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. Author manuscript; available in PMC: 2010 Aug 1.
Published in final edited form as: Nat Rev Neurosci. 2009 Aug;10(8):549–560. doi: 10.1038/nrn2683

Table 1.

The best characterized non-mammalian animal models currently used in sleep research, together with major similarities and differences relative to sleep in mice and other mammals.

Aspects of sleep documented in mice and other mammals Fruit fly (Drosophila melanogaster) Zebrafish (Danio rerio) Caenorhabditis elegans
Behavioral definition of sleep is met yes: quiescence and increased arousal threshold 88,132 yes: quiescence and increased arousal threshold 14–16 yes: quiescence and increased arousal threshold during development (lethargus) 17; preliminary evidence for quiescence and increased rest after deprivation in adults 133
Documented changes in brain activity yes: brain electrical activity is reliably correlated with behavioral state 134
Homeostatic regulation of sleep is present yes: increase in sleep time, arousal threshold, duration of sleep episodes and decrease in brief awakenings after sleep deprivation; homeostatic regulation largely independent of the circadian clock 88,132,135; however, sleep is more fragmented in cycle and Clock mutants, and female (but not male) cycle mutants show exaggerated response to sleep deprivation 40,97 yes: increase in sleep time, arousal threshold, and duration of sleep episodes after sleep deprivation by electrical stimulation or vibration; weak or no homeostatic response after sleep deprivation by light exposure 14,16 yes: following deprivation quiescence occurs earlier, is more consolidated; arousal threshold increased relative to baseline 17
Circadian regulation of sleep is present yes: sleep mainly at night in entrained light:dark conditions or constant darkness; arrhythmic sleep after lesions of the circadian clock 88 yes: sleep mainly at night 14–16 Lethargus is time locked to the expression of Lin-42, the C. elegans ortholog of the circadian gene Period 136
Changes in brain gene expression associated with sleep and waking yes: some are similar to those seen in mammals79,84
Changes in sleep parameters with aging yes:sleep fragmentation in old flies 137 (not tested?) (sleep-like state well defined only during larval development)
Drugs and signaling pathways: similarities with mammals increase in waking with caffeine, modafinil, amphetamines, octopamine (insect equivalent of norepinephrine), increase in sleep with antihistamines 88,132,138–140

  • - dopamine; a DAT mutation called Fumin (sleepless in Japanese) decreases daily sleep amount by ~ 60% 141, consistent with reduced NREM sleep in DAT KO mice 142

  • - GABA; genetic manipulations that decrease GABA transmission result in reduced sleep 143

  • -cAMP-dependent protein kinaseA (PKA)-CREB activity: inverse relationship with daily sleep amount in flies and mice 98,144.

 increased sleep with melatonin, GABAergic hypnotics, alpha2-adrenergic agonists, histaminergic H1 antagonists 14,145,146 most major mammalian neurotransmitters present (ACh, glutamate, dopamine, serotonin, GABA)
As in mammals, genetic manipulations that increase the EGFR pathway block locomotion and feeding 147, but untested whether this quiescence is a sleep-like state (i.e. with increased arousal threshold)
Drugs and signaling pathways: differences with mammals

  • - epidermal growth factor receptor (EGFR) signaling; in mammals, the pathway affects more and/or only the circadian regulation of sleep but not sleep amount 148–150; in flies, genetic manipulations that increase/decrease this EGFR pathway increase/decrease sleep amount without affecting its circadian regulation 151.

  • - serotonin; complex role in mammals, where it may increase/decrease sleep depending on time of day 152; sleep-promoting role in flies 153

 unclear whether the hypocretin/orexin system is wake-promoting as in mammals 15, or sleep- promoting 16
Major differences relative to mammals

  • - REM-like phase not identified

  • - neuroanatomy

  • - some neurochemistry (tyramine/octopamine but no norepinephrine; no hypocretin/orexin homologue identified)

  • - REM-like phase not identified

  • - REM-like phase not identified

  • - neuroanatomy

  • - some neurochemistry (tyramine/octopamine but no norepinephrine; no histamine)
Major strengths and limitations as animal model for sleep

  • + advanced genetics, fast results, cheap

  • + limited genome redundancy

  • - difficult to perform electrophysiological studies in CNS

  • - genetic screens that target the effects of mutations specifically on the fly brain not yet available

  • + advanced genetics

  • +vertebrate; CNS organization more similar to mammals; easily visualized brain cholinergic/monoaminergic/hypocretin cell groups conserved (refs in 16)

  • + easy drug screening

  • + advanced genetics, fast results, cheap

  • + simple nervous system, neurons/connections fully characterized

  • - in adults quality-high food induces quiescence, but it remains untested whether this state is sleep-like (with increased arousal threshold) and homeostatically regulated 154

  • - high-throughput assay to measure sleep/waking not yet available