Department of Comparative Biosciences, University of Wisconsin, Madison, Wisconsin, United States.
Breathing Research and Therapeutics Center, University of Florida, Gainesville, Florida, United States.
J Neurophysiol. 2023 Feb 1;129(2):455-464. doi: 10.1152/jn.00345.2022. Epub 2023 Jan 25.
Moderate acute intermittent hypoxia (mAIH) elicits a form of phrenic motor plasticity known as phrenic long-term facilitation (pLTF), which requires spinal 5-HT receptor activation, ERK/MAP kinase signaling, and new brain-derived neurotrophic factor (BDNF) synthesis. New BDNF protein activates TrkB receptors that normally signal through PKCθ to elicit pLTF. Phrenic motor plasticity elicited by spinal drug administration (e.g., BDNF) is referred to by a more general term: phrenic motor facilitation (pMF). Although mild systemic inflammation elicited by a low lipopolysaccharide (LPS) dose (100 µg/kg; 24 h prior) undermines mAIH-induced pLTF upstream from BDNF protein synthesis, it augments pMF induced by spinal BDNF administration through unknown mechanisms. Here, we tested the hypothesis that mild inflammation shifts BDNF/TrkB signaling from PKCθ to alternative pathways that enhance pMF. We examined the role of three known signaling pathways associated with TrkB (MEK/ERK MAP kinase, PI3 kinase/Akt, and PKCθ) in BDNF-induced pMF in anesthetized, paralyzed, and ventilated Sprague Dawley rats 24 h post-LPS. Spinal PKCθ inhibitor (TIP) attenuated early BDNF-induced pMF (≤30 min), with minimal effect 60-90 min post-BDNF injection. In contrast, MEK inhibition (U0126) abolished BDNF-induced pMF at 60 and 90 min. PI3K/Akt inhibition (PI-828) had no effect on BDNF-induced pMF at any time. Thus, whereas BDNF-induced pMF is exclusively PKCθ-dependent in normal rats, MEK/ERK is recruited by neuroinflammation to sustain, and even augment downstream plasticity. Because AIH is being developed as a therapeutic modality to restore breathing in people living with multiple neurological disorders, it is important to understand how inflammation, a common comorbidity in many traumatic or degenerative central nervous system disorders, impacts phrenic motor plasticity. We demonstrate that even mild systemic inflammation shifts signaling mechanisms giving rise to BDNF-induced phrenic motor plasticity. This finding has important experimental, biological, and translational implications, particularly since BDNF-dependent spinal plasticity is being translated to restore breathing and nonrespiratory movements in diverse clinical disorders, such as spinal cord injury (SCI) and amyotrophic lateral sclerosis (ALS).
中度急性间歇性低氧（mAIH）引起一种膈神经运动的可塑性，称为膈神经长期易化（pLTF），这需要脊髓 5-羟色胺受体的激活、ERK/MAP 激酶信号转导和新的脑源性神经营养因子（BDNF）合成。新的 BDNF 蛋白激活 TrkB 受体，通过通常通过 PKCθ 发出信号来引起 pLTF。通过脊髓给药（例如 BDNF）引起的膈神经运动可塑性被称为膈神经运动易化（pMF）。虽然低剂量脂多糖（LPS）（24 小时前 100μg/kg）引起的轻度全身炎症会破坏 BDNF 蛋白合成之前的 mAIH 诱导的 pLTF，但它通过未知机制增强了脊髓 BDNF 给药引起的 pMF。在这里，我们测试了这样一个假设，即轻度炎症将 BDNF/TrkB 信号从 PKCθ 转移到增强 pMF 的替代途径。我们在麻醉、麻痹和通气的 Sprague Dawley 大鼠中检查了与 TrkB 相关的三种已知信号通路（MEK/ERK MAP 激酶、PI3 激酶/Akt 和 PKCθ）在 LPS 后 24 小时内的 BDNF 诱导的 pMF 中的作用。脊髓 PKCθ 抑制剂（TIP）减弱了早期 BDNF 诱导的 pMF（≤30 分钟），在 BDNF 注射后 60-90 分钟时影响最小。相比之下，MEK 抑制（U0126）在 60 和 90 分钟时完全消除了 BDNF 诱导的 pMF。PI3K/Akt 抑制（PI-828）在任何时间都对 BDNF 诱导的 pMF 没有影响。因此，在正常大鼠中，BDNF 诱导的 pMF 完全依赖于 PKCθ，而在神经炎症中，MEK/ERK 被募集来维持甚至增强下游可塑性。由于 AIH 正在被开发为一种治疗方法，以恢复患有多种神经障碍的人的呼吸，因此了解炎症（许多创伤性或退行性中枢神经系统疾病的常见合并症）如何影响膈神经运动的可塑性非常重要。我们证明，即使是轻度的全身炎症也会改变导致 BDNF 诱导的膈神经运动可塑性的信号机制。这一发现具有重要的实验、生物学和转化意义，特别是因为 BDNF 依赖性脊髓可塑性正在被转化为恢复呼吸和非呼吸运动，用于治疗多种临床疾病，如脊髓损伤（SCI）和肌萎缩性侧索硬化症（ALS）。
