Naked mole rats exhibit metabolic but not ventilatory plasticity following chronic sustained hypoxia

Naked mole rats are among the most hypoxia-tolerant mammals identified and live in chronic hypoxia throughout their lives. The mechanisms underlying this tolerance, however, are poorly understood. Most vertebrates hyperventilate in acute hypoxia and exhibit an enhanced hyperventilation following acclimatization to chronic sustained hypoxia (CSH). Conversely, naked mole rats do not hyperventilate in acute hypoxia and their response to CSH has not been examined. In this study we explored mechanisms of plasticity in the control of the hypoxic ventilatory response (HVR) and hypoxic metabolic response (HMR) of freely behaving naked mole rats following 8-10 days of chronic sustained normoxia (CSN) or CSH. Specifically, we investigated the role of the major inhibitory neurotransmitter γ-amino butyric acid (GABA) in mediating these responses. Our study yielded three important findings. First, naked mole rats did not exhibit ventilatory plasticity following CSH, which is unique among adult animals studied to date. Second, GABA receptor (GABAR) antagonism altered breathing patterns in CSN and CSH animals and modulated the acute HVR in CSN animals. Third, naked mole rats exhibited GABAR-dependent metabolic plasticity following long-term hypoxia, such that the basal metabolic rate was ~25% higher in normoxic CSH animals than CSN animals, and GABAR antagonists modulated this increase.

裸鼹鼠（naked mole rats）是目前已发现的最耐低氧的哺乳动物类群之一，且终生生活在慢性低氧环境中。然而，其耐低氧的潜在生理与分子机制仍未被充分阐明。多数脊椎动物在急性低氧条件下会出现过度通气，且经慢性持续性低氧（chronic sustained hypoxia, CSH）适应后，过度通气反应会进一步增强。与之截然相反，裸鼹鼠在急性低氧环境下并不会产生过度通气，且其对CSH的响应尚未被相关研究探讨过。
本研究针对经8至10天慢性持续性常氧（chronic sustained normoxia, CSN）或CSH处理后的自由活动裸鼹鼠，探究了其低氧通气反应（hypoxic ventilatory response, HVR）与低氧代谢反应（hypoxic metabolic response, HMR）的可塑性调控机制。具体而言，我们研究了主要抑制性神经递质γ-氨基丁酸（γ-amino butyric acid, GABA）在介导上述两类反应中的作用。
本研究获得三项重要发现：第一，裸鼹鼠经CSH处理后未表现出通气可塑性，这在迄今已研究的成年动物中实属独有；第二，γ-氨基丁酸受体（GABAR）拮抗作用可改变CSN与CSH组动物的呼吸模式，并可调节CSN组动物的急性低氧通气反应；第三，裸鼹鼠在长期低氧暴露后表现出依赖GABAR的代谢可塑性：在常氧条件下，CSH组动物的基础代谢率较CSN组高出约25%，且GABAR拮抗剂可调控这一代谢差异。