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，经历了持续的伤害感受和负面 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 慢性疼痛的感官和情感特征，部分是因为它们缺乏调节不同的特异性 神经细胞类型和过程。虽然诊断成像工具与情感上的不愉快相关 跨大脑区域的慢性疼痛和功能障碍，例如基底外侧杏仁核（BLA）和核 伏尊（NAC） - 他们缺乏识别可能是基础的单个功能细胞类型的特异性 适应不良的可塑性。识别和靶向情感伤害性神经回路的关键第一步是 可视化情感动机大脑区域之间的伤害感受性传播的动力学 从急性到慢性疼痛的过渡。拟议项目的研究目标是在功能上表征 伤害性BLA到NAC电路，导致急性和慢性的负情感动机行为 伤害性状态。 BLA功能障碍与慢性疼痛和神经精神疾病有关 通过将价分配给内部和外部感觉信息的过程。 BLA包含一个 负价神经元的功能亚群对于伤害感受的情感厌恶方面必不可少 （bla“ 0 ci）。抑制乳纤维神经元可降低对急性有害刺激的情感动机反应， 慢性伤心状态。 BLA神经元向包括NAC在内的许多下游目标发送远距离轴突 纹状体结构对于驱动食欲和厌恶行为很重要。初步数据表明Blanoci 神经元项目针对“边缘” NAC壳子区域（NACSH）。此外，还有一组神经元 对NACSH（“内角”; NACSH1H）内的有害刺激的反应很强 支配。但是，尚不清楚Blanoci神经元是否将情感伤害性信息传递给NACSH1H 如果NACSH1H神经元对于推动与伤害感受相关的情感动机行为至关重要。 AIM 1在功能上将使用急性和慢性伤心态在急性和慢性伤害状态的NACSH1H电路的功能表征。 在醒着的受试者中，体内钙成像和光遗传学激活。目标2 将使用钙成像在急性和慢性伤害性态中图像并操纵NACSH1H神经元活性 NACSH1H神经活动的光学遗传操作。这些提议的目标的完成将导致 BLA和NACSH1H之间的潜在钥匙情感电路的表征编码急性和慢性 伤害性信息。该提案的结果将有助于情感疼痛神经科学领域 了解健康和病理状态的神经回路功能。此外，这项研究可能会告知 未来对慢性疼痛负面情感症状的治疗方法的翻译研究。完成 这项奖学金将实现扩大沃吉克女士在系统中的技术专业知识的培训目标 神经科学并促进了她成为情感疼痛研究领先专家的职业目标。