Functional characterization of an amygdala to accumbens nociceptive circuit

杏仁核到伏核伤害感受回路的功能特征

• 批准号: 10671478
• 负责人: Jessica Anne Wojick
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10671478
• 关键词: Absence of pain sensation; Acute; Affect; Affective; Affective Symptoms; American; Amygdaloid structure; Animals; Appetitive Behavior; Automobile Driving; Axon; Behavior; Behavioral; Brain; Brain region; Calcium; Chronic; Clinical Research; Complement; Corpus striatum structure; Data; Desire for food; Development; Diagnostic Imaging; Diagnostic tests; Emotional; Emotions; Fellowship; Fiber Optics; Functional disorder; Future; Glutamates; Goals; Horns; Human; Hyperactivity; Hypersensitivity; Image; Imaging Device; Implant; Individual; Injury; Light; Medial; Mentors; Motivation; Mus; Negative Valence; Neurons; Neuropathy; Neurosciences; Nociception; Nociceptive Stimulus; Nucleus Accumbens; Operative Surgical Procedures; Opsin; Outcome; Output; Pain; Pain Research; Pain management; Pathologic; Population; Presynaptic Terminals; Process; Research; Resolution; Role; Sensory; Specificity; Stimulus; Structure; System; Technical Expertise; Training; Translational Research; Viral; Visualization; avoidance behavior; awake; calcium indicator; career; cell type; chronic pain; chronic pain patient; chronic painful condition; experience; falls; functional group; in vivo calcium imaging; injured; negative affect; neural; neural circuit; neuronal cell body; neuropsychiatric disorder; neurotransmission; optical fiber; optogenetics; pain chronification; pain perception; persistent symptom; preclinical study; response; sensory stimulus; side effect; transcriptomics; transmission process

Over 100 million Americans suffer from chronic pain, experiencing persistent nociceptive sensory and negative affective symptoms. Currently available pain treatments are inadequate at safely and effectively relieving both the sensory and affective features of chronic pain, partly because of their lack of specificity to modulate distinct neural cell-types and processes. While diagnostic imaging tools have correlated the affective unpleasantness of chronic pain with dysfunction across broad brain regions-such as the basolateral amygdala (BLA) and nucleus accumbens (NAc)-they lack specificity to identify individual functional cell types that might underlie this maladaptive plasticity. A key first step towards identifying and targeting affective nociceptive neural circuits is to visualize the dynamics of nociceptive transmissions between affective-motivational brain regions during the transition from acute to chronic pain. The research goal of the proposed project is to functionally characterize a nociceptive BLA to NAc circuit that contributes to negative affective-motivational behavior in acute and chronic nociceptive states. Dysfunction of the BLA has been implicated in chronic pain and neuropsychiatric disorders through the process of assigning valence to internal and external sensory information. The BLA contains a functional subpopulation of negative valence neurons essential for the emotionally aversive aspect of nociception (BLA"0 ci). Inhibition of BLAnoci neurons reduces affective-motivational responses to noxious stimuli in acute and chronic nociceptive states. BLA neurons send long-range axons to many downstream targets, including the NAc, a striatal structure important for driving appetitive and aversive behaviors. Preliminary data suggests that BLAnoci neurons project to the "limbic" NAc Shell subregion (NAcSh). Furthermore, there is a group of neurons highly responsive to noxious stimuli within the NAcSh (the "inner-horn"; NAcSh1H) that a bundle of BLAnoci axons strongly innervate. However, it is unknown if BLAnoci neurons transmit affective nociceptive information to the NAcSh1H nor if NAcSh1H neurons are essential for driving nociception-related negative affective-motivational behaviors. Aim 1 will functionally characterize the BLA"0 ci to NAcSh1H circuit in acute and chronic nociceptive states using in vivo calcium imaging and optogenetic activation of BLAnoci axon terminals in awake behaving subjects. Aim 2 will image and manipulate NAcSh1H neuron activity in acute and chronic nociceptive states using calcium imaging and optogenetic manipulation of NAcSh1H neural activity. Completion of these proposed aims will result in the characterization of a potentially key affective circuit between the BLA and NAcSh1H encoding acute and chronic nociceptive information. The outcome of this proposal will help the field of affective pain neuroscience better understand neural circuit function in healthy and pathological states. Furthermore, this research may inform future translational investigations into treatments for the negative affective symptoms of chronic pain. Completion of this fellowship will achieve the training goals of expanding the technical expertise of Ms. Wojick in systems neuroscience and facilitate her career goal of becoming a leading expert in affective pain research.

超过1亿美国人患有慢性疼痛，经历持续的伤害性感觉和负性疼痛。 情感症状目前可用的疼痛治疗不足以安全有效地缓解两者 慢性疼痛的感觉和情感特征，部分原因是它们缺乏特异性， 神经细胞类型和过程。虽然诊断成像工具已经将情感上的不愉快与 慢性疼痛伴广泛脑区功能障碍，如基底外侧杏仁核（BLA）和核 NAc-它们缺乏特异性来识别可能构成此基础的单个功能细胞类型 适应不良的可塑性识别和靶向情感伤害感受神经回路的关键第一步是 可视化的动态伤害性传输之间的情感动机的大脑区域在 从急性疼痛到慢性疼痛。拟议项目的研究目标是在功能上表征一个 伤害性BLA至NAc回路，在急性和慢性中导致消极情感动机行为 伤害感受状态BLA功能障碍与慢性疼痛和神经精神疾病有关 通过给内部和外部感觉信息赋值的过程。BLA包含 负价神经元的功能亚群对伤害感受的情绪厌恶方面至关重要 (BLA”0 ci）。抑制BLANOCI神经元可减少急性和慢性炎症患者对伤害性刺激的情感-动机反应， 慢性伤害感受状态BLA神经元将长距离轴突发送到许多下游目标，包括NAc， 一种对驱动食欲和厌恶行为很重要的纹状体结构。初步数据显示， 神经元投射到“边缘”NAc壳亚区（NAcSh）。此外，有一组神经元高度 对NAcSh（“内角”; NAcSh 1H）内的伤害性刺激有反应，一束Blanoci轴突强烈地 使神经活动。然而，尚不清楚BLAnoci神经元是否将情感伤害性信息传递到NAcSh 1H 也不知道NAcSh 1H神经元是否是驱动伤害感受相关的消极情感动机行为所必需的。 目的1将在急性和慢性伤害感受状态下使用以下方法功能性地表征BLA-0 ci至NAcSh 1H回路： 清醒行为受试者中BLAnoci轴突终末的体内钙成像和光遗传学激活。目的2 将使用钙成像成像和操纵急性和慢性伤害感受状态下的NAcSh 1H神经元活动 和NAcSh 1H神经活性的光遗传学操纵。完成这些拟议目标将导致 表征BLA和NAcSh 1H编码急性和慢性之间的潜在关键情感回路 伤害性信息这一建议的结果将有助于情感疼痛神经科学领域更好地 了解健康和病理状态下的神经回路功能。此外，这项研究可以提供信息， 对慢性疼痛负性情感症状治疗的未来转化研究。完成 该奖学金将实现扩大Wojick女士在系统方面的技术专长的培训目标。 神经科学和促进她的职业目标，成为情感疼痛研究的领先专家。