Synaptic Homeostasis and Restructuring across the Sleep-Wake Cycle

Sleep is critical for hippocampus-dependent memory consolidation. However, the underlying mechanisms of synaptic plasticity are poorly understood. The central controversy is on whether long-term potentiation (LTP) takes a role during sleep and which would be its specific effect on memory. To address this question, we used immunohistochemistry to measure phosphorylation of Ca2+/calmodulin-dependent protein kinase II (pCaMKIIα) in the rat hippocampus immediately after specific sleep-wake states were interrupted. Control animals not exposed to novel objects during waking (WK) showed stable pCaMKIIα levels across the sleep-wake cycle, but animals exposed to novel objects showed a decrease during subsequent slow-wave sleep (SWS) followed by a rebound during rapid-eye-movement sleep (REM). The levels of pCaMKIIα during REM were proportional to cortical spindles near SWS/REM transitions. Based on these results, we modeled sleep-dependent LTP on a network of fully connected excitatory neurons fed with spikes recorded from the rat hippocampus across WK, SWS and REM. Sleep without LTP orderly rescaled synaptic weights to a narrow range of intermediate values. In contrast, LTP triggered near the SWS/REM transition led to marked swaps in synaptic weight ranking. To better understand the interaction between rescaling and restructuring during sleep, we implemented synaptic homeostasis and embossing in a detailed hippocampal-cortical model with both excitatory and inhibitory neurons. Synaptic homeostasis was implemented by weakening potentiation and strengthening depression, while synaptic embossing was simulated by evoking LTP on selected synapses. We observed that synaptic homeostasis facilitates controlled synaptic restructuring. The results imply a mechanism for a cognitive synergy between SWS and REM, and suggest that LTP at the SWS/REM transition critically influences the effect of sleep: Its lack determines synaptic homeostasis, its presence causes synaptic restructuring.

[1]  Ryohei Yasuda,et al.  Postsynaptic signaling during plasticity of dendritic spines , 2012, Trends in Neurosciences.

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

[3]  M. Lavine,et al.  Long-Lasting Novelty-Induced Neuronal Reverberation during Slow-Wave Sleep in Multiple Forebrain Areas , 2004, PLoS biology.

[4]  R. Stickgold,et al.  Sleep, memory, and plasticity. , 2006, Annual review of psychology.

[5]  Jean-Christophe Comte,et al.  Paradoxical (REM) sleep deprivation causes a large and rapidly reversible decrease in long-term potentiation, synaptic transmission, glutamate receptor protein levels, and ERK/MAPK activation in the dorsal hippocampus. , 2009, Sleep.

[6]  J. Born,et al.  The memory function of sleep , 2010, Nature Reviews Neuroscience.

[7]  Matthew P Walker,et al.  The role of sleep in directed forgetting and remembering of human memories. , 2011, Cerebral cortex.

[8]  Paul F. M. J. Verschure,et al.  A Signature of Attractor Dynamics in the CA3 Region of the Hippocampus , 2014, PLoS Comput. Biol..

[9]  M. Wilson,et al.  Coordinated Interactions between Hippocampal Ripples and Cortical Spindles during Slow-Wave Sleep , 1998, Neuron.

[10]  J. Born,et al.  Sleep inspires insight , 2004, Nature.

[11]  G. Tononi,et al.  Cortical metabolic rates as measured by 2-deoxyglucose-uptake are increased after waking and decreased after sleep in mice , 2008, Brain Research Bulletin.

[12]  J. Lisman.  A mechanism for memory storage insensitive to molecular turnover: a bistable autophosphorylating kinase. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Matthew S. Thimgan,et al.  Inducing Sleep by Remote Control Facilitates Memory Consolidation in Drosophila , 2011, Science.

[14]  J. Lisman,et al.  The molecular basis of CaMKII function in synaptic and behavioural memory , 2002, Nature Reviews Neuroscience.

