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: 10285423
• 负责人: Claire Manning
• 金额: $ 6.64万
• 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/10285423
• 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; Gap Junctions; 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; 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的一种形式，是由体感神经系统的病变或疾病引发的 影响全球多达10％的人。神经性疼痛导致透射性修饰 向中枢神经系统传播的周围神经系统。这种CNS可塑性在慢性 疼痛还构成了慢性疼痛的情感和情感成分。由于治疗选择 神经性疼痛有限且有效不佳，情绪调节和认知控制会改变疼痛 处理，研究情感脑循环将提供对神经性疼痛复杂体验的见解 及其处理。 VTA是情感和增强学习的联系，是 中质临床多巴胺，并控制伤害感受线索和疼痛的整合。 VTA多巴胺（DA） 神经元在神经性疼痛期间的发射率通常降低，在疼痛期间驱动VTA DA神经元 导致镇痛。这突出了VTA是神经性疼痛治疗的潜在靶标。然而， 发射速率降低的基础机制被研究了。该建议将解决这个问题 通过检查慢性神经性疼痛模型的VTA神经元及其突触来通过检查知识差距： 幸运的神经损伤（SNI）。在AIM 1中，我将使用离体切片电生理评估DA细胞功能以记录 从SNI或假手术后的小鼠中标记的神经元，检验了神经性损伤的假设 降低了内在的兴奋性或降低VTA DA神经元上的兴奋性突触。在AIM 2中，我将评估GABA 遵循细胞功能，检验神经性损伤会增加内在兴奋性或增强性的假设 VTA GABA神经元上的兴奋性突触。然后在AIM 3中，我将研究针对电路的贡献 可塑性和疼痛行为，结合了体内光遗传学和离体切片电生理学。 总之，这些研究将增加我们对神经性疼痛神经基础的理解。更大 了解神经性疼痛引起的神经塑性的脊柱上脊髓机制将导致更多 在复杂的慢性疼痛问题中有针对性的疗法。进行这些实验将使我获得 在杰出的VTA电生理学家的指导下，技术和主题专业知识：考尔博士。 她的培训与本提交中概述的专业发展培训相结合，将有所改善 我传达科学，通过增强的分析技能来提高科学严谨性的能力以及 发展我的领导能力。这些实验和活动在一起将使我准备自己成功 独立研究实验室。