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:
- 金额:$ 4.07万
- 依托单位:
- 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:
- 关键词:Absence of pain sensationAcuteAddressAffectAffectiveAmygdaloid structureAnimal BehaviorAnimalsAnteriorAreaAutomobile DrivingBehaviorBehavioralBrainBrain regionCell physiologyCellsComplexCoupledCuesDepressed moodDevelopmentDiseaseDistantDopamineDopamine ReceptorElectrophysiology (science)EmotionalEsthesiaExcitatory SynapseGlutamatesGoalsInjuryInterneuronsKnowledgeLabelLaboratory ResearchLeadLeadershipLearningLesionMeasuresMental DepressionModelingModificationMolecularMoodsMusNervous system structureNeuraxisNeurobiologyNeuronal PlasticityNeuronsNeuropathyNociceptionNucleus AccumbensPainPain managementPeripheralPeripheral Nervous SystemPersonsPlayPopulationPre-Clinical ModelProceduresPropertyPsychological reinforcementRoleRunningScienceSignal TransductionSiteSliceSourceSubstance Use DisorderSynapsesTestingTrainingUnited StatesVentral Tegmental AreaWorkbehavior testburden of illnesschronic neuropathic painchronic paincingulate cortexcognitive controlcomorbiditydopaminergic neuronemotion regulationexperienceexperimental studygamma-Aminobutyric Acidhigh rewardhigh riskimprovedin vivoinsightmotivated behaviornerve injuryneuroadaptationneurotransmissionoptogeneticspain behaviorpain processingpain sensitivitypainful neuropathyparabrachial nucleuspostsynapticpresynapticreceptor bindingrelating to nervous systemresponsesham surgeryskillssomatosensoryspared nervesynaptic functiontargeted 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
神经性疼痛是慢性疼痛的一种形式,由躯体感觉神经系统的损伤或疾病引起。
影响全球高达10%的人。神经病理性疼痛引起的跨突触改变来自
传播到中枢神经系统的外周神经系统。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感成分的基础。由于可选择的治疗方法
神经性疼痛是有限且效果不佳的,情绪调节和认知控制会改变疼痛。
处理,研究情感脑回路将提供对神经病理性疼痛的复杂体验的洞察
以及它的治疗方法。VTA是情感学习和强化学习的纽带,是
中皮质边缘多巴胺,并控制伤害性线索和疼痛的整合。VTA多巴胺(DA)
神经元通常在神经病理性疼痛时放电频率降低,并在疼痛期间驱动VTA DA神经元
结果有止痛作用。这突出了VTA作为神经病理性疼痛治疗的潜在靶点。然而,
这种射击率下降背后的机制还没有得到充分的研究。这项提案将解决这一问题
根据慢性神经病理性疼痛模型检查VTA神经元及其突触的知识差距:
避免神经损伤(SNI)。在目标1中,我将使用体外脑片电生理记录来评估DA细胞的功能
来自SNI或假手术后小鼠的标记神经元,验证了神经病理性损伤的假设
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,测试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,我将研究特定于电路的贡献
结合体内光遗传学和体外切片电生理学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。一个更伟大的
对神经病理性疼痛诱导的神经可塑性的椎管上机制的理解将导致更多
针对慢性疼痛这一复杂问题的靶向治疗。进行这些实验将使我获得
在杰出的VTA电生理学家考尔博士的指导下,获得了技术和主题方面的专业知识。
她的培训,与本意见书中概述的职业发展培训相结合,将会有所改善
我交流科学的能力,通过增强分析技能来提高我的科学严谨性,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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Claire Manning其他文献
Claire Manning的其他文献
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{{ truncateString('Claire Manning', 18)}}的其他基金
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 - 财政年份:2021
- 资助金额:
$ 4.07万 - 项目类别:
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