The human body is not designed to forgo sleep. The record for continued wakefulness is 11 days and 25 minutes—the equivalent of binge-watching the Titanic 81 times! Luckily, we have evolved intrinsic time-keeping mechanisms that anticipate day-night cycles. Multiple transcription-translation feedback loops (TTFLs) function ubiquitously to regulate circadian rhythms (CRs) in the 20,000 neurons of the suprachiasmatic nucleus (SCN), a central mammalian brain structure that is the central CR oscillator [1]. The SCN receives daily optic light inputs, adjusts individual neuronal oscillation phases, and orchestrates CRs globally by sending temporal information to peripheral tissues and organs [1,2].

Seasonal variations in the length of days, known as the photoperiod, can profoundly affect animal behaviour and physiology. However, the mechanisms behind SCN seasonal adaptations remain to be explored [3]. Recently, Dr. Hai-Ying (Mary) Cheng’s laboratory at the University of Toronto discovered that day length variations change the SCN’s timing mechanisms and neuronal morphology [3].

Dr. Cheng’s laboratory discovered that the conditional knockout (cKO) of miR-132/212, a non-coding microRNA gene cluster that regulates post-transcriptional gene expression, impacts SCN dendrite spine
morphology and proteomic landscape [3]. They also found that cKO mice adapt faster to shorter “winter” days and adapt slower to longer “summer” days, compared to wild-type mice expressing miR-132/212 [3]. SCN expression of PERIOD2, a key CR regulator, is noticeably enhanced in cKO mice during shorter days and remains tightly synchronized during longer days, unlike wildtype mice [3]. The authors suggest that deletion of miR-132/212 changes CR regulation when manipulating day length [3].

SCN responses to environmental changes, such as crossing time zones, depend on neuronal network properties rather than individual neuron behaviour [3]. With new experiences, neuronal networks exhibit functional and structural plasticity [3]. Quantitative mass spectrometry revealed an attenuated time of day-dependent protein expression within the SCN of cKO mice [3]. Deletion of miR-132/212 affected
a group of proteins regulating cytoskeletal organization, which suggested abnormal neuronal morphology in the SCN [3]. Using morphometric analysis, the authors demonstrated that dendrite spine density
in the SCN was significantly reduced in cKO mice [3]. They confirmed the link between SCN seasonal adaptation and miR-132/212 expression using Syrian hamsters [3]. Here, miR-132/212 levels and dendritic spine density varied according to the photoperiod [3]. Compared to longer days, shorter days elicited a decrease in miR-132/212 levels and dendritic spine density [3].

Surprisingly, the authors found that knocking out another gene, MeCP2, reversed the effects of miR-132/212 ablation by rescuing cKO dendrite spine density to levels observed in wild-type neurons [3]. The authors suggested that miR-132/212 affected dendritic morphology by regulating MeCP2 expression [3]. MeCP2 is a genetic factor for autism and the causative gene for Rett syndrome, a neurodevelopmental disorder that affects females [3]. Interestingly, both disorders are characterized by strong circadian disruptions [3]. How the miR-132/212-MeCP2 pathway contributes to circadian disturbances in these diseases remains unknown [3].

Dr. Cheng’s laboratory elucidated the novel role of miR- 132/212 encoding day length information by modulating SCN neuronal architecture [3]. The findings of this research raise the possibility that structural neuronal changes strongly impact SCN plasticity across seasons [3]. This discovery sheds light on the roles of specific genes in SCN function, which may further illuminate potential therapeutics for sleep-related disorders [3].