Function of the Parabrachial Nucleus to Central Amydala Pathway in Pain-Related Plasticity

项目总结 每年用于慢性疼痛的全国医疗费用在5600亿至6350亿美元之间， 这比癌症、糖尿病和心血管疾病的总和还要高。慢性疼痛患者 生活质量较低，患者频繁合并心理健康更是雪上加霜 精神障碍和药物滥用问题。尽管这是一个重大的健康问题，但生物机制 潜在的慢性疼痛状况尚未完全确定。最近，中央杏仁核(CEA) 已经被认为是痛觉调制的重要中枢，通过 两种不同细胞群的活性：促进疼痛(伤害性)蛋白激酶C增量表达 细胞(CEA-PKCδ+)和表达生长抑素的抗伤害性细胞。这项研究提案的目的是 通过研究突触连接来进一步了解这些发现背后的电路机制 CEA-PKCδ+细胞致痛功能的变化。这项提议的中心假设是 选择性增强CEA-PKCδ+神经元的伤害性传入是行为超敏反应的基础 在受伤之后。已知伤害性信息通过从 臂旁外侧核(LPB)是一种对疼痛相关信息处理至关重要的桥脑结构。因此， 这项建议将测试LpB到CEA途径的损伤相关增强是否是CEA-PKCδ+所特有的 神经元，这种增强是否驱动疼痛相关的行为过敏，以及这种增强是否 对于损伤诱导的行为过敏来说是必要的。在目标1中，初步数据显示伤害导致 兴奋性突触传递对CEA-PKCδ+神经元的增强作用将进一步研究 使用体外光遗传学辅助的电路标测来解剖兴奋性LPB输入的功能。在目标2中， 从CEA-PKCδ+神经元看自由活动动物体内LpB-CEA通路的动态变化 活动和疼痛相关的行为过敏症将被确立。此外，目标3的目标是 LPB与癌胚抗原途径功能、疼痛相关行为和癌胚抗原-蛋白激酶Cδ+细胞之间的因果联系 神经元激活。目标1的实验将为受训者提供改善其现有经验的机会 活体电生理技能。AIMS 2和AIMS 3的实验将为学员提供获得 对体内尖端神经回路工具进行培训，以完成拟议的实验并解决 这些目标中的生物学问题。从拟议的研究中获得的结果将扩大我们的 了解大脑如何调节疼痛，这最终可能导致识别更好的 为患有慢性疼痛的个人提供治疗选择。

PROJECT SUMMARY The annual national health cost for chronic pain conditions ranges between 560 to 635 billion dollars, which is higher than the combined costs for cancer, diabetes, and cardiovascular diseases. Chronic pain patients live with a lower quality of life that is further aggravated by patients’ frequent comorbidities with mental health disorders and substance abuse problems. Despite being a significant health concern, the biological mechanisms underlying chronic pain conditions have not been completely identified. Recently, the central amygdala (CeA) has been identified as an important center for pain modulation, with a dual function on pain perception through the activity of two separate cell populations: pain-promoting (pronociceptive) protein kinase c delta-expressing cells (CeA-PKCδ+) and antinociceptive somatostatin-expressing cells. The purpose of this research proposal is to further understand the circuit mechanisms underlying those findings by studying the synaptic connectivity changes behind CeA-PKCδ+ cells pronociceptive function. The central hypothesis of this proposal is that selective strengthening of nociceptive inputs to CeA-PKCδ+ neurons underlies behavioral hypersensitivity following injury. It is known that nociceptive information is conveyed to the CeA by projections sent from the lateral parabrachial nucleus (LPB), a pontine structure critical for pain-related information processing. Therefore, this proposal will test whether injury-related potentiation of the LPB to CeA pathway is specific to CeA-PKCδ+ neurons, whether this potentiation drives pain-related behavioral hypersensitivity, and whether this potentiation is necessary for injury-induced behavioral hypersensitivity. In Aim 1, the preliminary data showing injury-induced potentiation of excitatory synaptic transmission onto CeA-PKCδ+ neurons will be further investigated by dissecting the function of excitatory LPB inputs using ex vivo optogenetically-assisted circuit mapping. In Aim 2, the in vivo dynamics of the LPB to CeA pathway in freely behaving animals in terms of CeA-PKCδ+ neuronal activity and pain-related behavioral hypersensitivity will be established. Furthermore, the goal in Aim 3 is to establish a causal link between LPB to CeA pathway function, pain-related behaviors, and CeA-PKCδ+ cells neuronal activation. The experiments of Aim 1 will provide the trainee the opportunity to improve his current ex vivo electrophysiological skills. The experiments of Aims 2 and 3 will provide the trainee the opportunity to receive training in cutting-edge in vivo neurocircuitry tools to complete the experiments proposed and to address the biological questions in these aims. The findings obtained from the proposed research will expand our understanding of how the brain modulates pain, which might ultimately lead to the identification of better treatment options for individuals suffering from chronic pain conditions.