Department of Physiology, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea.
Department of Biochemistry and Molecular Biology, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea.
Neuroscience. 2018 May 21;379:219-227. doi: 10.1016/j.neuroscience.2018.03.036. Epub 2018 Mar 29.
During pregnancy, the progesterone metabolite, allopregnanolone (ALLO), becomes elevated and has been associated with altered levels within the CNS and resulting changes in GABA receptor function. Pregnant animals poorly compensate reflexes for a decrease in blood pressure during hemorrhage. Previous works suggested that ALLO decreases baroreflex responses by central actions, however, the underlying mechanisms are poorly understood. In this study, we tested ALLO actions on visceral afferent synaptic transmission at second-order neurons within medial portions of the nucleus tractus solitarius (NTS) using hindbrain slices from non-pregnant female rats. Solitary tract (ST) stimulation-evoked excitatory postsynaptic currents (ST-eEPSCs) in NTS neurons directly connected to vagal afferents within the ST. ST-eEPSCs were functionally identified as monosynaptic by the latency characteristics (low jitter = standard deviation of latency, ≤200 μs) to ST stimulation. Such second-order neurons all displayed spontaneous inhibitory postsynaptic currents (sIPSCs), and low micromolar concentrations of ALLO increased frequency and decay time. At submicromolar concentrations, ALLO induced a tonic, GABAergic inhibitory current and suppressed ST-eEPSCs' amplitude. While GABA receptor antagonist, bicuculline, blocked all ALLO effects, gabazine only blocked sIPSC actions. In current-clamp mode, ALLO perfusion increased failure of ST stimulation to trigger action potentials in most neurons. Thus, our results indicate that ALLO acts to suppress visceral afferent ST synaptic transmission at first synapses by activating pharmacologically distinct GABA subtypes at different concentration ranges. This ALLO-mediated attenuated visceral afferent signal integration in NTS may underlie reflex changes in blood pressure during gestation.
在怀孕期间，孕激素代谢物孕烷醇酮（ALLO）水平升高，并与中枢神经系统内的水平变化以及 GABA 受体功能的变化有关。怀孕动物在出血时对血压下降的反射反应代偿不良。以前的研究表明，ALLO 通过中枢作用降低了压力反射反应，但其潜在机制尚不清楚。在这项研究中，我们使用非怀孕雌性大鼠的延髓切片，在孤束核（NTS）的中间部分测试了 ALLO 对内脏传入突触传递的作用。孤束刺激引起与孤束内迷走传入直接相连的 NTS 神经元的兴奋性突触后电流（ST-eEPSC）。ST-eEPSC 通过潜伏期特征（低抖动=潜伏期的标准差，≤200μs）直接鉴定为与 ST 刺激的单突触。这种二阶神经元均显示自发抑制性突触后电流（sIPSCs），并且低微摩尔浓度的 ALLO 增加了频率和衰减时间。在亚微摩尔浓度下，ALLO 诱导了一种紧张的 GABA 能抑制电流，并抑制了 ST-eEPSC 的幅度。虽然 GABA 受体拮抗剂，荷包牡丹碱，阻断了 ALLO 的所有作用，但gabazine 仅阻断了 sIPSC 的作用。在电流钳模式下，ALLO 灌流增加了 ST 刺激触发大多数神经元动作电位失败的频率。因此，我们的结果表明，ALLO 通过在不同浓度范围内激活药理学上不同的 GABA 亚型，在第一突触处抑制内脏传入 ST 突触传递。这种 NTS 中内脏传入信号整合的 ALLO 介导的衰减可能是怀孕期间血压反射变化的基础。
