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广为人知，但也获得了 作为神经对疼痛反应的内源性调节器，越来越多的关注。接触有害刺激 激活哺乳动物的神经内分泌和中枢投射产生OXT的神经元 下丘脑，这两个群体都已被证明具有止痛作用。此外，中央- 投射群通过梨状核的靶点影响疼痛相关行为，如恐惧条件反射 皮质和杏仁核。而这些细胞抑制敏锐感知和长期记忆的能力 痛苦经历使其与创伤后疼痛障碍的临床治疗高度相关 压力和其他条件，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，或者更广泛地说，它们可能如何影响其他疼痛- 相关现象。 这个项目将利用斑马鱼幼体提供的实验杠杆，通过 哪些OXT神经元增强感觉运动回路对疼痛刺激的敏感性并促进防御 行为。我们的中心模型是，刺激强度由OXT亚群中的分级活动编码 投射到脊髓投射神经元上的神经元，通过分化激活或敏化脊髓投射神经元。 释放牛磺酸和谷氨酸。我们将通过结合使用钙成像来验证这一假设， 光遗传学、电生理学和行为学：(1)确定OXT神经元的亚群 由疼痛激活的包括投射到SPN的细胞，以及这些神经元是否特定地介导 OXT对防御行为的影响；(2)量化OXT和共传播的个体贡献 谷氨酸对SPN激活和行为敏化的影响；(3)确定 谷氨酸和OXT释放与尖峰频率的不同耦合使OXT神经元从 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模式。这些 实验将展示催产素能神经元的基本细胞和电路特性如何塑造 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.