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

基本信息

批准号：
10515854
负责人：
Suna Li
金额：
$ 2.63万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-11-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10515854
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 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 Nociceptors 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 chronic pain management 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

项目摘要

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.

项目摘要尽管急性疼痛和急性瘙痒感觉具有必不可少的保护功能，但某些病理疾病会导致衰弱的慢性疼痛和慢性瘙痒症，从而极大地损害了生活质量。一个更好地了解疼痛和瘙痒的神经机制对于更好地发展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步分化，人类的一些功能成像研究显示了大脑之间的显着重叠与疼痛和瘙痒活动相关的区域，提出有关这些感觉方式的问题在中枢神经系统（CNS）中区分。目前，电路和细胞机制在中枢神经系统中，疼痛和瘙痒在中枢神经系统中的处理方式相似或不同。我的初步结果显示外侧Habenula（LHB）的强激活，该区域对于整合负价信息很重要并驱动动机行为，以应对三叉神经疼痛或瘙痒刺激。鉴于独特的刻板印象疼痛和瘙痒感产生的行为，LHB可能在区分疼痛和痒。另外，LHB可能会处理与两种感觉相关的共享厌恶信号。然而，LHB功能塑造疼痛和瘙痒感的精确电路具有未定义。在拟议的工作中，我将确定LHB的发散或收敛功能在三叉神经疼痛和瘙痒途径中。在AIM 1中，我将确定三叉神经疼痛和瘙痒激活的LHB是否通过比较LHB中已知分子标记的共表达，种群共享或分歧。到进一步确定这些人群之间重叠或隔离的程度，我将结合遗传捕获活化的神经元和组织学技术，以直接比较疼痛和瘙痒激活同样的LHB。在AIM 2中，我将使用病毒追踪来确定突触前的输入和下游投影疼痛和瘙痒激活的LHB神经元，并深入了解神经之间的差异和/或相似之处介导疼痛和瘙痒感觉的途径。最后，在AIM 3中，我将确定LHB在介导疼痛和瘙痒感/行为。具体而言，我将研究疼痛和疼痛的动态活性瘙痒激活的LHB神经元通过体内钙成像。我还将测试这些LHB的要求通过选择性地消灭疼痛/瘙痒感和行为的种群。预期结果提案将提高我们对疼痛和瘙痒感觉如何发散或收敛的理解在中枢神经系统中处理。鉴于LHB的已知作用，我的工作可能揭示了对神经的新见解电路介导疼痛和瘙痒的情感动机维度。