental Area; Work; behavior test; burden of illness; chronic neuropathic pain; chronic pain; cingulate cortex; cognitive control; comorbidity; dopaminergic neuron; emotion regulation; experience; experimental study; gamma-Aminobutyric Acid; high reward; high risk; improved; in vivo; insight; motivated behavior; nerve injury; neuroadaptation; neurotransmission; optogenetics; pain behavior; pain processing; pain sensitivity; painful neuropathy; parabrachial nucleus; postsynaptic; presynaptic; receptor binding; relating to nervous system; response; sham surgery; skills; somatosensory; spared nerve; synaptic function; targeted treatment

PROJECT SUMMARY Neuropathic pain, a form of chronic pain, is initiated by lesions or disease of the somatosensory nervous system affects up to 10% of people across the globe. Neuropathic pain results in transsynaptic modifications from the peripheral nervous system which are propagated to the central nervous system. This CNS plasticity in chronic pain also underlies the affective and emotional components of chronic pain. Since treatment options for neuropathic pain are limited and poorly effective, and emotional regulation and cognitive control alters pain processing, studying affective brain circuity will provide insights into the complex experience of neuropathic pain and its treatment. The VTA, a nexus of affective and reinforcement learning, is the primary source of mesocorticolimbic dopamine, and controls the integration of nociceptive cues and pain. VTA dopamine (DA) neurons generally have reduced firing rates during neuropathic pain, and driving VTA DA neurons during pain results in analgesia. This highlights the VTA as a potential target for therapeutics for neuropathic pain. However, the mechanisms underlying this reduction in firing rate are understudied. This proposal will address this knowledge gap by examining VTA neurons and their synapses following a model of chronic neuropathic pain: spared nerve injury (SNI). In Aim 1 I will assess DA cell function using ex vivo slice electrophysiology to record from labelled neurons in mice following SNI or sham surgery, testing the hypothesis that neuropathic injury reduces intrinsic excitability or depresses excitatory synapses on VTA DA neurons. In Aim 2 I will assess GABA cell function following, testing the hypothesis that neuropathic injury increases intrinsic excitability or potentiates excitatory synapses on VTA GABA neurons. Then in Aim 3, I will examine circuit-specific contributions to plasticity and pain behaviors using a combination of in vivo optogenetics and ex vivo slice electrophysiology. Together, these studies will increase our understanding of neural underpinnings of neuropathic pain. A greater understanding of the supraspinal mechanisms of neuropathic pain-induced neuroplasticity will lead to more targeted therapies in the complex issue of chronic pain. Performing these experiments will allow me to gain technical and subject matter expertise under the tutelage of an outstanding VTA electrophysiologist: Dr. Kauer. Her training, in combination with the professional development trainings outlined in this submission, will improve my ability to communicate my science, increase my scientific rigor through enhanced analytical skills, and develop my leadership skills. Together these experiments and activities will prepare me to run my own successful independent research laboratory.

项目摘要 神经性疼痛是一种慢性疼痛，由躯体感觉神经系统的病变或疾病引起 影响了地球仪上10%的人神经病理性疼痛导致来自神经元的跨突触修饰。 中枢神经系统的中枢神经系统的中枢神经系统。慢性病中的这种中枢神经系统可塑性 疼痛也是慢性疼痛的情感和情绪成分的基础。由于治疗方案 神经性疼痛是有限的，效果差，情绪调节和认知控制改变疼痛 处理，研究情感脑回路将提供深入了解神经性疼痛的复杂经验， 以及它的治疗。VTA是情感学习和强化学习的纽带，是学习的主要来源。 中皮质边缘多巴胺，并控制伤害性线索和疼痛的整合。腹侧被盖区多巴胺（DA） 神经元通常在神经性疼痛期间具有降低的放电率，并且在疼痛期间驱动VTA DA神经元 导致镇痛。这突出了VTA作为神经性疼痛治疗的潜在靶点。然而，在这方面， 这种放电率降低的机制还没有得到充分研究。本提案将解决这一问题 通过在慢性神经性疼痛模型后检查腹侧被盖神经元及其突触来了解知识差距： 保留神经损伤（SNI）。在目标1中，我将使用离体切片电生理学来评估DA细胞功能，以记录 从SNI或假手术后小鼠的标记神经元中，测试神经病理性损伤 降低VTA DA神经元的内在兴奋性或抑制兴奋性突触。在目标2中，我将评估GABA 细胞功能，测试神经性损伤增加内在兴奋性或增强 VTA GABA神经元上的兴奋性突触。然后在目标3中，我将研究特定于电路的贡献， 使用体内光遗传学和离体切片电生理学的组合的可塑性和疼痛行为。 总之，这些研究将增加我们对神经病理性疼痛的神经基础的理解。更大 对神经病理性疼痛诱导的神经可塑性的脊髓上机制的理解将导致更多的 慢性疼痛这一复杂问题的靶向治疗。做这些实验可以让我 在一位杰出的VTA电生理学家Kauer博士的指导下， 她的培训，结合本提交文件中概述的专业发展培训， 我的科学交流能力，通过增强分析技能提高科学严谨性， 培养我的领导能力这些实验和活动将为我成功地经营自己的事业做好准备。 独立研究实验室。