Deconstructing the network mechanisms of chronic pain and reward in the amygdala

解构杏仁核慢性疼痛和奖赏的网络机制

基本信息

批准号：
9294783
负责人：
Gregory Corder
金额：
$ 17.48万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9294783
关键词：
Absence of pain sensation Acute Acute Pain Affect Affective American Amygdaloid structure Analgesics Anatomy Anhedonia Anxiety Applications Grants Architecture Automobile Driving Award Behavior Biological Neural Networks Brain Brain region Cell Nucleus Chronic Clinical Code Cognitive Comorbidity Data Desire for food Development Disease Drug abuse Drug usage Electrophysiology (science)Emotional Employee Strikes Esthesia Food Foundations Functional disorder Future Generations Goals Health Benefit Image Injury Instinct Lead Learning Mediating Mental Depression Mentors Molecular Monitor Motivation Mus Negative Valence Neurons Nociception Nociceptive Reflex Nucleus Accumbens Opioid Output Pain Pathologic Patients Pattern Perception Pharmaceutical Preparations Phase Positive Valence Prevalence Process Psychological reinforcement Public Health Research Rewards Risk Scientist Sensory Sensory Disorders Shapes Signal Transduction Slice Stimulus Structure Supervision Synapses Techniques Testing Therapeutic Intervention Time Training United States National Institutes of Health Work base career career development chronic pain comorbid depression depressive symptoms drug of abuse endogenous opioids experience fluorescence microscope hedonic improved in vivo innovation learned behavior mental state motivated behavior mu opioid receptors negative affect nervous system disorder network dysfunction neuronal circuitry neurotransmission novel optogenetics pain behavior pain symptom painful neuropathy patch clamp persistent symptom pleasure prescription opioid programs psychologic public health priorities relating to nervous system sensory input sensory integration sex

项目摘要

Summary Chronic pain is not merely a persistent sensory disorder, but a neurological disease of affective dysfunction that negatively impacts the mental state, professional goals, and personal relationships of over 100 million Americans. Emotionally-guided behaviors, such as avoiding pain and seeking pleasure, are derived from valence information generated by the limbic brain. The ability of valence circuits to categorize external and internal sensory information as either ‘pleasant’ or ‘unpleasant’ is essential for behavior selection, protective learning, and survival. However, miscoding of sensory information due to pathological plasticity within these valence circuits can produce unwanted psychological effects, including the suffering and depression associated with chronic pain. The amygdala is a brain region critical for processing emotional valence and influencing motivational drive. However, the functional relevance of amygdalar valence processing to the generation of hedonic perception and behavior-selection is defined primarily by its output connectivity with effector structures in limbic and cortical regions. Recent evidence proposes the existence of innate and distinct neuronal circuits for opposing positive and negative valence processing in the basolateral nucleus of the amygdala (BLA) that also diverge based on the downstream target structures, such as the nucleus accumbens (NAc). However the network-level interface between these opposing BLA valence circuits has been largely unexplored. Here, I propose to uncover the dynamic interactions of BLA valence circuits to determine their contribution to pain and hedonic affect, both locally within the BLA and at their long-range targets in the NAc. During the mentored K99 phase, my career development and training will be supervised by my co-mentors, Drs. Gregory Scherrer and Mark Schnitzer, with additional support from Drs. Robert Malenka, Sean Mackey, and Brian Kobilka. To investigate the neural network mechanisms driving pain unpleasantness and comorbid anhedonia, I will receive expert training in optogenetic-guided brain slice electrophysiology and time-lapse in vivo Ca2+ imaging in freely behaving mice to uncover the functional interactions of neural ensembles encoding nociceptive and appetitive sensory information throughout the development of chronic pain. During the independent R00 phase, I will determine whether BLA valence circuits that differently innervate the NAc define functionally and anatomically distinct “hedonic zones” within opioidergic circuits. I will further investigate the relevance of these zones to behavior-selection and reinforcement during acute and chronic pain, and during drug use conditions. The advanced training I will receive during this K99/R00 award will lay the foundations for my future research program and NIH grant applications. This award will help me advance my own scientific capabilities, and bolster my career as a successful, independent research scientist and mentor. The successful completion of this work will also have important public health benefits as it will guide future efforts on novel analgesic strategies to reduce pain and lessen the need for prescription opioids.

概括慢性疼痛不仅是一种持续的感觉障碍，而且是情感功能障碍的神经疾病这会对超过1亿多人的精神状态，职业目标和个人关系产生负面影响美国人。情感引导的行为，例如避免痛苦和寻求愉悦，是从中得出的边缘大脑产生的价信息。价电路对外部和内部感官信息是“愉快”或“不愉快”，对于行为选择至关重要，保护学习和生存。但是，由于其中的病理可塑性而导致的感官信息错误编码价电路可能会产生不必要的心理影响，包括痛苦和抑郁症与慢性疼痛有关。杏仁核是一个大脑区域，对于处理情感价和影响动机。但是，杏仁核价与处理的功能相关性享乐感感知和行为选择的产生是通过其输出连接与边缘和皮质区域的效应器结构。最近的证据提出了先天和独特的存在神经元电路，用于反对的基底外侧核的正价处理杏仁核（BLA）也基于下游目标结构，例如伏隔核（NAC）。但是，这些相反的BLA价电路之间的网络级界面在很大程度上是未探索。在这里，我建议揭示Bla Valence圈的动态相互作用，以确定它们在BLA及其在NAC中的远程目标内，对疼痛和享乐影响的贡献。在受过指导的K99阶段，我的职业发展和培训将由我的联席会员监督，博士。 Gregory Scherrer和Mark Schnitzer，在DRS的额外支持下。罗伯特·马伦卡（Robert Malenka），肖恩·麦基（Sean Mackey），和Brian Kobilka。调查驱动疼痛不愉快和合并的神经网络机制 Anhedonia，我将接受光遗传学引导的脑切片电学和延时的专业培训自由行为小鼠中的体内Ca2+成像，以发现神经合奏编码的功能相互作用在整个慢性疼痛的发展过程中，伤害性和食欲的感官信息。在独立的R00相，我将确定BLA价电路对NAC的支配有所不同。在功能和解剖学上不同的“享乐区”。我将进一步调查这些区域与急性和慢性疼痛期间的行为选择和加强的相关性以及吸毒条件。我将在此K99/R00奖励期间接受的高级培训将为我未来的研究计划和NIH赠款申请。这个奖项将帮助我推进自己的科学能力，并增强我作为成功的独立研究科学家和精神的职业。这项工作的完成还将具有重要的公共卫生益处，因为它将指导未来的小说努力减轻疼痛并减轻处方OID的需求的镇痛策略。