BDNF shifts excitatory-inhibitory balance in the paraventricular nucleus of the hypothalamus to elevate blood pressure.
BDNF shifts excitatory-inhibitory balance in the paraventricular nucleus of the hypothalamus to elevate blood pressure.
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BDNF 改变下丘脑室旁核的兴奋-抑制平衡，从而升高血压。
DOI：
10.1152/jn.00247.2021
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发表时间：
2021
影响因子：
2.5
通讯作者：
Erdos,Benedek
中科院分区：
文献类型：
--
作者：
Thorsdottir,Daniella;Einwag,Zachary;Erdos,Benedek
下丘脑室旁核（PVN）内的前交感神经元在心血管调节中起着重要作用。我们以前已经表明，脑源性神经营养因子（BDNF），在PVN中起作用，增加交感神经活动和血压，并作为应激诱导的高血压反应的关键调节因子。已知BDNF在中枢神经系统中广泛改变谷氨酸能和GABA能信号，但BDNF在PVN中是否具有类似的作用仍有待研究。在此，我们验证了PVN中BDNF表达增加通过增强N-甲基-d-天冬氨酸（NMDA）受体（NMDAR）和抑制GABA A受体（GABAAR）介导的信号传导而升高血压的假设。Sprague-Dawley大鼠接受表达绿色荧光蛋白（GFP）或BDNF的AAV 2病毒载体的双侧PVN注射。3周后，在α-氯醛糖-乌拉坦麻醉下记录PVN注射NMDAR和GABAAR激动剂和拮抗剂的心血管反应。此外，使用免疫荧光法评估PVN中兴奋性和抑制性信号成分的表达。我们的研究结果表明，NMDAR抑制导致BDNF组与GFP组相比血压降低更大，而GABAAR抑制导致GFP组与BDNF组相比血压升高更大。相反，GABAAR激活降低血压显着更多的GFP与BDNF大鼠。此外，室旁核中BDNF过表达上调了NMDAR 1的免疫反应性，同时下调了GABAAR-α1和K+/Cl−协同转运蛋白2。总之，我们的研究结果表明，BDNF在PVN内的高血压作用是介导的，至少部分是通过增加NMDAR和减少GABAAR信号传导。新的和值得注意的是，我们已经表明，BDNF，在PVN中发挥作用，部分通过增加NMDA受体介导的兴奋性输入和减少GABAAR受体介导的抑制性输入PVN神经元来升高血压。此外，我们证明，BDNF在PVN表达上调NMDA受体免疫反应性和下调GABAA受体以及KCC 2转运蛋白免疫反应性。
Presympathetic neurons in the paraventricular nucleus of the hypothalamus (PVN) play a key role in cardiovascular regulation. We have previously shown that brain-derived neurotrophic factor (BDNF), acting in the PVN, increases sympathetic activity and blood pressure and serves as a key regulator of stress-induced hypertensive responses. BDNF is known to alter glutamatergic and GABA-ergic signaling broadly in the central nervous system, but whether BDNF has similar actions in the PVN remains to be investigated. Here, we tested the hypothesis that increased BDNF expression in the PVN elevates blood pressure by enhancingN-methyl-d-aspartate (NMDA) receptor (NMDAR)- and inhibiting GABAAreceptor (GABAAR)-mediated signaling. Sprague-Dawley rats received bilateral PVN injections of AAV2 viral vectors expressing green fluorescent protein (GFP) or BDNF. Three weeks later, cardiovascular responses to PVN injections of NMDAR and GABAAR agonists and antagonists were recorded under α-chloralose-urethane anesthesia. In addition, expressions of excitatory and inhibitory signaling components in the PVN were assessed using immunofluorescence. Our results showed that NMDAR inhibition led to a greater decrease in blood pressure in the BDNF vs. GFP group, while GABAAR inhibition led to greater increases in blood pressure in the GFP group compared to BDNF. Conversely, GABAAR activation decreased blood pressure significantly more in GFP vs. BDNF rats. In addition, immunoreactivity of NMDAR1 was upregulated, while GABAAR-α1 and K+/Cl−cotransporter 2 were downregulated by BDNF overexpression in the PVN. In summary, our findings indicate that hypertensive actions of BDNF within the PVN are mediated, at least in part, by augmented NMDAR and reduced GABAAR signaling.NEW & NOTEWORTHYWe have shown that BDNF, acting in the PVN, elevates blood pressure in part by augmenting NMDA receptor-mediated excitatory input and by diminishing GABAAreceptor-mediated inhibitory input to PVN neurons. In addition, we demonstrate that elevated BDNF expression in the PVN upregulates NMDA receptor immunoreactivity and downregulates GABAAreceptor as well as KCC2 transporter immunoreactivity.