The role of the lateral habenula in central pain and itch processing

外侧缰核在中枢疼痛和瘙痒处理中的作用

• 批准号: 9906547
• 负责人: Suna Li
• 金额: $ 4.58万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2021-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906547
• 关键词: Acute; Acute Pain; Affective; American; Anatomy; Animals; Anxiety; Automobile Driving; Basal Ganglia; Behavior; Behavioral; Brain; Brain Stem; Brain region; Calcium; Cheek structure; Chemicals; Code; Communication; Data; Dimensions; Diphtheria Toxin; Disease; Dissection; Esthesia; Expression Profiling; FOS gene; Fiber; Fluorescent in Situ Hybridization; Functional Imaging; Generations; Genetic; Genetic Recombination; Habenula; Histological Techniques; Human; Immunohistochemistry; Impairment; Injections; Knowledge; Label; Lateral; Lead; Light; Link; Maps; Mediating; Modality; Modeling; Molecular; Motivation; Mus; Negative Valence; Neural Pathways; Neuraxis; Neurons; Nociception; Pain; Pathologic; Pathway interactions; Peripheral; Photometry; Physiological; Play; Population; Positioning Attribute; Process; Prosencephalon; Pruritus; Quality of life; Rabies virus; Rewards; Role; Sensory; Shapes; Signal Transduction; Stereotyped Behavior; Stereotyping; Stimulus; Testing; Therapeutic; Trigeminal Pain; Viral; Work; adeno-associated viral vector; behavioral response; central pain; chronic itch; chronic pain; effective therapy; experience; experimental study; imaging study; improved; in vivo; in vivo calcium imaging; information processing; insight; molecular marker; motivated behavior; neural circuit; neuromechanism; novel; novel therapeutics; pain sensation; peripheral pain; presynaptic; response; reward processing; segregation; sensory stimulus; stressor

Project Summary Although acute pain and acute itch sensations serve essential protective functions, certain pathological conditions can lead to debilitating chronic pain and chronic itch disorders that greatly impair quality of life. A better understanding of the neural mechanisms underlying pain and itch is essential for developing better therapeutic options for these disorders. Despite recent advances in our knowledge of peripheral pain and itch differentiation, a few functional imaging studies in humans have shown significant overlap between brain regions associated with pain and itch activity, raising questions as to how these sensory modalities are distinguished in the central nervous system (CNS). At present, the circuitry and cellular mechanisms by which pain and itch are similarly or differently processed in the CNS remain unclear. My preliminary results show strong activation of the lateral habenula (LHb), a region important for integrating negative valence information and driving motivated behaviors, in response to trigeminal pain or itch stimuli. Given the distinct stereotyped behaviors produced by pain and itch sensation, the LHb may play an important role in differentiating pain and itch. Alternatively, the LHb may process shared aversive signals associated with both sensations. Nevertheless, the precise circuits in which the LHb functions to shape pain and itch sensory experiences have not been defined. In the proposed work, I will determine the divergent or convergent functional role of the LHb in trigeminal pain and itch pathways. In Aim 1, I will determine whether trigeminal pain- and itch-activated LHb populations are shared or divergent by comparing co-expression of known molecular markers in the LHb. To further establish the extent of overlap or segregation between these populations, I will combine genetic trapping of activated neurons and histological techniques to directly compare pain and itch activation in the same LHb. In Aim 2, I will use viral tracing to determine the presynaptic inputs and downstream projections of pain- and itch-activated LHb neurons, and gain insight into the differences and/or similarities between neural pathways mediating pain and itch sensations. Lastly, in Aim 3, I will determine the functional role of the LHb in mediating pain and itch sensations/behaviors. Specifically, I will investigate the dynamic activity of pain- and itch-activated LHb neurons by using in vivo calcium imaging. I will also test the requirement of these LHb populations for pain/itch sensation and behavior by selectively ablating them. The anticipated results of this proposal will improve our understanding about how pain and itch sensations are divergently or convergently processed in the CNS. Given the known role of the LHb, my work may reveal novel insight into the neural circuits mediating the affective-motivational dimensions of pain and itch.

项目概要 尽管急性疼痛和急性瘙痒感具有基本的保护功能，但某些病理性 这些病症会导致使人衰弱的慢性疼痛和慢性瘙痒症，从而极大地损害生活质量。一个 更好地了解疼痛和瘙痒背后的神经机制对于更好地发育至关重要 这些疾病的治疗选择。尽管我们对周围疼痛和瘙痒的了解最近取得了进展 分化，一些人类功能成像研究表明大脑之间存在显着重叠 与疼痛和瘙痒活动相关的区域，提出了这些感觉方式如何发生的问题 在中枢神经系统（CNS）中表现突出。目前，其电路和细胞机制 疼痛和瘙痒在中枢神经系统中的处理方式相似或不同，目前尚不清楚。我的初步结果显示 外侧缰核 (LHb) 的强烈激活，该区域对于整合负价信息非常重要 并驱动动机行为，以应对三叉神经疼痛或瘙痒刺激。鉴于鲜明的刻板印象 由于疼痛和瘙痒感产生的行为，LHb 可能在区分疼痛和瘙痒感方面发挥重要作用。 痒。或者，LHb 可以处理与两种感觉相关的共享厌恶信号。 然而，LHb 塑造疼痛和瘙痒感觉体验的精确回路已经被证实。 没有被定义。在拟议的工作中，我将确定 LHb 的发散或聚合功能作用 在三叉神经疼痛和瘙痒通路中。在目标 1 中，我将确定三叉神经疼痛和瘙痒是否激活 LHb 通过比较 LHb 中已知分子标记的共表达，可以看出群体是共享的还是不同的。到 为了进一步确定这些人群之间重叠或隔离的程度，我将结合遗传 捕获激活的神经元和组织学技术来直接比较疼痛和瘙痒的激活 相同的 LHb。在目标 2 中，我将使用病毒追踪来确定突触前输入和下游预测 疼痛和瘙痒激活的 LHb 神经元，并深入了解神经元之间的差异和/或相似之处 介导疼痛和瘙痒感觉的通路。最后，在目标 3 中，我将确定 LHb 在 调节疼痛和瘙痒的感觉/行为。具体来说，我将研究疼痛和疼痛的动态活动 通过体内钙成像激活痒激活的 LHb 神经元。我也会测试这些LHb的要求 通过选择性消融来改变人群的疼痛/瘙痒感觉和行为。本次活动的预期结果 该提案将提高我们对疼痛和瘙痒感如何发散或聚合的理解 在中枢神经系统中处理。鉴于 LHb 的已知作用，我的工作可能会揭示对神经网络的新见解 介导疼痛和瘙痒的情感动机维度的回路。