Glucocorticoids and endocannabinoids in vagal complex

这项研究拨款计划中的实验将确定细胞和突触的影响 内源性大麻素(ECB)配体和糖皮质激素诱导的背侧运动中ECB的释放 迷走神经核(DMV)。DMV中的神经元调节着对大多数 因此严格控制摄食、消化、葡萄糖和胰岛素的分泌， 和其他新陈代谢功能。它们的活动在很大程度上是由DMV的突触输入控制的，这是 受当地释放的化学物质和循环荷尔蒙的调节。中枢神经系统对DMV神经元的调节 大麻素、香草素和糖皮质激素已被提出；当集中应用时，这些 化合物能深刻改变副交感神经的功能。几个欧洲央行的配体，被认为是 从细胞膜逆行释放，激活两个大麻素1型受体(CB1R) 和瞬时受体电位香草型1(TRPV1)。在车管所，TRPV1的激活增强 神经递质释放，而CB1R倾向于抑制突触。这两种效果都是通过激活 突触前终末上的受体。初步证据表明，欧洲央行的配体从 DMV神经元，糖皮质激素或去极化可以诱导这种释放。因此，欧洲央行在欧洲央行的活动 DMV可能同时调节TRPV1和CB1R的活性。无论是欧洲央行公布的配体类型(S)， 大多数ECB配体对突触活性的影响，也不是DMV中ECB释放的触发或机制 都是已知的。我们将使用脑干切片中DMV神经元的全细胞膜片钳记录来 确定ECB配体对DMV中细胞活动的影响，并将确定释放的化合物 由该地区的细胞使用药理和生化方法。这些实验将由以下人员指导 三个具体目标：1)区分ECB配体对DMV中CB1R和TRPV1的影响；2)确定 欧洲央行参与调节糖皮质激素对DMV局部回路的快速影响；以及3) 确定糖皮质激素效应的细胞途径。我们将测试ECB改变的假设 在特定和可预测的空间、时间、功能相关的DMV中的TRPV1和CBR1活动， 和活性依赖模式，糖皮质激素通过作用于 DMV神经元上的膜结合G蛋白偶联受体。基于欧洲央行系统的药品有 被研究用于治疗各种神经系统病理，包括疾病 与进食、消化和肥胖有关。在某些系统中释放ECB的糖皮质激素是 被广泛处方，也可以通过压力刺激释放。这些研究的结果将对 预测和了解这些化合物如何相互作用并影响副交感神经 功能。可能的转换好处也存在，因为控制欧洲央行的水平 糖皮质激素升高患者的迷走神经系统。

The experiments in this research grant proposal will identify the cellular and synaptic effects of endogenous cannabinoid (eCB) ligands and of glucocorticoid-induced release of eCBs in the dorsal motor nucleus of the vagus (DMV). Neurons in the DMV regulate parasympathetic output to most of the subdiaphragmatic viscera and therefore critically control feeding, digestion, glucose and insulin secretion, and other metabolic functions. Their activity is largely controlled by synaptic input to the DMV, which is modulated by locally released chemicals and circulating hormones. Regulation of DMV neurons by cannabinoids, vanilloids, and glucocorticoids has been suggested; when applied centrally these compounds profoundly alter parasympathetic function. Several eCB ligands, which are thought to be released from cell membranes in a retrograde fashion, activate both cannabinoid type 1 receptors (CB1R) and transient receptor potential vanilloid type 1 (TRPV1). In the DMV, activation of TRPV1 enhances neurotransmitter release, whereas CB1R tends to inhibit synapses. Both effects occur by activation of receptors on presynaptic terminals. Preliminary evidence suggests that eCB ligands are released from DMV neurons, and that glucocorticoids or depolarization can induce this release. Thus, eCB activity in the DMV may modulate both TRPV1 and CB1R activity. Neither the type(s) of eCB ligands released, the effects of most eCB ligands on synaptic activity, nor the trigger or mechanism of eCB release in the DMV are known. We will use whole-cell patch-clamp recordings from DMV neurons in brainstem slices to identify effects of eCB ligands on cellular activity in the DMV, and will also identify the compounds released by cells in the area using pharmacological and biochemical methods. The experiments will be guided by three specific aims: 1) Differentiate effects of eCB ligands on CB1R and TRPV1 in the DMV; 2) Determine the eCB involvement in mediating rapid effects of glucocorticoids on local circuitry in the DMV; and 3) Identify the cellular pathway of the glucocorticoid effect. We will test the hypotheses that eCBs alter TRPV1 and CBR1 activity in the DMV in specific and predictable spatial, temporal, functionally relevant, and activity-dependent patterns, and that glucocorticoids induce eCB release from DMV cells by acting at membrane-bound G protein-coupled receptors on DMV neurons. Drugs based on the eCB system are being investigated for therapeutic use in a variety of nervous system pathologies, including disorders related to feeding, digestion, and obesity. Glucocorticoids, which release eCBs in some systems, are widely prescribed, and are also released by stressful stimuli. Results of these studies will be critical to predicting and understanding how these compounds interact with each other and affect parasympathetic function. Possible translational benefits also exist because of the benefit in controlling eCB levels in the vagal system of patients with elevated glucocorticoids.