Sleep architecture and homeostasis in mice with partial ablation of melanin-concentrating hormone neurons

- Using an original model of transgenic mice, we provide new insights regarding the contribution of the hypothalamic MCH-expressing neurons to the regulation of vigilance states.
- We indeed show that adult MCHAtax mice with a severe alteration of central MCH system depicted subtle but deleterious qualitative and quantitative alterations of sleep.
- Whereas MCH neurons are thought to be involved in REM sleep physiology, our data suggests that when activated they also improve the depth of slow wave sleep (SWS) by favoring both its consolidation and related slow-wave activity (SWA).
- Such mechanisms could be recruited for restoring function of sleep especially following homeostatic challenge as sleep deprivation or learning/memory processes.

Recent reports support a key role of tuberal hypothalamic neurons secreting melanin concentrating-hormone (MCH) in the promotion of Paradoxical Sleep (PS). Controversies remain concerning their concomitant involvement in Slow-Wave Sleep (SWS). We studied the effects of their selective loss achieved by an Ataxin 3-mediated ablation strategy to decipher the contribution of MCH neurons to SWS and/or PS. Polysomnographic recordings were performed on male adult transgenic mice expressing Ataxin-3 transgene within MCH neurons (MCHAtax) and their wild-type littermates (MCHWT) bred on two genetic backgrounds (FVB/N and C57BL/6). Compared to MCHWT mice, MCHAtax mice were characterized by a significant drop in MCH mRNAs (−70%), a partial loss of MCH-immunoreactive neurons (−30%) and a marked reduction in brain density of MCH-immunoreactive fibers. Under basal condition, such MCHAtax mice exhibited higher PS amounts during the light period and a pronounced SWS fragmentation without any modification of SWS quantities. Moreover, SWS and PS rebounds following 4-h total sleep deprivation were quantitatively similar in MCHAtaxvs. MCHWT mice. Additionally, MCHAtax mice were unable to consolidate SWS and increase slow-wave activity (SWA) in response to this homeostatic challenge as observed in MCHWT littermates. Here, we show that the partial loss of MCH neurons is sufficient to disturb the fine-tuning of sleep. Our data provided new insights into their contribution to subtle process managing SWS quality and its efficiency rather than SWS quantities, as evidenced by the deleterious impact on two powerful markers of sleep depth, i.e., SWS consolidation/fragmentation and SWA intensity under basal condition and under high sleep pressure.