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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.

项目总结