Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Biochemistry, Cellular and Molecular Biology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Neuron. 2024 Nov 20;112(22):3750-3767.e7. doi: 10.1016/j.neuron.2024.08.013. Epub 2024 Sep 19.
Circadian rhythms are generated by the master pacemaker suprachiasmatic nucleus (SCN) in concert with local clocks throughout the body. Although many brain regions exhibit cycling clock gene expression, the identity of a discrete extra-SCN brain oscillator that produces rhythmic behavior has remained elusive. Here, we show that an extra-SCN oscillator in the lateral amygdala (LA) is defined by expression of the clock-output molecule mWAKE/ANKFN1. mWAKE is enriched in the anterior/dorsal LA (adLA), and, strikingly, selective disruption of clock function or excitatory signaling in adLA neurons abolishes Period2 (PER2) rhythms throughout the LA. mWAKE levels rise at night and promote rhythmic excitability of adLA neurons by upregulating Ca-activated K channel activity specifically at night. adLA neurons coordinate rhythmic sensory perception and anxiety in a clock-dependent and WAKE-dependent manner. Together, these data reveal the cellular identity of an extra-SCN brain oscillator and suggest a multi-level hierarchical system organizing molecular and behavioral rhythms.
昼夜节律是由主生物钟视交叉上核(SCN)与全身各处的局部时钟协同产生的。尽管许多脑区都表现出时钟基因表达的循环,但产生节律行为的离散的 SCN 外脑振荡器的身份仍然难以捉摸。在这里,我们表明,外侧杏仁核(LA)中的 SCN 外振荡器由时钟输出分子 mWAKE/ANKFN1 的表达所定义。mWAKE 在 LA 的前/背侧(adLA)中富集,而且令人惊讶的是,选择性破坏 adLA 神经元中的时钟功能或兴奋性信号传导会消除整个 LA 中的 PER2 节律。mWAKE 水平在夜间升高,并通过在夜间特异性地上调钙激活的钾通道活性来促进 adLA 神经元的节律性兴奋性。adLA 神经元以时钟依赖和 WAKE 依赖的方式协调节律性感觉感知和焦虑。总之,这些数据揭示了 SCN 外脑振荡器的细胞身份,并提出了一个多层次的分层系统,用于组织分子和行为节律。