It has been a minute since I have done a Neury Thursday post where I highlight an article from the most current issue of Journal of Neuroscience. Well this week I am pleased to say that there is very familiar research, names, labs, and institutions in one of the featured articles. We started this project 2.5 years ago and have generated handfuls of interesting data from it. As you may recall, there are two biological processes that govern daily amounts and timing of sleep. There is a classic homeostatic process known as Process S which basically “encourages” us to sleep more if we get a night of insufficient sleep. There is also Process C which is governed by the ticking and speed of our internal biological clock located in the hypothalamus. In the present study, we aimed to study both of these processes in an animal model of Angelman Syndrome. Angelman Syndrome is a genetically-determined neurological disorder. It is characterized by severe motor and mental impairments, seizures, and sleep distrubances.
As an attempt to model Angelman Syndrome in mice, we used transgenic mice lacking expression of the maternal Ube3a gene in the brain. The paternal Ube3a gene is typically silenced. In the first set of experiments, we characterized daily activity and molecular rhythms in the central biological clock–the suprachiasmatic nucleus–of the hypothalamus.
Interestingly, there was no disruption to general circadian timekeeping (Process C) at the level of behavior and the brain. Mice lacking maternal Ube3a were equally as active as mice expressing Ube3a and responded and adapted to an intermittent light pulse presented early or late in the night at similar rates compared to mice expressing Ube3a. Despite this, if you look closer at the activity plots in (A) you’ll notice that the distribution of daily activity looks different. Well, it is different.
Additional analyses revealed that mice lacking maternal Ube3a do not nap during the mid-dark period like most normal mouse strains. They keep running on their wheels right through it!
From here, we examined the impact of Ube3a on daily amounts of sleep and responsiveness and adaptation to short-term sleep loss. Like many of our studies, we deprive mice of sleep for the first six hours of the light-phase when the propensity to sleep is at its highest. In looking at daily amounts of sleep and wakefulness under undisturbed, baseline conditions, EEG indeed confirmed that mice lacking maternal Ube3a are active through the siesta.
This reorganization of sleep and wake carried over into how the mice responded to short-term sleep deprivation. Not only did the mice lacking maternal Ube3a not recover as much sleep after sleep deprivation as mice expressing Ube3a, but their EEGs were less saturated with slow wave activity which is an electrophysiological correlate of sleepiness. In all, we can conclude that the brains of mice lacking Ube3a are wired differently favoring states of arousal and wakefulness. This likely explains the sleep disturbances common in individuals suffering from Angelman Syndrome.
Ehlen, J., Jones, K., Pinckney, L., Gray, C., Burette, S., Weinberg, R., Evans, J., Brager, A., Zylka, M., Paul, K., Philpot, B., & DeBruyne, J. (2015). Maternal Ube3a Loss Disrupts Sleep Homeostasis But Leaves Circadian Rhythmicity Largely Intact Journal of Neuroscience, 35 (40), 13587-13598 DOI: 10.1523/JNEUROSCI.2194-15.2015