Molecular and Anatomical Signatures of Sleep Deprivation in the Mouse Brain

Sleep deprivation (SD) leads to a suite of cognitive and behavioral impairments, and yet the molecular consequences of SD in the brain are poorly understood. Using a systematic immediate-early gene (IEG) mapping to detect neuronal activation, the consequences of SD were mapped primarily to forebrain regions. SD was found to both induce and suppress IEG expression (and thus neuronal activity) in subregions of neocortex, striatum, and other brain regions. Laser microdissection and cDNA microarrays were used to identify the molecular consequences of SD in seven brain regions. In situ hybridization (ISH) for 222 genes selected from the microarray data and other sources confirmed that robust molecular changes were largely restricted to the forebrain. Analysis of the ISH data for 222 genes (publicly accessible at http://sleep.alleninstitute.org) provided a molecular and anatomic signature of the effects of SD on the brain. The suprachiasmatic nucleus (SCN) and the neocortex exhibited differential regulation of the same genes, such that in the SCN genes exhibited time-of-day effects while in the neocortex, genes exhibited only SD and waking (W) effects. In the neocortex, SD activated gene expression in areal-, layer-, and cell type-specific manner. In the forebrain, SD preferentially activated excitatory neurons, as demonstrated by double-labeling, except for striatum which consists primarily of inhibitory neurons. These data provide a characterization of the anatomical and cell type-specific signatures of SD on neuronal activity and gene expression that may account for the associated cognitive and behavioral effects.

[1]  G. Tononi,et al.  Extensive and Divergent Effects of Sleep and Wakefulness on Brain Gene Expression , 2004, Neuron.

[2]  Kenneth S. Koblan,et al.  Refined anatomical isolation of functional sleep circuits exhibits distinctive regional and circadian gene transcriptional profiles , 2009, Brain Research.

[3]  Rae Silver,et al.  Orchestrating time: arrangements of the brain circadian clock , 2005, Trends in Neurosciences.

[4]  Hong Wei Dong,et al.  Allen reference atlas : a digital color brain atlas of the C57Black/6J male mouse , 2008 .

[5]  H. Heller,et al.  Separating the contribution of glucocorticoids and wakefulness to the molecular and electrophysiological correlates of sleep homeostasis. , 2010, Sleep.

[6]  H. Heller,et al.  Region-specific changes in immediate early gene expression in response to sleep deprivation and recovery sleep in the mouse brain , 2003, Neuroscience.

[7]  H. Heller,et al.  Prepro-hypocretin (prepro-orexin) expression is unaffected by short-term sleep deprivation in rats and mice. , 2000, Sleep.

[8]  G. Churchill,et al.  What are microarrays teaching us about sleep? , 2009, Trends in molecular medicine.

[9]  I. Black,et al.  NGF and BDNF are differentially modulated by visual experience in the developing geniculocortical pathway. , 1995, Brain research. Developmental brain research.

[10]  Allan R. Jones,et al.  Genomic Anatomy of the Hippocampus , 2008, Neuron.

[11]  Cheng Li,et al.  Adjusting batch effects in microarray expression data using empirical Bayes methods. , 2007, Biostatistics.

[12]  G. Tononi,et al.  Differences in gene expression between sleep and waking as revealed by mRNA differential display. , 1998, Brain research. Molecular brain research.

[13]  N. Naidoo,et al.  Eif-2a Protects Brainstem Motoneurons in a Murine Model of Sleep Apnea , 2008, The Journal of Neuroscience.

[14]  A. Pitkänen,et al.  Projections from the lateral, basal and accessory basal nuclei of the amygdala to the perirhinal and postrhinal cortices in rat. , 2001, Cerebral cortex.

[15]  R. McCarley,et al.  Activation of Ventrolateral Preoptic Neurons During Sleep , 1996, Science.

[16]  R. Lefkowitz,et al.  The role of beta-arrestins in the termination and transduction of G-protein-coupled receptor signals. , 2002, Journal of cell science.

[17]  Brian B. Avants,et al.  Neuroinformatics for Genome-Wide 3-D Gene Expression Mapping in the Mouse Brain , 2007, IEEE/ACM Transactions on Computational Biology and Bioinformatics.

[18]  H. Heller,et al.  A non-circadian role for clock-genes in sleep homeostasis:a strain comparison , 2007, BMC Neuroscience.

[19]  J. Besharse,et al.  Immediate early response of the circadian polyA ribonuclease nocturnin to two extracellular stimuli. , 2007, RNA.

[20]  G. Tononi,et al.  On the functional significance of c-fos induction during the sleep-waking cycle. , 2000, Sleep.

