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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要神经性疼痛是一种慢性疼痛，由躯体感觉神经系统病变或疾病引发影响全球多达 10% 的人。神经性疼痛导致突触修饰周围神经系统传播到中枢神经系统。慢性中枢神经系统的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效果有限且效果不佳，情绪调节和认知控制会改变疼痛处理，研究情感大脑回路将有助于深入了解神经性疼痛的复杂体验及其治疗。 VTA 是情感学习和强化学习的纽带，是情感学习的主要来源。中皮质边缘多巴胺，控制伤害性信号和疼痛的整合。 VTA 多巴胺 (DA) 在神经病理性疼痛期间，神经元的放电率通常会降低，并且在疼痛期间驱动 VTA DA 神经元从而产生镇痛作用。这凸显了 VTA 作为神经性疼痛治疗的潜在靶点。然而，发射率降低的机制尚未得到充分研究。本提案将解决这个问题通过遵循慢性神经病理性疼痛模型检查 VTA 神经元及其突触来弥补知识差距：幸免神经损伤（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，以记录来自 SNI 或假手术后小鼠的标记神经元，检验神经性损伤的假设降低 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 细胞功能跟踪，检验神经性损伤增加内在兴奋性或增强的假设 VTA GABA 神经元上的兴奋性突触。然后在目标 3 中，我将研究电路特定的贡献结合体内光遗传学和离体切片电生理学来研究可塑性和疼痛行为。总之，这些研究将增加我们对神经性疼痛的神经基础的理解。一个更大的了解神经性疼痛引起的神经可塑性的脊髓上机制将导致更多针对复杂的慢性疼痛问题的靶向治疗。进行这些实验将使我获得在杰出的 VTA 电生理学家 Kauer 博士的指导下获得技术和主题专业知识。她的培训与本提交中概述的专业发展培训相结合，将改善我传播科学的能力，通过增强分析技能提高科学严谨性的能力，以及培养我的领导能力。这些实验和活动将使我为自己的成功做好准备独立研究实验室。