Sympathetic control and hypertension via brainstem cannabinoid signaling

这项研究计划的总体目标是评估 调节心血管的延髓头端腹外侧环路中的内源性大麻素 功能。中枢神经系统直接参与动脉血压的调节， 主要通过交感神经系统对肾功能和血管系统的作用。RVLm是一种 中枢神经通路中的关键组成部分，因为交感前RVLM神经元从 多个脑区和脊髓，因此调节许多心血管反射。高血压 可能是由于交感血管运动神经元活性和抑制它的细胞之间的不平衡造成的。一个 交感神经系统活动的增加通常与RVLM神经元的去抑制有关； 然而，潜在的机制仍不清楚。ECB是一种内源性配体，具有广泛的 激活的心血管效应：(1)G蛋白偶联的大麻素1型受体(CB1R)，(2)短暂的 受体电位香草型1(TRPV1)，或(3)两者兼有，表明功能的二元性。我们的初步数据 证明TRPV1的激活也降低了交感前RVLM神经元的兴奋性 以ABP和肾交感神经活动(RSNA)为指标。此外，还发现了TRPV1表达神经元。 下丘脑外侧核(LH)和这些神经元投射到RVLM。我们的多学科方法将 利用大鼠在体肾神经和ABP记录在ECBS注入RVLM后，光遗传学 结合遥测ABP、荧光免疫染色和体外膜片钳 转基因小鼠已鉴定的交感前RVLM神经元突触电流的记录。我们将测试 交感前RVLM神经元接受TRPV1和CB1R表达抑制输入的假说 确定RVLM神经元的兴奋性，从而控制ABP。描述脑干的这些机制 ECB对于预测其对心血管功能的中枢控制的影响是必不可少的 激活TRPV1和/或CB1R。我们相信，我们的结果将具有临床意义，通过提供直接的 大麻素调节ABP的证据，并将有助于开发新的治疗方法 高血压的治疗策略。

The overall goal of this research proposal is to assess the physiological significance of the endocannabinoids (eCBs) in the rostral ventrolateral medulla (RVLM) circuits which regulate cardiovascular function. The central nervous system is directly involved in the regulation of arterial blood pressure (ABP), largely through actions of the sympathetic nervous system on renal function and vasculature. The RVLM is a critical component in the central neural pathway since presympathetic RVLM neurons receive inputs from multiple brain areas and from the spinal cord, and thus mediate many cardiovascular reflexes. Hypertension may result from an imbalance between sympathetic vasomotor neuron activity and those cells that inhibit it. An increase in sympathetic nervous system activity is often associated with disinhibition of RVLM neurons; however, the underlying mechanisms remain unidentified. eCBs are endogenous ligands with a broad range of cardiovascular effects which activate: (1) G protein-coupled cannabinoid type-1 receptor (CB1R), (2) transient receptor potential vanilloid type 1 (TRPV1), or (3) both, indicating a duality of function. Our preliminary data demonstrate that activation of TRPV1 decreases both the excitability of presympathetic RVLM neurons as well as ABP and renal sympathetic nerve activity (RSNA). In addition, TRPV1 expressing neurons were identified in the lateral hypothalamus (LH) and these neurons project to the RVLM. Our multi-disciplinary approaches will use in vivo renal nerve and ABP recordings in rats following eCBs administration into RVLM, optogenetics in combination with telemetry measurements of ABP, fluorescent immunostaining, and in vitro patch-clamp recordings of synaptic currents in identified presympathetic RVLM neurons of transgenic mice. We will test the hypothesis that presympathetic RVLM neurons receive TRPV1 and CB1R expressing inhibitory inputs which determine the excitability of RVLM neurons and thus control ABP. Delineating these mechanisms of brainstem eCBs is essential to predict their impact on the central control of cardiovascular function caused by the activation of TRPV1 and/or CB1R. We believe our results will have clinical significance by providing direct evidence about the regulation of ABP by cannabinoids and will allow the development of novel therapeutic strategies for the treatment of hypertension.