[21]  DM Dorsa,et al.  Differential effects of haloperidol and clozapine on neurotensin gene transcription in rat neostriatum , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[22]  J. Monti,et al.  The roles of dopamine and serotonin, and of their receptors, in regulating sleep and waking. , 2008, Progress in brain research.

[23]  I. Tobler,et al.  Sleep and EEG spectra in the Syrian hamster (Mesocricetus auratus) under baseline conditions and following sleep deprivation , 1987, Journal of Comparative Physiology A.

[24]  B. H. Miller,et al.  Coordinated Transcription of Key Pathways in the Mouse by the Circadian Clock , 2002, Cell.

[25]  J. Besharse,et al.  Rhythmic expression of Nocturnin mRNA in multiple tissues of the mouse , 2001, BMC Developmental Biology.

[26]  Allan R. Jones,et al.  Neuroinformatics for Genome-Wide 3-D Gene Expression Mapping in the Mouse Brain , 2007, TCBB.

[27]  U. Ungerstedt,et al.  Neurotensin increases endogenous glutamate release in the neostriatum of the awake rat. , 1995, Synapse.

[28]  Reto Huber,et al.  Effects of sleep deprivation on sleep and sleep EEG in three mouse strains: empirical data and simulations , 2000, Brain Research.

[29]  M. Massimini,et al.  Glial and neuronal interactions during slow wave and paroxysmal activities in the neocortex. , 2002, Cerebral cortex.

[30]  M. Walker,et al.  The human emotional brain without sleep — a prefrontal amygdala disconnect , 2007, Current Biology.

[31]  N. Horike,et al.  Salt-inducible kinase-1 represses cAMP response element-binding protein activity both in the nucleus and in the cytoplasm. , 2004, European journal of biochemistry.

[32]  E. Nofzinger.  Functional neuroimaging of sleep. , 2005, Seminars in neurology.

[33]  G. Tononi,et al.  Molecular and electrophysiological evidence for net synaptic potentiation in wake and depression in sleep , 2008, Nature Neuroscience.

[34]  J. Besharse,et al.  Identification of a novel vertebrate circadian clock-regulated gene encoding the protein nocturnin. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[35]  Michael M. Halassa,et al.  Astrocytic Modulation of Sleep Homeostasis and Cognitive Consequences of Sleep Loss , 2009, Neuron.

[36]  Allan R. Jones,et al.  An anatomic gene expression atlas of the adult mouse brain , 2009, Nature Neuroscience.

[37]  C. Degueldre,et al.  Sleep after spatial learning promotes covert reorganization of brain activity. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[38]  Takeshi Sakurai,et al.  Identification of a population of sleep-active cerebral cortex neurons , 2008, Proceedings of the National Academy of Sciences.

[39]  Steven M. Reppert,et al.  Rhythmic histone acetylation underlies transcription in the mammalian circadian clock , 2003, Nature.

[40]  C. Saper,et al.  Hypothalamic regulation of sleep and circadian rhythms , 2005, Nature.

[41]  M. Modirrousta,et al.  Orexin and MCH neurons express c‐Fos differently after sleep deprivation vs. recovery and bear different adrenergic receptors , 2005, The European journal of neuroscience.

[42]  O. Bosler,et al.  Glucocorticoids up‐regulate the expression of glial fibrillary acidic protein in the rat suprachiasmatic nucleus , 2000, Glia.

[43]  G. Tononi,et al.  Gene expression in the brain across the sleep–waking cycle 1 1 Published on the World Wide Web on 30 October 2000. , 2000, Brain Research.

[44]  K. Fuxe,et al.  Nigral neurotensin receptor regulation of nigral glutamate and nigroventral thalamic GABA transmission: a dual-probe microdialysis study in intact conscious rat brain , 2001, Neuroscience.

[45]  T. Curran,et al.  Stimulus-transcription coupling in the nervous system: involvement of the inducible proto-oncogenes fos and jun. , 1991, Annual review of neuroscience.

[46]  Nora D. Volkow,et al.  Hyperstimulation of striatal D2 receptors with sleep deprivation: Implications for cognitive impairment , 2009, NeuroImage.

[47]  Allan R. Jones,et al.  Genome-wide atlas of gene expression in the adult mouse brain , 2007, Nature.

[48]  Maria V. Sanchez-Vives,et al.  Cellular and network mechanisms of rhythmic recurrent activity in neocortex , 2000, Nature Neuroscience.

[49]  M. Steriade.  Grouping of brain rhythms in corticothalamic systems , 2006, Neuroscience.

[50]  C. Cirelli.  Cellular consequences of sleep deprivation in the brain. , 2006, Sleep medicine reviews.

