Day and night, breakfast and dinner, winter and summer, wake and sleep…our lives are dominated by interacting rhythms in our environment and our behavior. Why is it that we sleep at night and not during the day? Why are heart attacks and strokes more common in the morning than the evening? How do animals adapt to winter and summer? Why do we get jet-lag, and what is it, exactly? All these questions revolve around a central subject in neuroscience: circadian clocks. During day 1 of the Society for Neuroscience annual meeting in San Diego, CA, I was treated to a nanosymposium (timely insights in circadian regulation) highlighting new and exciting research in this area. Chaired by Steven Brown and Alessandra Porcu, this session covered all aspects of circadian biology, from behavior to neuronal circuits, and from synapses to molecules.
The suprachiasmatic nuclei (pictured above) serve as the master clocks controlling mammalian circadian rhythms (Credit: Jeremy C. Borniger, PhD; Stanford)
Here, I highlight a few of the talks that I found the most interesting. Unfortunately, I am not able to cover everything, and some really cool stuff slipped through! That’s the downside of this immense conference…there’s never enough time to see everything!
Two talks on the same protein (one in flies and the other in mammals) grabbed my attention. These talks were given by Masashi Tabuchi and Benjamin Bell, two researchers from Johns Hopkins University. During Masashi’s talk, he described a potential mechanism by which the protein Wide Awake (WAKE) regulates sleep/wake cycles in flies.
WAKE regulates sleep quality through appropriate timing of neural firing codes (Credit: Tabuchi et al., 2018; Cell)
He showed that irregular neural firing rates during the day (regulated by WAKE) promote arousal while regular firing patterns during the night promote sleep.
Ben Bell followed up his talk by taking their findings in flies to mammals, describing a mammalian ortholog to the fly WAKE protein (called mWAKE). mWAKE is highly enriched in the master clock, the suprachiasmatic nucleus (SCN) suggesting it plays a role in circadian time keeping or regulation.
Unlike in flies, knockout of mWAKE in mice only caused mild problems in sleep/wake states. However, through measuring locomotor activity, the researchers found that these mice were extremely hyperactive (>5 times more active than wild-type mice). Curiously, this trait (phenotype) only came about during the dark phase (mice are nocturnal, so active during the dark phase). To investigate this further, the researchers examined the firing rates of SCN neurons during the day and night. Normal mice have a large difference between the night and day in SCN firing rates, with peak neural activity occurring during the day. However, mWAKE knockout mice showed no difference between day and night, with firing rates remaining high all the time!
Additionally, cells lacking mWAKE showed blunted responses to the inhibitory neurotransmitter GABA, and this lack of inhibition may explain the hyperactive profile mice lacking mWAKE had. Finally, they examined (using an mWAKE reporter mouse) where mWAKE expressing cells project to throughout the brain. They found that cell bodies were distributed throughout the brain, in all major arousal centers. Importantly, they seemed to be discrete from other neuromodulator systems present in these areas, like hypocretin/orexin neurons in the lateral hypothalamus, or histamine neurons in the tuberomammillary nucleus.
mWAKE-cre mice reveal that mWAKE+ cells project to all major arousal centers throughout the brain (Credit: Benjamin Bell, JHU).
Significant more research is required to fully understand the role this protein plays in sleep/wake states. Is it a ‘master regulator’ of arousal? Does it interact with every ‘arousal center’ differently or does it have a distributed ‘homogenous’ effect across the brain. When does mWAKE start to express during development? Does this coincide with changes to sleep-wake behavior during early age? I’m excited to follow this story going forward!
That’s all for now, I’ll see you soon!
Jeremy C Borniger, PhD
Department of Psychiatry & Behavioral Sciences
Stanford University SoM