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

项目摘要 每年用于慢性疼痛的国家医疗费用在5600亿到6350亿美元之间， 这比癌症、糖尿病和心血管疾病的总成本还要高。慢性疼痛患者 生活质量较低，患者经常患有精神健康的共病， 精神障碍和药物滥用问题。尽管这是一个重大的健康问题， 潜在的慢性疼痛状况尚未完全确定。最近，中央杏仁核（CeA） 已被确定为疼痛调节的重要中心，通过以下方式对疼痛感知具有双重功能： 两个单独细胞群的活性：表达促痛（疼痛感受）蛋白激酶C δ 细胞（CeA-PKCδ+）和抗伤害感受性生长抑素表达细胞。本研究提案的目的是 通过研究突触连接性进一步了解这些发现背后的电路机制 CeA-PKCδ+细胞原伤害感受功能的改变。这一提议的核心假设是， 选择性加强CeA-PKCδ+神经元的伤害性传入是行为超敏反应的基础 受伤后。已知伤害性信息通过从小脑顶发出的投射传递到CeA。 外侧臂旁核（LPB），一个对疼痛相关信息处理至关重要的脑桥结构。因此，我们认为， 该提案将测试LPB对CeA通路的损伤相关增强作用是否对CeA-PKCδ+具有特异性 神经元，这种增强是否驱动疼痛相关的行为超敏反应，以及这种增强是否 是损伤诱导的行为超敏反应所必需的在目标1中，初步数据显示， 将进一步研究CeA-PKCδ+神经元上兴奋性突触传递的增强， 使用离体光遗传学辅助电路映射剖析兴奋性LPB输入的功能。在目标2中， 在自由行为动物中，LPB至CeA通路在CeA-PKCδ+神经元方面的体内动力学 将建立活动和疼痛相关的行为超敏反应。此外，目标3的目标是 建立LPB与CeA通路功能、疼痛相关行为和CeA-PKCδ+细胞之间的因果关系 神经元激活目标1的实验将为受训者提供机会，以提高他目前的经验。 活体电生理技能目标2和目标3的实验将为受训者提供机会， 尖端体内神经回路工具的培训，以完成拟议的实验，并解决 生物学问题在这些目标。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，这可能最终导致更好的识别 为患有慢性疼痛病症的个体提供治疗选择。

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.