COMMENTARY
Sleep Homeostasis: Finding Odysseus among the Mnesteres
Commentary on Mongrain et al. Separating the contribution of glucocorticoids and wakefulness to the molecular and
electrophysiological correlates of sleep homeostasis. SLEEP 2010;33:1147-1157.
Sigrid Veasey, MD
Department of Medicine, University of Pennsylvania, Philadelphia, PA
IN HOMER’S THE ODYSSEY1 PENELOPE IS ONLY CONVINCED SHE HAS FOUND HER LONG LOST HUSBAND
AMONG THE TRIBE OF RANCOROUS SUITORS BY
Odysseus’ knowledge of the origins of their bed, around which
the house was built. Simply seeing him (albeit 20 years later),
hearing him and watching him string his “unmanageable for
mortals” bow and send a single arrow deftly through 12 ax head
sockets was not enough to unveil his identity. Until thoroughly
convinced that Odysseus had returned, Penelope maintained
her reservation.
Sleep research has a task—no less formidable than Penelope’s—of sorting through thousands of candidate genes to
identify those that truly influence sleep homeostasis and might
provide clues about the roles sleep serves. In this month’s issue
of SLEEP, Mongrain and colleagues2 have used a clever strategy
to impressively narrow down the list of candidate sleep genes for
sleep homeostasis. Among the (many) confounds in sleep deprivation paradigms is the stress related to the increased handling
of sleep-deprived animals, necessary to maintain wakefulness.
The stress of sleep deprivation perturbs the hypothalamic pituitary axis, resulting in, among other physiological responses,
increased corticosterone.3,4 Corticosterone heads a major stress
response with profound effects on nitric oxide synthase activity, glucose utilization, mitochondrial activity, and transcription
(sufficient to induce synaptic plasticity and reduce neurotrophic
factors).5,6 Identifying a mouse strain with higher cortisol levels
yet lower homeostatic drive than two other strains, Mongrain et
al., hypothesized that the corticosterone response was not critical for the sleep-deprivation response and set forth to remove
corticosterone as a confounder in sleep homeostasis.2 Indeed,
mice with adrenalectomy evidenced normal sleep and showed
similar homeostatic responses to sleep loss as sham-operated
mice. This finding, in turn, enabled the investigators to analyze
the microarray gene response to sleep loss without corticosterone’s effects on mRNA, thereby narrowing the list from 1500
genes modified by sleep deprivation to 500. Taking advantage
of a second circadian time point after spontaneous wakefulness
in the mouse when delta power is elevated (6 hours after lights
off for the mouse), the investigators were able to further narrow
the list to 80 genes modified by extended wakefulness with or
without adrenalectomy at both time points.2
Does this significantly narrowed list provide new insight into
the role of sleep and homeostatic regulation? Mackiewicz and
colleagues recently summarized the collective findings from
the past decade of sleep deprivation microarray studies.7 Consistent findings across various experimental paradigms showed
that only a few functional groups of genes vary across sleep and
wakefulness. Genes upregulated by sleep deprivation include
subsets of molecular chaperones and synaptic plasticity genes;
while macromolecular synthesis and energy production genes
are down-regulated in response to prolonged wakefulness.8-11
In the present study, adrenalectomy removed almost all of the
macromolecular synthesis and energy production genes from
sleep homeostasis transcriptional responses.2 The list still includes a number of protein chaperone genes that fit nicely with
the hypothesis that prolonged sleep deprivation activates chaperone-mediated protein folding (endoplasmic reticulum) and
degradation (both ubiquitination and autophagy). The refined
list also includes genes involved in neuronal differentiation and
growth, including upregulation of many transcription factors.
Few genes in this narrowed homeostasis array list, however, are
considered to influence neuronal excitability and might, therefore, play a direct role in slow wave sleep or the homeostatic
response to sleep loss. Those present in the list include a few
ERK/MAPK signaling genes and a few synaptic genes, including Homer1.
Homer1 (Homer1a) is the gene that has shown up in all microarray analyses of sleep deprivation, including the present,
and for which an increase in its protein in sleep deprivation
has been shown.12,13 Is Homer1 our Odysseus? Homer proteins
are post-synaptic density and growth cone scaffolding proteins,
and Homer1 contributes to intracellular calcium homeostasis through modifying ryanodine and IP3 calcium release in
response to receptor activation, including metabotropic glutamate receptors. In addition, Homer1 is critical for axon guidance, where reductions in Homer1 switch axon growth cone
responses from attraction to repulsion. In light of these critical
and significant roles in normal neuronal function, we excitedly
await studies examining local acute modulation (up and down)
of Homer1 along various points in the thalamocortical circuit
to critically test its role in local and/or whole brain sleep homeostasis.
