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

项目摘要 虽然急性疼痛和急性瘙痒感具有重要的保护功能，但某些病理性的疼痛和瘙痒感可能会导致严重的疼痛。 这些病症可导致使人衰弱的慢性疼痛和慢性瘙痒病症，从而极大地损害生活质量。一 更好地理解疼痛和瘙痒的神经机制对于开发更好的 这些疾病的治疗选择。尽管我们对周围疼痛和瘙痒的认识有了新的进展 分化，在人类中的一些功能成像研究已经显示出大脑之间的显著重叠 与疼痛和瘙痒活动相关的区域，提出了关于这些感觉方式如何 在中枢神经系统（CNS）中有区别。目前，神经系统和细胞机制， 疼痛和瘙痒在中枢神经系统中是相似还是不同的过程仍不清楚。我的初步结果显示 外侧缰核（LHb）的强烈激活，这是一个整合负价信息的重要区域 以及对三叉神经疼痛或瘙痒刺激做出反应而驱动动机性行为。鉴于不同的刻板印象 LHb可能在区分疼痛和瘙痒的过程中起重要作用， 发痒.或者，LHb可以处理与两种感觉相关联的共享厌恶信号。 尽管如此，LHb发挥作用以形成疼痛和瘙痒感觉体验的精确回路， 没有被定义。在拟议的工作中，我将确定LHb的发散或收敛功能作用 三叉神经疼痛和瘙痒的通路。在目标1中，我将确定三叉神经痛和瘙痒激活的LHb是否 通过比较已知分子标记在LHb中的共表达来确定群体是共享的还是不同的。到 为了进一步确定这些种群之间的重叠或分离程度，我将联合收割机的遗传 捕获激活的神经元和组织学技术，直接比较疼痛和瘙痒的激活， 同样的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投射。 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。 传递疼痛和瘙痒感觉的通路。最后，在目标3中，我将确定LHb在以下方面的功能作用： 介导疼痛和瘙痒感觉/行为。具体来说，我将研究疼痛的动态活动， 瘙痒激活的LHb神经元通过使用体内钙成像。我也将测试这些LHb的要求 通过选择性地消融疼痛/瘙痒的感觉和行为。预期的结果是， 这项提案将提高我们对疼痛和瘙痒感觉是如何发散或收敛的理解 在CNS中处理。鉴于LHb的已知作用，我的工作可能会揭示神经系统的新见解。 调节疼痛和瘙痒的情感-动机维度的回路。

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.