Cellular and circuit mechanisms enabling oxytocinergic control of pain defense

项目摘要 神经递质催产素（OXT）因其社会和生殖作用而闻名，但也获得了 增加注意力作为对疼痛的神经反应的内源性调节剂。暴露于伤害性刺激 激活哺乳动物中神经内分泌和中枢投射的OXT产生神经元 下丘脑，这两个群体已被证明发挥镇痛作用。此外，中央- 投射组通过梨状核的靶点影响疼痛相关行为，如恐惧条件反射 大脑皮层和杏仁核虽然这些细胞抑制急性感知和长期记忆的能力 疼痛的经验，使他们高度相关的疼痛障碍，创伤后的临床治疗， 压力和其他条件下，对细胞和电路机制知之甚少， 下丘脑OXT神经元影响疼痛处理，或者更一般地说，它们如何影响其他疼痛- 相关现象。 该项目将利用斑马鱼幼鱼提供的实验杠杆来研究 OXT神经元增强感觉运动回路对疼痛刺激的敏感性， 行为。我们的中心模型是刺激强度是由OXT亚群中的分级活动编码的 投射到脊髓投射神经元（spinal projection neurons，SPNs）上并通过分化的神经元激活或敏化脊髓投射神经元， OXT和谷氨酸的释放。我们将通过使用钙成像， 光遗传学、电生理学和行为学，以：（1）确定OXT神经元的亚群是否 疼痛激活的神经元包括投射到SPNs上的细胞，以及这些神经元是否特异性介导 OXT对防御行为的影响;（2）量化OXT和共同传播的个体贡献 谷氨酸对伤害性经验过程中SPN激活和行为敏化的影响;（3）确定是否 谷氨酸和OXT释放与尖峰频率的差异偶联使OXT神经元能够从 在高刺激强度下，从简单的兴奋性活动模式转变为更强的调节性活动模式。这些 实验将显示催产素能神经元的基本细胞和电路特性如何塑造 在脊椎动物模型中对疼痛的行为反应。

Project Summary The neurotransmitter oxytocin (OXT) is well known for its social and reproductive roles, but has also gained increasing attention as an endogenous regulator of the neural response to pain. Exposure to noxious stimuli activates both neuroendocrine and centrally-projecting OXT-producing neurons in the mammalian hypothalamus, and both populations have been shown to exert analgesic effects. Additionally, the centrally- projecting group influences pain-related behaviors such as fear conditioning through targets in the piriform cortex and the amygdala. While the ability of these cells to dampen the acute perception and long-term memory of painful experience makes them highly relevant to the clinical treatment of pain disorders, post-traumatic stress, and other conditions, very little is known about the cellular and circuit mechanisms by which hypothalamic OXT neurons influence pain processing, or more generally how they might affect other pain- related phenomena. This project will exploit the experimental leverage offered by the larval zebrafish to investigate the means by which OXT neurons enhance the sensitivity of a sensorimotor circuit to painful stimuli and promote defensive behaviors. Our central model is that stimulus intensity is encoded by graded activity in a subpopulation of OXT neurons which project onto and activate or sensitize spinal projection neurons (SPNs) through the differential release of OXT and glutamate. We will test this hypothesis by using a combination of calcium imaging, optogenetics, electrophysiology, and behavior to: (1) Determine whether the subpopulation of OXT neurons activated by pain includes cells that project onto the SPNs, and whether those neurons specifically mediate OXT’s effects on defensive behavior; (2) Quantify the individual contributions of OXT and co-transmitted glutamate to SPN activation and behavioral sensitization during noxious experience; (3) Determine whether differential coupling of glutamate and OXT release to spike frequency enables the OXT neurons to switch from a simple, excitatory mode of activity to a stronger, modulatory mode at high stimulus intensities. These experiments will show how the basic cellular and circuit properties of oxytocinergic neurons shape the behavioral response to pain in a vertebrate model.