By excluding the corticosterone component of sleep deprivation, have we thrown out Telemachus (Odysseus’ son) with
the bathwater? In interpreting the microarray findings, it is important to distinguish which questions may be answered effectively with a given experimental paradigm. The adrenalectomy
strategy, employed by Mongrain et al.,2 is the proper approach
to elucidate clues regarding slow wave sleep responses to sleep
Submitted for publication July, 2010
Accepted for publication July, 2010
Address correspondence to: Sigrid Veasey, MD, Department of Medicine,
University of Pennsylvania,125 S 31st St Room 2115, Philadelphia, PA
19104; Tel: (215) 746-4812; E-mail: [email protected]
SLEEP, Vol. 33, No. 9, 2010
1131
Commentary—Veasey
REFERENCES
deprivation. From this approach, we can conclude that genes
for many myelin molecules, membrane and cytoskeleton proteins are suppressed by enforced wakefulness in a corticosterone-dependent fashion. If we wish to answer what processes
are disrupted by prolonged sleep restriction, or why do we need
to sleep, the adrenals must remain intact, and the approach used
by Mackiewicz et al.,13 with several durations of sleep deprivation that provide different levels of homeostatic drive, would
be preferable.
Let us be as cautious as Penelope in our quest for sleep homeostasis genes. Does a focused proteomics screen (for this
mRNA array list) support involvement of these genes in sleep
homeostasis? Does Homer1 or any other candidate gene show
a dose-dependent response to sleep loss that predicts the homeostatic drive across several strains of mice? Does this gene
increase to a larger extent in youth with increased homeostatic
drive and does this response deteriorate with aging in parallel
with changes in homeostatic drive? Does the candidate gene
increase locally in a brain region activated in specific motor or
visual challenges across wakefulness and where rebound slow
wave sleep is enhanced? Penelope did not find Odysseus by
herself; she was helped in her quest by her son, her maid, the
gods and Odysseus. We, too, will likely have to put forth a wellplanned collaborative effort to find our Odysseus.
1. Homer, The Odyssey, Book XXIII, Written 800 B.C.E., Translated by
Samuel Butler.
2. Mongrain et al. Separating the contribution of glucocorticoids and wakefulness to the molecular and electrophysiological correlates of sleep homeostasis. SLEEP 2010;33:1147-1157.
3. Tobler I, Murison R, Ursin R, Ursin H, Borbély AA. The effect of sleep
deprivation and recovery sleep on plasma corticosterone in the rat. Neurosci Lett 1983;35:297-300.
4. Meerlo P, Koehl M, van der Borght K, Turek FW. Sleep restriction alters
the hypothalamic-pituitary-adrenal response to stress. J Neuroendocrinol
2002;14:397-402.
5. Meijer OC. Coregulator proteins and corticosteroid action in the brain. J
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6. Joëls M, Vreugdenhil E. Corticosteroids in the brain. Cellular and molecular actions. Mol Neurobiol 1998;17:87-108.
7. Mackiewicz M, Zimmerman JE, Shockley KR, Churchill GA, Pack
AI. What are microarrays teaching us about sleep? Trends Mol Med
2009;15:79-87.
8. Cirelli C, Faraguna U, Tononi G. Changes in brain gene expression after
long-term sleep deprivation. J Neurochem 2006;98:1632-45.
9. Cirelli C, LaVaute TM, Tononi G. Sleep and wakefulness modulate gene
expression in Drosophila. J Neurochem 2005;94:1411-9.
10. Mackiewicz M, Shockley KR, Romer MA, et al. Macromolecule biosynthesis: a key function of sleep. Physiol Genomics 2007;31:441-57.
11. Jones S, Pfister-Genskow M, Benca RM, Cirelli C. Molecular correlates
of sleep and wakefulness in the brain of the white-crowned sparrow. J
Neurochem 2008;105:46-62.
12. Maret S, Dorsaz S, Gurcel L, et al. Homer1a is a core brain molecular
correlate of sleep loss. Proc Natl Acad Sci U S A 2007;104:20090-5.
13. Mackiewicz M, Paigen B, Naidoo N, Pack AI. Analysis of the QTL for
sleep homeostasis in mice: Homer1a is a likely candidate. Physiol Genomics 2008;33:91-9.
DISCLOSURE STATEMENT
Dr. Veasey has indicated no financial conflicts of interest.
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Commentary—Veasey