Enhanced phrenic motor neuron BDNF expression elicited by daily acute intermittent hypoxia is undermined in rats with chronic cervical spinal cord injury

IF 1.9 4区医学 Q3 PHYSIOLOGY

Respiratory Physiology & Neurobiology Pub Date : 2024-11-12 DOI:10.1016/j.resp.2024.104369

Aaron A. Jones , Jose R. Oberto , Marissa C. Ciesla , Yasin B. Seven , Latoya L. Allen , Elisa J. Gonzalez-Rothi, Gordon S. Mitchell

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引用次数: 0

Abstract

Acute intermittent hypoxia (AIH) elicits spinal neuroplasticity and is emerging as a potential therapeutic modality to improve respiratory and non-respiratory motor function in people with chronic incomplete spinal cord injury (SCI). Brain-derived neurotrophic factor (BDNF) is necessary and sufficient for moderate AIH-induced phrenic long-term facilitation, a well-studied form of respiratory motor plasticity. Repetitive daily AIH (dAIH) enhances BDNF expression within the phrenic motor neurons of normal rats, but its effects on BDNF after chronic cervical spinal cord injury (cSCI) are unknown. In contrast to AIH, chronic intermittent hypoxia (CIH), simulating that experienced during sleep apnea, elicits neuropathology and undermines plasticity. Here, we tested the hypothesis that daily AIH vs CIH differentially regulate phrenic motor neuron BDNF expression in spinally intact and injured rats. Rats with and without C2 hemisection (C2Hx; 8 weeks post-injury) were exposed to 28 days of: 1) sham normoxia (Nx, 21 % O₂); 2) daily AIH (dAIH: 10, 5 min episodes of 10.5 % O₂ per day; 5 min normoxic intervals); 3) mild CIH (CIH5/5: 5 min of 10.5 % O₂, 5 min intervals, 8 hrs/day); or 4) moderate CIH (CIH2/2: 2 min of 10.5 % O₂, 2 min intervals, 8 hrs/day). After 28 days of daily exposure (i.e., 12 weeks post-injury), BDNF immunoreactivity was assessed within phrenic motor neurons identified via retrograde cholera toxin B fragment labeling. In intact rats, daily AIH increased BDNF protein levels in phrenic motor neurons (∼31 %) but not in rats with C2Hx. CIH had no effects on phrenic motor neuron BDNF levels in intact rats, although there was a trend towards increased phrenic motor neuron BDNF after C2Hx, suggesting the need for further study. Since dAIH effects on phrenic motor neuron BDNF are not observed in rats with chronic cervical SCI, the potential of dAIH to enhance BDNF-dependent phrenic motor plasticity may be suppressed by conditions prevailing with chronic cSCI.

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慢性颈脊髓损伤大鼠每日急性间歇性缺氧引起的膈运动神经元BDNF表达增强会被削弱。

急性间歇性缺氧（AIH）可引起脊髓神经可塑性，正在成为改善慢性不完全脊髓损伤（SCI）患者呼吸和非呼吸运动功能的一种潜在治疗方式。脑源性神经营养因子（BDNF）对于中度AIH诱导的膈肌长期促进是必要且充分的，这是一种经过充分研究的呼吸运动可塑性形式。每天重复性AIH（dAIH）可增强正常大鼠膈肌运动神经元中BDNF的表达，但其对慢性颈脊髓损伤（cSCI）后BDNF的影响尚不清楚。与 AIH 不同，模拟睡眠呼吸暂停过程的慢性间歇性缺氧（CIH）会引起神经病理变化并破坏可塑性。在这里，我们测试了一个假设，即在脊髓完好和受伤的大鼠中，每天的 AIH 与 CIH 对膈运动神经元 BDNF 的表达有不同的调节作用。对患有和未患有 C2 半切除术（C2Hx；伤后 8 周）的大鼠进行 28 天的暴露：1）假常氧（Nx，21% O2）；2）每日 AIH（dAIH：10，每天 5 分钟 10.5% O2；5 分钟常氧间隔）；3）轻度 CIH（CIH5/5：5 分钟 10.5% O2，5 分钟间隔，8 小时/天）；或 4）中度 CIH（CIH2/2：2 分钟 10.5% O2，2 分钟间隔，8 小时/天）。每天暴露 28 天后（即受伤后 12 周），通过逆行霍乱毒素 B 片段标记，评估膈运动神经元内的 BDNF 免疫反应。在完整大鼠中，每日 AIH 可增加膈运动神经元中的 BDNF 蛋白水平（约 31%），但在 C2Hx 大鼠中则没有增加。CIH 对完整大鼠的膈运动神经元 BDNF 水平没有影响，但 C2Hx 后膈运动神经元 BDNF 有增加的趋势，这表明需要进一步研究。由于在慢性颈椎 SCI 大鼠中未观察到 dAIH 对膈运动神经元 BDNF 的影响，因此 dAIH 增强 BDNF 依赖性膈运动可塑性的潜力可能会被慢性颈椎 SCI 的普遍条件所抑制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Respiratory Physiology & Neurobiology 医学-呼吸系统

CiteScore

4.80

自引率

8.70%

发文量

104

审稿时长

54 days

期刊介绍： Respiratory Physiology & Neurobiology (RESPNB) publishes original articles and invited reviews concerning physiology and pathophysiology of respiration in its broadest sense. Although a special focus is on topics in neurobiology, high quality papers in respiratory molecular and cellular biology are also welcome, as are high-quality papers in traditional areas, such as: -Mechanics of breathing- Gas exchange and acid-base balance- Respiration at rest and exercise- Respiration in unusual conditions, like high or low pressure or changes of temperature, low ambient oxygen- Embryonic and adult respiration- Comparative respiratory physiology. Papers on clinical aspects, original methods, as well as theoretical papers are also considered as long as they foster the understanding of respiratory physiology and pathophysiology.