Homer1a is a core brain molecular correlate of sleep loss

Center for Integrative Genomics and Lausanne DNA Array Facility, University of Lausanne, Génopode, CH-1015 Lausanne, Switzerland.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2008; 104(50):20090-5. DOI: 10.1073/pnas.0710131104
Source: PubMed

ABSTRACT Sleep is regulated by a homeostatic process that determines its need and by a circadian process that determines its timing. By using sleep deprivation and transcriptome profiling in inbred mouse strains, we show that genetic background affects susceptibility to sleep loss at the transcriptional level in a tissue-dependent manner. In the brain, Homer1a expression best reflects the response to sleep loss. Time-course gene expression analysis suggests that 2,032 brain transcripts are under circadian control. However, only 391 remain rhythmic when mice are sleep-deprived at four time points around the clock, suggesting that most diurnal changes in gene transcription are, in fact, sleep-wake-dependent. By generating a transgenic mouse line, we show that in Homer1-expressing cells specifically, apart from Homer1a, three other activity-induced genes (Ptgs2, Jph3, and Nptx2) are overexpressed after sleep loss. All four genes play a role in recovery from glutamate-induced neuronal hyperactivity. The consistent activation of Homer1a suggests a role for sleep in intracellular calcium homeostasis for protecting and recovering from the neuronal activation imposed by wakefulness.

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Available from: Bruce F O'Hara, Sep 26, 2015
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    • "Given 146 their diverse functions and origins, more studies and deeper sequencing are required to reveal 147 a causal role of non-coding RNAs to chronic pain (Stefani and Slack, 2008;Mercer et al., 148 2009). 149 A growing body of literature using sequencing technology has revealed transcriptome 150 signatures in illnesses that are co-morbid with chronic pain in the PFC, including depression 151 (Sibille et al., 2004), sleep disorders (Maret et al., 2007), anxiety (Sibille et al., 2004;Virok et 152 al., 2011), and cognitive impairment (Wood et al., 2013;Humphries and Kohli, 2014). While 153 geneticists have long sought a heritable mutational basis for disease susceptibility, genome- 154 wide association studies and the search for such genes have found few risk alleles that 155 account for these phenomena in a broader population (Kraft and Hunter, 2009). "
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    ABSTRACT: Chronic pain is accompanied with long-term sensory, affective and cognitive disturbances. What are the mechanisms that mediate the long-term consequences of painful experiences and embed them in the genome? We hypothesize that alterations in DNA methylation, an enzymatic covalent modification of cytosine bases in DNA, serve as a “genomic” memory of pain in the adult cortex. DNA methylation is an epigenetic mechanism for long-term regulation of gene expression. Neuronal plasticity at the neuroanatomical, functional, morphological, physiological and molecular levels has been demonstrated throughout the neuroaxis in response to persistent pain, including in the adult prefrontal cortex (PFC). We have previously reported widespread changes in gene expression and DNA methylation in the PFC many months following peripheral nerve injury. In support of this hypothesis, we show here that up-regulation of a gene involved with synaptic function, Synaptotagmin II (syt2), in the PFC in a chronic pain model is associated with long-term changes in DNA methylation. The challenges of understanding the contributions of epigenetic mechanisms such as DNA methylation within the PFC to pain chronicity and their therapeutic implications are discussed.
    Frontiers in Cellular Neuroscience 02/2015; 9(88). DOI:10.3389/fncel.2015.00088 · 4.29 Impact Factor
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    • "Sleep Deprivation and Gene Expression the evening (active period); similar results of a lesser magnitude were obtained for Homer1bc (Nelson et al. 2004). Homer1a is significantly overexpressed in the cerebral cortex, hippocampus, and striatum in three different mouse genotypes (Maret et al. 2007). Another study using microarray analysis and the disk-overwater method presented compatible results: Rats deprived of sleep for 8 h showed upregulated Homer1a levels in comparison with animals allowed to sleep, while sleep deprivation for 7 days yielded a non-significant tendency for transcriptional downregulation in comparison with short-term sleep deprivation (8 h) and spontaneous waking (Cirelli et al. 2006). "
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    ABSTRACT: Sleep occurs in a wide range of animal species as a vital process for the maintenance of homeostasis, metabolic restoration, physiological regulation, and adaptive cognitive functions in the central nervous system. Long-term perturbations induced by the lack of sleepSleep are mostly mediated by changes at the level of transcription and translation. This chapter reviews studies in humans, rodents, and flies to address the various ways by which sleep deprivation affects gene expressionGene expression in the nervous system, with a focus on genes related to neuronal plasticity, brain function, and cognitionCognition . However, the effects of sleep deprivation on gene expression and the functional consequences of sleep loss are clearly not restricted to the cognitive domain but may include increased inflammationInflammation , expression of stress-related genes, general impairment of protein translation, metabolic imbalance, and thermalThermoregulation deregulation.
    Current Topics in Behavioral Neurosciences 02/2015; 25. DOI:10.1007/7854_2014_360
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    • "BMAL1 KO mice have a significant disruption of the normal diurnal distribution of NREM and REM sleep over the light-dark cycle (Laposky et al., 2005), suggesting that BMAL1 is necessary for time-of-day dependent behavior even in the presence of a zeitgeber. BMAL1 expression has also been shown to be affected by sleep loss (Maret et al., 2007), and can influence the homeostatic response to sleep deprivation (Laposky et al., 2005) and certain aspects of memory formation (Kondratova et al., 2010). In addition to sleep and memory, core molecular clock mechanisms influence synaptic plasticity, further evidence for a neurophysiological role outside of the establishment of circadian locomotor rhythms (Gerstner and Yin, 2010). "
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    ABSTRACT: The epilepsies are a heterogeneous group of neurological diseases defined by the occurrence of unprovoked seizures which, in many cases, are correlated with diurnal rhythms. In order to gain insight into the biological mechanisms controlling this phenomenon, we characterized time-of-day effects on electrical seizure threshold in mice. Male C57BL/6J wild-type mice were maintained on a 14/10 h light/dark cycle, from birth until 6 weeks of age for seizure testing. Seizure thresholds were measured using a step-wise paradigm involving a single daily electrical stimulus. Results showed that the current required to elicit both generalized and maximal seizures was significantly higher in mice tested during the dark phase of the diurnal cycle compared to mice tested during the light phase. This rhythm was absent in BMAL1 knockout (KO) mice. BMAL1 KO also exhibited significantly reduced seizure thresholds at all times tested, compared to C57BL/6J mice. Results document a significant influence of time-of-day on electrical seizure threshold in mice and suggest that this effect is under the control of genes that are known to regulate circadian behaviors. Furthermore, low seizure thresholds in BMAL1 KO mice suggest that BMAL1 itself is directly involved in controlling neuronal excitability.
    Frontiers in Systems Neuroscience 06/2014; 8:121. DOI:10.3389/fnsys.2014.00121
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