Activation of brain-derived neurotrophic factor-tropomyosin receptor kinase B signaling in the pedunculopontine tegmental nucleus: a novel mechanism for the homeostatic regulation of rapid eye movement sleep.
Activation of brain-derived neurotrophic factor-tropomyosin receptor kinase B signaling in the pedunculopontine tegmental nucleus: a novel mechanism for the homeostatic regulation of rapid eye movement sleep.
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DOI：
10.1111/jnc.13938
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发表时间：
2017-04
影响因子：
4.7
通讯作者：
Datta S
中科院分区：
文献类型：
--
作者：
Barnes AK;Koul-Tiwari R;Garner JM;Geist PA;Datta S
快速眼动（REM）睡眠失调是许多神经精神疾病的一种症状，但REM睡眠稳态调节的机制尚不完全清楚。我们已经证明，在快速眼动睡眠剥夺后，桥脚被盖核（PPT）在快速眼动睡眠恢复的产生中起着关键作用。在这项研究中，我们使用多学科技术来显示PPT中脑源性神经营养因子(BDNF) -原肌球蛋白受体激酶B （TrkB）信号传导与快速眼动睡眠稳态驱动的发展之间的因果关系。大鼠被随机分配到无限制睡眠或选择性快速眼动睡眠剥夺（RSD）的条件下，用PPT微注射载体对照或TrkB受体抑制剂（2、3或4 nmol K252a或4 nmol ANA‐12）。在实验当天，大鼠接受PPT显微注射，并记录其睡眠-清醒生理信号3或6小时，在前3小时进行选择性RSD。在所有3小时记录结束时，大鼠被杀死，PPT被解剖用于BDNF定量。我们的研究结果表明，K252a和ANA‐12剂量依赖性地降低了对选择性RSD的稳态反应。具体而言，TrkB受体抑制降低了REM睡眠的内稳态驱动，限制了REM睡眠反弹。PPT BDNF的上调也存在剂量依赖性抑制，回归分析显示REM睡眠稳态驱动与PPT BDNF表达水平呈显著正相关。这些数据提供了第一个直接证据，证明PPT中BDNF - TrkB信号的激活是快速眼动睡眠稳态驱动发展的关键步骤。
Rapid eye movement (REM) sleep dysregulation is a symptom of many neuropsychiatric disorders, yet the mechanisms of REM sleep homeostatic regulation are not fully understood. We have shown that, after REM sleep deprivation, the pedunculopontine tegmental nucleus (PPT) plays a critical role in the generation of recovery REM sleep. In this study, we used multidisciplinary techniques to show a causal relationship between brain‐derived neurotrophic factor (BDNF)‐tropomyosin receptor kinase B (TrkB) signaling in the PPT and the development of REM sleep homeostatic drive. Rats were randomly assigned to conditions of unrestricted sleep or selective REM sleep deprivation (RSD) with PPT microinjections of vehicle control or a dose of a TrkB receptor inhibitor (2, 3, or 4 nmol K252a or 4 nmol ANA‐12). On experimental days, rats received PPT microinjections and their sleep‐wake physiological signals were recorded for 3 or 6 h, during which selective RSD was performed in the first 3 h. At the end of all 3 h recordings, rats were killed and the PPT was dissected out for BDNF quantification. Our results show that K252a and ANA‐12 dose‐dependently reduced the homeostatic responses to selective RSD. Specifically, TrkB receptor inhibition reduced REM sleep homeostatic drive and limited REM sleep rebound. There was also a dose‐dependent suppression of PPT BDNF up‐regulation, and regression analysis revealed a significant positive relationship between REM sleep homeostatic drive and the level of PPT BDNF expression. These data provide the first direct evidence that activation of BDNF‐TrkB signaling in the PPT is a critical step for the development of REM sleep homeostatic drive.