Hypoxia tolerance in the vertebrate brain often involves chemical modulators that arrest neuronal activity to conserve energy. However, in intact networks, it can be difficult to determine whether hypoxia triggers modulators to stop activity in a protective manner or whether activity stops because rates of ATP synthesis are insufficient to support network function. Here, we assessed the extent to which neuromodulation or metabolic limitations arrest activity in the respiratory network of bullfrogs-a circuit that survives moderate periods of oxygen deprivation, presumably, by activating an inhibitory noradrenergic pathway. We confirmed that hypoxia and norepinephrine (NE) reduce network output, consistent with the view that hypoxia may cause the release of NE to inhibit activity. However, these responses differed qualitatively; hypoxia, but not NE, elicited a large motor burst and silenced the network. The stereotyped response to hypoxia persisted in the presence of both NE and an adrenergic receptor blocker that eliminates sensitivity to NE, indicating that noradrenergic signaling does not cause the arrest. Pharmacological inhibition of glycolysis and mitochondrial respiration recapitulated all features of hypoxia, implying that reduced ATP synthesis underlies the effects of hypoxia on network activity. Finally, activating modulatory mechanisms that dampen neuronal excitability when ATP falls, K_ATP channels and AMP-dependent protein kinase, did not resemble the hypoxic response. These results suggest energy failure- rather than inhibitory modulation- silences the respiratory network during hypoxia and emphasize the need to account for metabolic limitations before concluding that modulators arrest activity as an adaptation for energy conservation in the nervous system.

中文翻译：

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神经调节或能量衰竭？代谢限制使缺氧两栖动物脑干的网络输出沉默


脊椎动物大脑的缺氧耐受性通常涉及化学调节剂，这些调节剂可以阻止神经元活动以保存能量。然而，在完整的网络中，很难确定缺氧是否会触发调节剂以保护性方式停止活动，或者活动是否因为 ATP 合成速率不足以支持网络功能而停止。在这里，我们评估了神经调节或代谢限制在牛蛙呼吸网络中阻止活动的程度，牛蛙呼吸网络是一个在中度缺氧时期存活下来的回路，大概是通过激活抑制性去甲肾上腺素能途径来实现的。我们证实缺氧和去甲肾上腺素（NE）会降低网络输出，这与缺氧可能导致NE释放抑制活性的观点一致。然而，这些反应在性质上有所不同；缺氧（而非 NE）引起了巨大的运动爆发并使网络陷入沉默。在 NE 和消除对 NE 敏感性的肾上腺素能受体阻滞剂存在的情况下，对缺氧的刻板反应仍然存在，表明去甲肾上腺素能信号传导不会导致逮捕。糖酵解和线粒体呼吸的药理抑制概括了缺氧的所有特征，这意味着 ATP 合成的减少是缺氧对网络活动影响的基础。最后，当 ATP、K _ATP通道和 AMP 依赖性蛋白激酶下降时，激活抑制神经元兴奋性的调节机制与缺氧反应并不相似。 这些结果表明，能量衰竭（而不是抑制性调节）在缺氧期间使呼吸网络沉默，并强调在得出调节剂阻止活性作为神经系统能量保存的适应的结论之前需要考虑代谢限制。