Breathing Research and Therapeutics Center, Department of Physical Therapy and McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA.
Function (Oxf). 2023 Aug 8;4(6):zqad041. doi: 10.1093/function/zqad041. eCollection 2023.
Plasticity is a fundamental property of the neural system controlling breathing. One key example of respiratory motor plasticity is phrenic long-term facilitation (pLTF), a persistent increase in phrenic nerve activity elicited by acute intermittent hypoxia (AIH). pLTF can arise from distinct cell signaling cascades initiated by serotonin versus adenosine receptor activation, respectively, and interact via powerful cross-talk inhibition. Here, we demonstrate that the daily rest/active phase and the duration of hypoxic episodes within an AIH protocol have profound impact on the magnitude and mechanism of pLTF due to shifts in serotonin/adenosine balance. Using the historical "standard" AIH protocol (3, 5-min moderate hypoxic episodes), we demonstrate that pLTF magnitude is unaffected by exposure in the midactive versus midrest phase, yet the mechanism driving pLTF shifts from serotonin-dominant (midrest) to adenosine-dominant (midactive). This mechanistic "flip" results from combined influences of hypoxia-evoked adenosine release and daily fluctuations in basal spinal adenosine. Since AIH evokes less adenosine with shorter (15, 1-min) hypoxic episodes, midrest pLTF is amplified due to diminished adenosine constraint on serotonin-driven plasticity; in contrast, elevated background adenosine during the midactive phase suppresses serotonin-dominant pLTF. These findings demonstrate the importance of the serotonin/adenosine balance in regulating the amplitude and mechanism of AIH-induced pLTF. Since AIH is emerging as a promising therapeutic modality to restore respiratory and nonrespiratory movements in people with spinal cord injury or ALS, knowledge of how time-of-day and hypoxic episode duration impact the serotonin/adenosine balance and the magnitude and mechanism of pLTF has profound biological, experimental, and translational implications.
可塑性是控制呼吸的神经系统的基本特性。呼吸运动可塑性的一个关键例子是膈神经长期易化（pLTF），这是急性间歇性低氧（AIH）引起的膈神经活动持续增加。pLTF 可以分别由 5-羟色胺与腺苷受体激活引发的不同细胞信号级联反应产生，并通过强大的交叉抑制相互作用。在这里，我们证明了 AIH 方案中的日常休息/活动期和缺氧期持续时间会由于 5-羟色胺/腺苷平衡的变化对 pLTF 的幅度和机制产生深远影响。使用历史上的“标准”AIH 方案（3 个、5 分钟中度缺氧期），我们证明了 pLTF 幅度不受暴露于中活动期与中休息期的影响，但是驱动 pLTF 的机制从 5-羟色胺主导（中休息期）转变为腺苷主导（中活动期）。这种机制“翻转”是由缺氧诱导的腺苷释放和基础脊髓腺苷的日常波动的综合影响引起的。由于 AIH 用较短（15 分钟、1 分钟）的缺氧期引起较少的腺苷，因此由于腺苷对 5-羟色胺驱动的可塑性的约束减少，中休息期的 pLTF 被放大；相反，在中活动期升高的背景腺苷会抑制 5-羟色胺主导的 pLTF。这些发现表明 5-羟色胺/腺苷平衡在调节 AIH 诱导的 pLTF 的幅度和机制方面的重要性。由于 AIH 作为一种有前途的治疗方式，正在恢复脊髓损伤或 ALS 患者的呼吸和非呼吸运动，了解时间和缺氧期持续时间如何影响 5-羟色胺/腺苷平衡以及 pLTF 的幅度和机制具有深远的生物学、实验和转化意义。
