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具有基本的保护功能，但某些病理上的 这些情况会导致衰弱的慢性疼痛和慢性瘙痒障碍，从而极大地损害生活质量。一个 更好地理解疼痛和瘙痒的神经机制对于更好地发展是必不可少的。 这些疾病的治疗选择。尽管我们对外周疼痛和瘙痒的认识最近取得了进展 分化，一些对人类的功能成像研究表明，大脑与 与疼痛和瘙痒活动相关的区域，引发了关于这些感觉模式是如何 在中枢神经系统(CNS)中独树一帜。目前，电路和细胞机制，通过它 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，这是整合负价信息的重要区域 以及驱动动机行为，以回应三叉神经疼痛或瘙痒刺激。鉴于截然不同的刻板印象 由疼痛和瘙痒感觉产生的行为，LHb可能在区分疼痛和瘙痒 很痒。或者，LHb可以处理与两种感觉相关联的共享厌恶信号。 然而，LHb作用于形成疼痛和瘙痒感觉的精确回路有 未定义。在拟议的工作中，我将确定LHb的发散或收敛的功能角色 三叉神经疼痛和瘙痒通路。在目标1中，我将确定三叉神经疼痛和瘙痒激活的LHb 通过比较已知分子标记在LHb中的共表达，将群体共享或分散。至 进一步确定这些种群之间的重叠或隔离程度，我将结合基因 捕捉激活的神经元和组织学技术直接比较疼痛和瘙痒的激活 相同的LHb。在目标2中，我将使用病毒跟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，并深入了解神经之间的差异和/或相似之处 调节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。具体地说，我将研究疼痛的动态活动--以及 用体内钙显像法激活瘙痒激活的LHb神经元。我也会测试这些LHB的要求 通过选择性地消融疼痛/瘙痒感觉和行为的人群。这样做的预期结果是什么 建议将提高我们对疼痛和瘙痒感觉是如何分散或收敛的理解 在中枢神经系统中处理。考虑到LHb的已知作用，我的工作可能会揭示对神经的新见解 调节疼痛和瘙痒的情感激励维度的回路。

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.