Study Objectives The neurotrophin brain-derived neurotrophic factor (BDNF) is hypothesized to be a molecular mediator of mammalian sleep homeostasis. This hypothesis is supported by correlational findings and results obtained from pharmacology. BDNF binds with high affinity to the membrane-bound receptor Neurotrophin Tyrosine Kinase Receptor B (NtrkB), which triggers several intracellular signaling cascades. It is therefore possible that BDNF’s role in sleep homeostasis is mediated via NtrkB. We examined this hypothesis using a chemical-genetic technique that allows for rapid and selective inhibition of NtrkB in vivo. Methods We used mutant mice bearing a point mutation in the NtrkB that allows for selective and reversible inactivation in the presence of a small binding molecule (1-NM-PP1). Using a crossover design, we determined the effects of NtrkB inhibition on baseline sleep architecture and sleep homeostasis. Results We find that NtrkB inhibition reduced rapid eye movement (REM) sleep time and changed state transitions but had no effect on sleep homeostasis. Conclusions These findings suggest that BDNF-NtrkB receptor signaling has subtle roles in sleep architecture, but no role in sleep homeostasis.

中文翻译：

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哺乳动物睡眠中 BDNF-NtrkB 信号传导的化学遗传学研究

研究目标 神经营养因子脑源性神经营养因子 (BDNF) 被假设为哺乳动物睡眠稳态的分子介质。这一假设得到了药理学的相关发现和结果的支持。BDNF 与膜结合受体 Neurotrophin Tyrosine Kinase Receptor B (NtrkB) 以高亲和力结合，从而触发几个细胞内信号级联。因此，BDNF 在睡眠稳态中的作用可能是通过 NtrkB 介导的。我们使用允许在体内快速和选择性抑制 NtrkB 的化学遗传技术检查了这一假设。方法 我们使用在 NtrkB 中带有点突变的突变小鼠，该突变允许在小结合分子 (1-NM-PP1) 存在的情况下进行选择性和可逆的失活。采用交叉设计，我们确定了 NtrkB 抑制对基线睡眠结构和睡眠稳态的影响。结果 我们发现 NtrkB 抑制减少了快速眼动 (REM) 睡眠时间并改变了状态转换，但对睡眠稳态没有影响。结论 这些发现表明 BDNF-NtrkB 受体信号传导在睡眠结构中具有微妙的作用，但在睡眠稳态中没有作用。