Dalton Cardiovascular Research Center, Department of Biomedical Sciences, University of Missouri, Columbia, Missouri 65211, USA.
J Neurosci. 2011 Aug 24;31(34):12318-29. doi: 10.1523/JNEUROSCI.0746-11.2011.
Brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, are highly expressed in the nucleus tractus solitarius (nTS), the principal target of cardiovascular primary afferent input to the brainstem. However, little is known about the role of BDNF signaling in nTS in cardiovascular homeostasis. We examined whether BDNF in nTS modulates cardiovascular function in vivo and regulates synaptic and/or neuronal activity in isolated brainstem slices. Microinjection of BDNF into the rat medial nTS (mnTS), a region critical for baroreflex control of sympathetic outflow, produced dose-dependent increases in mean arterial pressure (MAP), heart rate (HR), and lumbar sympathetic nerve activity (LSNA) that were blocked by the tyrosine kinase inhibitor K252a. In contrast, immunoneutralization of endogenous BDNF (anti-BDNF), or microinjection of K252a alone, decreased MAP, HR, and LSNA. The effects of anti-BDNF were abolished by blockade of ionotropic glutamate receptors, indicating a role for glutamate signaling in the response to BDNF. In vitro, BDNF reduced the amplitude of miniature EPSCs as well as solitary tract (TS) evoked EPSC amplitude and action potential discharge (APD) in second-order nTS neurons. BDNF effects on EPSCs were independent of GABAergic signaling and abolished by AMPA receptor blockade. In contrast, K252a increased spontaneous EPSC frequency and TS evoked EPSC amplitude. BDNF also attenuated APD evoked by injection of depolarizing current into second-order neurons, indicating reduced intrinsic neuronal excitability. Our data demonstrate that BDNF signaling in mnTS plays a tonic role in regulating cardiovascular function, likely via modulation of primary afferent glutamatergic excitatory transmission and neural activity.
脑源性神经营养因子（BDNF）及其受体 TrkB 在孤束核（nTS）中高度表达，孤束核是心血管初级传入输入脑干的主要靶点。然而，BDNF 信号在 nTS 中对心血管稳态的作用知之甚少。我们研究了 nTS 中的 BDNF 是否调节体内心血管功能，并调节离体脑片的突触和/或神经元活动。BDNF 微注射到大鼠内侧 nTS（mnTS），这是控制交感神经传出的压力反射的关键区域，导致平均动脉压（MAP）、心率（HR）和腰交感神经活动（LSNA）的剂量依赖性增加，这些增加被酪氨酸激酶抑制剂 K252a 阻断。相比之下，内源性 BDNF 的免疫中和（抗 BDNF）或单独微注射 K252a 降低了 MAP、HR 和 LSNA。抗 BDNF 的作用被离子型谷氨酸受体阻断剂所消除，表明谷氨酸信号在对 BDNF 的反应中起作用。在体外，BDNF 减少了第二级 nTS 神经元中小型 EPSC 的幅度以及孤束（TS）诱发的 EPSC 幅度和动作电位放电（APD）。BDNF 对 EPSC 的影响与 GABA 能信号无关，并且被 AMPA 受体阻断所消除。相比之下，K252a 增加了自发性 EPSC 频率和 TS 诱发的 EPSC 幅度。BDNF 还减弱了第二级神经元中注入去极化电流诱发的 APD，表明内在神经元兴奋性降低。我们的数据表明，mnTS 中的 BDNF 信号在调节心血管功能方面发挥着紧张作用，可能通过调节初级传入谷氨酸能兴奋性传递和神经活动来实现。
