Improved sleep scoring in mice reveals human-like stages

Abstract

Rodents are the main animal model to study sleep. Yet, in spite of a large consensus on the distinction between rapid-eye-movements sleep (REM) and non-REM sleep (NREM) in both humans and rodent, there is still no equivalent in mice of the NREM subdivision classically described in humans.Here we propose a classification of sleep stages in mice, inspired by human sleep scoring.By using chronic recordings in medial prefrontal cortex (mPFC) and hippocampus we can classify three NREM stages with a stage N1 devoid of any low oscillatory activity and N3 with a high density of delta waves. These stages displayed the same evolution observed in human during the whole sleep or within sleep cycles. Importantly, as in human, N1 in mice is the first stage observed at sleep onset and is increased after sleep fragmentation in Orexin-/mice, a mouse model of narcolepsy.We also show that these substages are associated to massive modification of neuronal activity. Moreover, considering these stages allows to predict mPFC neurons evolution of firing rates across sleep period. Notably, neurons preferentially active within N3 decreased their activity over sleep while the opposite is seen for those preferentially active in N1 and N2.Overall this new approach shows the feasibility of NREM sleep sub-classification in rodents, and, in regard to the similarity between sleep in both species, will pave the way for further studies in sleep pathologies given the perturbation of specific sleep substages in human pathologies such as insomnia, somnambulism, night terrors, or fibromyalgia.

Understanding the interplay of sleep and aging: Methodological challenges

“…Hence, stage 2 and SWS are often treated as proxies for the dominance of different sleep‐specific oscillatory brain signals (Genzel, Kroes, Dresler, & Battaglia, ; Hobson, ). Although generally accepted in human sleep research, the distinction between sleep stage 2 and SWS based on a certain amplitude and time criterion (Iber et al, ) is not without problems (Genzel et al, ; Lacroix et al, ; Silber et al, ; Webb & Dreblow, ). Challenges include the handling of potentially biased sleep stage estimates in different age groups and the comparability of estimates between human and animal research (e.g., Genzel et al, ; Lacroix et al, ).…”

“…Given the described challenges an NREM sleep subdivision bears, it may be hardly surprising that research in other species refrains from applying such a subclassification (but see Lacroix et al, , for a recent attempt for “human‐like” subclassification of NREM sleep in rodents). The term “SWS” is typically used to describe the whole continuum of NREM sleep, which has evoked pivotal misunderstandings when comparing human and animal research (Genzel et al, ).…”

Understanding the interplay of sleep and aging: Methodological challenges

“…Although generally accepted in human sleep research, the distinction between sleep stage 2 and SWS based on a certain amplitude and time criterion is not without problems (Genzel et al, 2014;Lacroix et al, 2018;Webb, 1982;Silber et al, 2007). Challenges include the handling of potentially biased sleep stage estimates in different age groups and the comparability of estimates between human and animal research (e.g., Genzel et al, 2014;Lacroix et al, 2018).…”

“…Given the described challenges a NREM sleep subdivision bears, it may be hardly surprising that research in other species refrains from applying such a sub-classification (but see Lacroix et al, 2018, for a recent attempt for 'human-like' sub-classification of NREM sleep in rodents). The term 'SWS' is typically used to describe the whole continuum of NREM sleep, which has evoked pivotal misunderstandings when comparing human and animal research (Genzel et al, 2014).…”

“…The term 'SWS' is typically used to describe the whole continuum of NREM sleep, which has evoked pivotal misunderstandings when comparing human and animal research (Genzel et al, 2014). This conception of NREM sleep may arise from the prevailing sleep scoring procedure in rodents that can easily distinguish between REM and NREM sleep on the basis of movements and spectral parameters of electrical neuronal activity during sleep, but less so between NREM sub-stages (Bagur et al, 2018;Lacroix et al, 2018). In humans, contemplating whole-night multitaper spectral EEG data irrespective of participants' age, the distinct natures of REM and NREM sleep becomes evident, whereas differences between SWS and stage 2 sleep are more subtle as they transition gradually To conclude, an explicit distinction between stage 2 and SWS bears not only methodological but also theoretical difficulties.…”