[51]  Federico Poloni.  Of Note , 2009 .

[52]  C. Peyron,et al.  Gene expression in the rat brain during sleep deprivation and recovery sleep: an Affymetrix GeneChip® study , 2006, Neuroscience.

[53]  K. Fuxe,et al.  The Striatal Neurotensin Receptor Modulates Striatal and Pallidal Glutamate and GABA Release: Functional Evidence for a Pallidal Glutamate–GABA Interaction via the Pallidal–Subthalamic Nucleus Loop , 1998, The Journal of Neuroscience.

[54]  Ook Joon Yoo,et al.  PERIOD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[55]  Lisa Y. M. Chuah,et al.  Functional neuroimaging insights into how sleep and sleep deprivation affect memory and cognition , 2008, Current opinion in neurology.

[56]  G. Tononi,et al.  Sleep function and synaptic homeostasis. , 2006, Sleep medicine reviews.

[57]  C. Gerfen,et al.  Coincident stimulation of convergent cortical inputs enhances immediate early gene induction in the striatum , 2005, Neuroscience.

[58]  Alexander A. Borbély,et al.  Effect of sleep deprivation on sleep and EEG power spectra in the rat , 1984, Behavioural Brain Research.

[59]  E. Lein,et al.  Sleep Deprivation Effects on Circadian Clock Gene Expression in the Cerebral Cortex Parallel Electroencephalographic Differences among Mouse Strains , 2008, The Journal of Neuroscience.

[60]  G. Tononi,et al.  Immediate‐early genes in spontaneous wakefulness and sleep: expression of c‐fos and NGFI‐A mRNA and protein , 1994, Journal of sleep research.

[61]  A. Deutch,et al.  Neurotensin: dual roles in psychostimulant and antipsychotic drug responses. , 2003, Life sciences.

[62]  J. Deniau,et al.  Effect of electrical stimulation of the cerebral cortex on the expression of the fos protein in the basal ganglia , 1997, Neuroscience.

[63]  Miguel Angel Guevara,et al.  Amplitude reduction in visual event-related potentials as a function of sleep deprivation. , 1999, Sleep.

[64]  Jean YH Yang,et al.  Bioconductor: open software development for computational biology and bioinformatics , 2004, Genome Biology.

[65]  H. Heller,et al.  Differential increase in the expression of heat shock protein family members during sleep deprivation and during sleep , 2003, Neuroscience.

[66]  Hongyue Dai,et al.  Rosetta error model for gene expression analysis , 2006, Bioinform..

[67]  K. Fuxe,et al.  Differential Effects of lntrastriatal Neurotensin(1–13) and Neurotensin(8–13) on Striatal Dopamine and Pallidal GABA Release. A Dual‐probe Microdialysis Study in the Awake Rat , 1997, The European journal of neuroscience.

[68]  J. Price.  :Allen Reference Atlas: A Digital Color Brain Atlas of the C57BL/6J Male Mouse , 2008 .

[69]  S. Pradervand,et al.  Homer1a is a core brain molecular correlate of sleep loss , 2007, Proceedings of the National Academy of Sciences.

[70]  Peter Meerlo,et al.  New neurons in the adult brain: the role of sleep and consequences of sleep loss. , 2009, Sleep medicine reviews.

[71]  G. Siegmund.  [Sleep and wakefulness]. , 1972, Krankenpflege.

[72]  Franck Delaunay,et al.  The Circadian Clock Component BMAL1 Is a Critical Regulator of p21WAF1/CIP1 Expression and Hepatocyte Proliferation* , 2008, Journal of Biological Chemistry.

[73]  P. Franken,et al.  Sleep and cortical temperature in the Djungarian hamster under baseline conditions and after sleep deprivation , 1994, Journal of Comparative Physiology A.

[74]  A. Pitkänen,et al.  Projections from the lateral, basal, and accessory basal nuclei of the amygdala to the hippocampal formation in rat , 1999, The Journal of comparative neurology.

[75]  J. Tepper,et al.  Functional diversity and specificity of neostriatal interneurons , 2004, Current Opinion in Neurobiology.

[76]  Y. Kawaguchi.  Neostriatal cell subtypes and their functional roles , 1997, Neuroscience Research.

[77]  T. Curran,et al.  Expression of c-fos protein in brain: metabolic mapping at the cellular level. , 1988, Science.

[78]  D. Hoyer,et al.  Region-specific transcriptional changes following the three antidepressant treatments electro convulsive therapy, sleep deprivation and fluoxetine , 2007, Molecular Psychiatry.

[79]  Shane T. Jensen,et al.  Macromolecule biosynthesis: a key function of sleep. , 2007, Physiological genomics.