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

基本信息

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
项目类别：
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

项目摘要

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面影响情感症状。目前可用的疼痛治疗方法不足以安全有效地缓解这两种情况慢性疼痛的感觉和情感特征，部分原因是它们缺乏调节不同的特异性神经细胞类型和过程。虽然诊断成像工具已将情感不愉快与慢性疼痛伴有广泛脑区功能障碍，例如基底外侧杏仁核 (BLA) 和核伏隔核 (NAc) - 它们缺乏特异性来识别可能构成此现象的个体功能细胞类型适应不良的可塑性。识别和针对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伤害性传输的动态从急性疼痛转变为慢性疼痛。该项目的研究目标是从功能上表征伤害性 BLA 至 NAc 回路，导致急性和慢性的负面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为内部和外部感官信息分配价的过程。 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疾病中对有害刺激的情感动机反应。慢性伤害性状态。 BLA 神经元将长距离轴突发送到许多下游目标，包括 NAc、对于驱动食欲和厌恶行为很重要的纹状体结构。初步数据表明 BLAnoci 神经元投射到“边缘”NAc Shell 亚区 (NAcSh)。此外，还有一组神经元高度对 NAcSh（“内角”；NAcSh1H）内的有害刺激做出反应，一束 BLAnoci 轴突强烈反应支配。然而，尚不清楚 BLAnoci 神经元是否将情感伤害信息传递给 NAcSh1H NAcSh1H 神经元是否对于驱动伤害感受相关的负面情感动机行为至关重要。目标 1 将使用以下方法对急性和慢性伤害感受状态下的 BLA"0 ci 至 NAcSh1H 电路进行功能表征清醒行为受试者体内 BLAnoci 轴突末端的体内钙成像和光遗传学激活。目标2 将使用钙成像对急性和慢性伤害感受状态下的 NAcSh1H 神经元活动进行成像和操纵 NAcSh1H 神经活动的光遗传学操作。完成这些拟议目标将导致编码急性和慢性的 BLA 和 NAcSh1H 之间潜在关键情感回路的表征伤害性信息。该提案的成果将更好地帮助情感疼痛神经科学领域了解健康和病理状态下的神经回路功能。此外，这项研究可能会告知未来对慢性疼痛负面情感症状治疗的转化研究。完成该奖学金的金额将实现扩大 Wojick 女士在系统方面的技术专业知识的培训目标神经科学，并促进她成为情感疼痛研究领域领先专家的职业目标。