Is lethargus really a 'sleep-like' state?

Hi,

Is Lethargus really a ‘sleep-like’ state?

A paper by Raizen et al. published in Nature in 2008, suggested that the behavioural quiescence observed during lethargus has all the hallmarks of a sleep-like state.

http://www.nature.com/nature/journal/v451/n7178/abs/nature06535.html

They reported/cited experimental evidence that shows lethargus in C. elegans;

  1. Maintains a constant temporal relationship via the expression of the Period homologue lin-42.
  2. That lethargus is reversible.
  3. That during lethargus, worms exhibit reduced responsiveness to mechanical and olfactory stimulation.
  4. That ‘enforced wakefulness’ during the L3 lethargus led to an extension of the subsequent (L4)lethargus period.

But is lethargus really a sleep-like state?
Or are each of these observations consistent with distinctive periods of developmental change where ‘resources’ and cellular activity are diverted to particular developmental goals and away from normal external sensory functioning?
Could it be that lin-42 is a (relatively) primitive developmental timer that evolved later into a circadian programmer?
Lethargus is reversible but so is the dauer stage and these two stages are designed ultimately to fulfill different goals.
Reduced responsiveness during lethargus seems to fit the model, but wouldn’t one expect to see differences just before and just after lethargus too? When I’m tired I certainly respond differently to stimuli than when I’ve just had a good night’s sleep.
The enforced wakefulness led to a prolonged subsequent lethargus period. But does this reflect ‘sleep deprivation’ or rather, that developmental ‘goals’ not accomplished during L3 lethargus were simply pushed into the L4 lethargus instead? Being deprived of sleep also makes me tired and certainly, if given the opportunity I would sleep for longer and more soundly at the next opportunity. However, if there was something important to sort out (like my development), I would be flexible enough to carry on as normal and then sleep.

All of this is not a critique of the paper (oh, ok, it is I guess), which I find very interesting……just want to hear what others think!

Steve

Hi Steve,

Interesting question. I think it’s highly likely that lin-42 started out as a developmental timer that later evolved into a circadian programmer. Alison Frand’s recent Current Biology paper (http://www.ncbi.nlm.nih.gov/pubmed/22137474) demonstrates that lin-42 mRNA levels peak during the molts and suggest that the rising and falling of LIN-42 levels regulate the start and completion of the molt. You point out that like the dauer stage, lethargus is reversible, but lethargus does not involve remodeling of the animal as in dauer. I suppose the larger and most interesting question is what is the nature of sleep. Maybe originally it was a way to couple energetically expensive cellular processes with periods of inactivity. This would be a nice link with lethargus to control of the molt. The animal must coordinate an intricate series of gene regulatory events, degradation of the cuticle, synthesis of a new cuticle, and behavioral alterations in order to minimize the chance of error in the process, which would increase chances of the animal’s death. So maybe worms sleep, but it’s difficult to anthropomorphize too much as clearly mammalian sleep and nematode lethargus differ on many levels.

It’s interesting to note that there is an intimate link between the S-phase replication checkpoint and circadian rhythm in many metazoans, but in worms the TIMELESS homolog (tim-1) is not a circadian rhythm gene but rather is involved in chromatid cohesion. I always wondered if this might be a common theme in nematodes where they don’t have classic circadian rhythms, but components are embedded into biological processes that cycle.

Best wishes,

Jordan

Hi Jordan,

thanks for your thoughts on my question. I take your point regarding the comparison between dauer and lethargus, I guess I was more concerned about the trend towards (as you also mention) anthropomorphising already complex processes in ‘simple’ animals as models of complex human disorders, For me, it would be interesting enough to understand how lethargus functions in C. elegans without having to juice it up as a model for sleep and by inference, sleep disorders. It seems the pressures of ever tighter funding budgets has taken its toll.
I find your idea of a semi-hardwired circadian components modulating physiological processes in C elegans very interesting, perhaps having embedded components instead of a general circadian rhythm relates to the need to respond quickly to changes in the environment and then to return to a ‘normal’ state without resetting the whole system? This would fit with the observation that delays in development that occur during arrest catch up when normal development recommences.

Just need to find a human disorder to link it to and I’m sure it will get funding :wink:

Regards

Steve