Department of Pharmacology and Physiology, The George Washington University, 2300 Eye Street NW, Washington, D.C. 20037, USA.
Neuroscience. 2012 May 3;209:12-20. doi: 10.1016/j.neuroscience.2012.02.020. Epub 2012 Feb 21.
Cardiac vagal neurons (CVNs) in the nucleus ambiguus (NA) are the major determinant of parasympathetic activity to the heart. Spontaneous GABAergic neurotransmission to CVNs is modulated by hypothalamic neuropeptide orexin-A in postnatal days 2-5 (P5) rats; however, during early postnatal development, orexin expression changes, and the role of orexin-A in modulating CVN activity at other stages of development is unknown. In this study, we compared changes in GABAergic inhibitory postsynaptic currents (IPSCs) in CVNs evoked by orexin-A in P5, P16-20 (P20), and P27-30 (P30) rats using an in vitro brain stem slice preparation. Bath-applied orexin-A enhanced GABAergic IPSCs in all CVNs tested in P5 and P30 animals and in the majority of neurons tested in P20 pups. Focal application of orexin-A ejected from a pipette positioned within 30 μm of the patched CVN did not alter GABAergic signaling in P5 pups. In contrast, in both P20 and P30 rats, focal application of orexin-A inhibited GABAergic IPSCs, and this inhibition persisted in the presence of tetrodotoxin. These results indicate orexin-A facilitates GABAergic IPSCs likely by activating preceding GABAergic neurons that project to CVNs. Orexin-A also likely acts at GABAergic presynaptic terminals surrounding CVNs within the NA to inhibit GABA release. The latter mechanism is absent in P5 pups but occurs in P20 and P30 rats. In conclusion, this study elucidates an important maturation of the parasympathetic cardiac control system. Alterations in these developmental mechanisms may play a role in pathogenesis of disorders related to a specific stage of development maturation.
迷走神经心脏神经元（CVN）在孤束核（NA）是迷走神经活动的主要决定因素对心脏。下丘脑神经肽orexin-A 在出生后第 2-5 天（P5）大鼠调节 CVN 的自发性 GABA 能神经传递；然而，在出生后的早期发育过程中，orexin 的表达发生变化，orexin-A 在其他发育阶段调节 CVN 活性的作用尚不清楚。在这项研究中，我们比较了 P5、P16-20（P20）和 P27-30（P30）大鼠离体脑干切片中 orexin-A 对 CVN 诱发的 GABA 能抑制性突触后电流（IPSCs）的变化。在 P5 和 P30 动物的所有测试 CVN 中，以及在 P20 幼鼠的大多数神经元中，浴应用 orexin-A 增强了 GABA 能 IPSCs。与 P5 幼鼠相比，从置于被 patched CVN 内 30μm 范围内的 pipette 中喷出的 orexin-A 对 GABA 能信号传递没有影响。相反，在 P20 和 P30 大鼠中，orexin-A 的局域应用抑制了 GABA 能 IPSCs，并且这种抑制在存在河豚毒素的情况下仍然存在。这些结果表明，orexin-A 可能通过激活投射到 CVN 的先前 GABA 能神经元来促进 GABA 能 IPSCs。orexin-A 还可能在 NA 内围绕 CVN 的 GABA 能 presynaptic 末端起作用，以抑制 GABA 释放。在后一种机制中，P5 幼鼠不存在，但在 P20 和 P30 大鼠中存在。总之，这项研究阐明了副交感心脏控制系统的重要成熟。这些发育机制的改变可能在与特定发育阶段成熟相关的疾病的发病机制中发挥作用。
