Functional Characterization of Parabrachial Circuits Processing Noxious Thermal Pain

臂旁回路处理有害热痛的功能特征

• 批准号: 9033665
• 负责人: Erica J Rodriguez
• 金额: $ 3.63万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9033665
• 关键词: Affective; Amygdaloid structure; Axon; Behavioral; Brain; Brain Stem; Brain region; Capsaicin; Chronic; Electrophysiology (science); Emotional; Emotions; Etiology; Exposure to; FOS gene; Face; Fiber; Fiber Optics; Foundations; Generations; Health; Heating; Homeostasis; Hypothalamic structure; Immediate-Early Genes; Implant; In Situ Hybridization; Injection of therapeutic agent; Knowledge; Label; Lateral; Lead; Limbic System; Medial; Methods; Molecular; Mus; Neural Pathways; Neurons; Neurotransmitters; Nociception; Opsin; Orofacial Pain; Output; Pain; Pathway interactions; Patients; Perception; Play; Probability; Process; Property; Proteins; Reflex action; Refractory; Research; Research Project Grants; Role; Sensory; Slice; Somatosensory Cortex; Spinal; Stimulus; Stream; Synapses; TRPV1 gene; Taste Perception; Techniques; Testing; Thalamic structure; Tomatoes; Trigeminal System; Visceral; Withdrawal; anatomical tracing; awake; chronic pain; coping; dorsal horn; experience; heat stimulus; innovation; insight; neural circuit; neurochemistry; new technology; novel; optogenetics; orofacial; pain behavior; pain inhibition; parabrachial nucleus; patch clamp; public health relevance; recombinase; relating to nervous system; response; sensory input; tool

 DESCRIPTION (provided by applicant): Pain is a subjective experience that arises from neural responses to noxious stimuli in multiple brain regions and has both discriminative and emotional components. Pain plays a crucial, protective role in preserving bodily homeostasis by triggering a reflex, such as withdrawal, to reduce exposure to harmful stimuli. However, pain processing can become abnormal, resulting in chronic pathological conditions. Pathological chronic pain is not only a physical ordeal, but also an emotional drain, and is refractory to currently available treatments. Thus, understanding the neural pathways that process the emotional, affective, and autonomous responses to painful stimuli is essential in forming the new foundations for understanding and treating pathological chronic pains. It is known that the emotional and affective pain pathway involves the parabrachial nucleus (PB) located in the brainstem, which is subdivided into two major divisions: lateral PB (PB-l) and medial PB (PB- m). Noxious information is relayed through PB to the limbic system to generate affective and autonomous responses. However, due to the lack of molecular tools, it had not been possible to study the precise connectivity and functions of different PB neurons activated by selected painful stimuli. In this proposal, I am using a highly innovative novel technology recently developed in our lab to investigate specifically the PB neural circuits involved in processing noxious thermal (orofacial-) pain in mouse. The hypothesis that I am going to test is: thermal nociceptive PB-l and PB-m neuronal ensembles are embedded in different sub-circuits, have different properties and different functions in regulating affective thermal (orofacial) pain perception. Specifically, using the novel technique, I will express fluorescent proteins or optogenetic tools in PB neurons activated by capsaicin, a surrogate for noxious heat stimulus. I will identify the axonal projection targets and certain inputs of thermal nociceptive PB-l and PB-m neurons. I will examine the neurochemical and electrophysiological properties as well as synaptic connectivity of capsaicin- activated PB neurons with slice electrophysiology. Finally, I will use optogenetic activation and inhibition to determine the functions of capsaicin-activated PB neurons in noxious heat pain perception using an operant orofacial pain behavior. These studies are expected to fill the knowledge gap of the PB neural pathways, and provide new insights into the circuit mechanism that process the emotional, affective, and autonomous responses to painful stimuli.

 描述（由申请人提供）：疼痛是一种主观体验，由多个脑区对有害刺激的神经反应引起，具有辨别和情感成分。疼痛通过触发反射（如退缩）来减少对有害刺激的暴露，在保持身体稳态方面起着至关重要的保护作用。然而，疼痛处理可能变得异常，导致慢性病理状况。病理性慢性疼痛不仅是一种身体上的折磨，也是一种情感上的消耗，并且是目前可用的治疗方法难以治愈的。因此，了解神经通路的过程中的情绪，情感和自主反应的疼痛刺激是必不可少的，在形成新的基础上理解和治疗病理性慢性疼痛。已知情绪和情感疼痛通路涉及位于脑干中的臂旁核（PB），其被细分为两个主要部分：外侧PB（PB-1）和内侧PB（PB- m）。认知信息通过PB传递到边缘系统，产生情感和自主反应。然而，由于缺乏分子工具，不可能研究由选定的疼痛刺激激活的不同PB神经元的精确连接和功能。在这个建议中，我使用了一个高度创新的新技术，最近在我们的实验室，专门研究PB神经回路参与处理有毒的热（orofacial-）疼痛的小鼠。我将要检验的假设是：热伤害感受性PB-1和PB-m神经元系综嵌入不同的子回路中，在调节情感性热（口面）疼痛感知中具有不同的性质和不同的功能。具体来说，使用新的技术，我将表达荧光蛋白或光遗传学工具在PB神经元激活辣椒素，替代有害的热刺激。我将确定轴突投射目标和热伤害感受PB-1和PB-m神经元的某些输入。本研究将利用切片电生理技术，探讨辣椒素活化PB神经元的神经化学、电生理特性及突触连接。最后，我将使用光遗传学激活和抑制来确定辣椒素激活的PB神经元在使用操作性口面疼痛行为的伤害性热疼痛感知中的功能。这些研究有望填补PB神经通路的知识空白，并为加工对疼痛刺激的情绪，情感和自主反应的回路机制提供新的见解。