Wang Huei Bin, Smale Natalie E, Brown Sarah H, Villanueva Sophia Anne Marie, Zhou David, Mulji Aly, Bhandal Deap S, Nguyen-Ngo Kyle, Harvey John R, Ghiani Cristina A, Colwell Christopher S
Molecular, Cellular, Integrative Physiology Graduate Program, University of California Los Angeles.
Department of Psychiatry & Biobehavioral Sciences, University of California Los Angeles.
bioRxiv. 2025 Mar 15:2024.09.16.613343. doi: 10.1101/2024.09.16.613343.
Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by the abnormal expansion of CGG repeats in the fragile X mental retardation 1 (FMR1) gene. Many FXS patients experience sleep disruptions, and we sought to explore these symptoms along with the possible benefits of a scheduled feeding intervention using the knockout (KO) mouse model. These mutants displayed clear evidence for sleep and circadian disturbances including delay in the onset of sleep and fragmented activity rhythms with increases in cycle-to-cycle variability. Importantly, the KO mice exhibited deficits in their circadian behavioral response to light with reduced masking, longer time to resetting to shifts in the Light-Dark cycle, altered synchronization to a skeleton photoperiod and lower magnitude light-induced phase shifts of activity rhythms. Investigation of the retinal input to the surprachiasmatic nucleus (SCN) with the neurotracer cholera toxin (β subunit) and quantification of the light-evoked cFos expression in the SCN revealed an abnormal retinal innervation of the SCN in the KO, providing a possible mechanistic explanation for the observed behavioral deficits. Interestingly, disruptions in social and repetitive behaviors correlated with sleep duration and fragmentation. Understanding the nature of the deficits, we decided to apply a scheduled feeding regimen (6-hr/18-hr feed/fast cycle) as a circadian-based strategy to boast circadian rhythms independently of light. This intervention significantly improved the activity rhythms and sleep in the mutants. Strikingly, the scheduled feeding ameliorated social interactions and reduced repetitive behaviors as well as the levels of Interferon-gamma and Interleukin-12 in the KO mutants, suggesting that timed eating may be an effective way to lessen inflammation. Collectively, this work adds support to efforts to develop circadian based interventions to help with symptoms of neurodevelopmental disorders.
脆性X综合征（FXS）是一种神经发育障碍，由脆性X智力低下1（FMR1）基因中CGG重复序列的异常扩增引起。许多FXS患者存在睡眠障碍，我们试图利用基因敲除（KO）小鼠模型探究这些症状以及定时喂养干预可能带来的益处。这些突变体表现出睡眠和昼夜节律紊乱的明显证据，包括睡眠开始延迟和活动节律碎片化，周期间变异性增加。重要的是，KO小鼠在对光的昼夜行为反应方面存在缺陷，表现为掩盖作用减弱、重新适应明暗周期变化的时间延长、对骨架光周期的同步改变以及光诱导的活动节律相位偏移幅度降低。用神经示踪剂霍乱毒素（β亚基）研究视网膜向视交叉上核（SCN）的输入，并对SCN中光诱发的cFos表达进行定量分析，结果显示KO小鼠的SCN存在异常的视网膜神经支配，这为观察到的行为缺陷提供了一种可能的机制解释。有趣的是，社交和重复行为的破坏与睡眠时间和碎片化程度相关。了解这些缺陷的本质后，我们决定采用定时喂养方案（6小时进食/18小时禁食周期）作为一种基于昼夜节律的策略，以独立于光来增强昼夜节律。这种干预显著改善了突变体的活动节律和睡眠。令人惊讶的是，定时喂养改善了社交互动，减少了重复行为以及KO突变体中γ干扰素和白细胞介素-12的水平，这表明定时进食可能是减轻炎症的有效方法。总的来说，这项工作为开发基于昼夜节律的干预措施以帮助缓解神经发育障碍症状的努力提供了支持。