[15]  J. Hobson,et al.  Sleep-Induced Changes in Associative Memory , 1999, Journal of Cognitive Neuroscience.

[16]  F. Attneave,et al.  The Organization of Behavior: A Neuropsychological Theory , 1949 .

[17]  J. Born,et al.  Learning-Dependent Increases in Sleep Spindle Density , 2002, The Journal of Neuroscience.

[18]  T. Sejnowski,et al.  Thalamocortical oscillations in the sleeping and aroused brain. , 1993, Science.

[19]  P. Kelly,et al.  The balance between postsynaptic Ca(2+)-dependent protein kinase and phosphatase activities controlling synaptic strength. , 1996, Learning & memory.

[20]  J A Hobson,et al.  Cortical unit activity in sleep and waking. , 1971, Electroencephalography and clinical neurophysiology.

[21]  Andrew Nere,et al.  Sleep-Dependent Synaptic Down-Selection (II): Single-Neuron Level Benefits for Matching, Selectivity, and Specificity , 2013, Front. Neurol..

[22]  J. Born,et al.  Sleep to Remember , 2006, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[23]  G. Tononi,et al.  Sleep and the Price of Plasticity: From Synaptic and Cellular Homeostasis to Memory Consolidation and Integration , 2014, Neuron.

[24]  G. Buzsáki,et al.  REM Sleep Reorganizes Hippocampal Excitability , 2012, Neuron.

[25]  M. Nicolelis,et al.  Global Forebrain Dynamics Predict Rat Behavioral States and Their Transitions , 2004, The Journal of Neuroscience.

[26]  I. Timofeev,et al.  Sleep Oscillations in the Thalamocortical System Induce Long-Term Neuronal Plasticity , 2012, Neuron.

[27]  D Debanne,et al.  Synaptic and non-synaptic plasticity between individual pyramidal cells in the rat hippocampus in vitro , 1996, Journal of Physiology-Paris.

[28]  H. Markram,et al.  Regulation of Synaptic Efficacy by Coincidence of Postsynaptic APs and EPSPs , 1997, Science.

[29]  W. Gan,et al.  Sleep promotes branch-specific formation of dendritic spines after learning , 2014, Science.

[30]  J. Henson,et al.  Plasticity , 2010, Neurology.

[31]  Paul F. M. J. Verschure,et al.  Neuron Report TheMechanismofRateRemappingintheDentateGyrus , 2010 .

[32]  Matthew P Walker,et al.  Sleep Facilitates Consolidation of Emotional Declarative Memory , 2006, Psychological science.

[33]  B. McNaughton,et al.  Reactivation of hippocampal ensemble memories during sleep. , 1994, Science.

[34]  Herman Martins Gomes,et al.  Cross-modal responses in the primary visual cortex encode complex objects and correlate with tactile discrimination , 2011, Proceedings of the National Academy of Sciences.

[35]  Elizabeth A. McDevitt,et al.  REM sleep rescues learning from interference , 2015, Neurobiology of Learning and Memory.

[36]  Nelson A. M. Lemos,et al.  Novel Experience Induces Persistent Sleep-Dependent Plasticity in the Cortex but not in the Hippocampus , 2007, Front. Neurosci..

[37]  Mattias P. Karlsson,et al.  Awake replay of remote experiences in the hippocampus , 2009, Nature Neuroscience.

[38]  G. Tononi,et al.  Sleep and synaptic renormalization: a computational study. , 2010, Journal of neurophysiology.

[39]  J. Born,et al.  Emotional memory formation is enhanced across sleep intervals with high amounts of rapid eye movement sleep. , 2001, Learning & memory.

[40]  Giulio Tononi,et al.  Sleep and Synaptic Homeostasis: Structural Evidence in Drosophila , 2011, Science.

[41]  Edgard Morya,et al.  Experience-dependent upregulation of multiple plasticity factors in the hippocampus during early REM sleep , 2015, Neurobiology of Learning and Memory.

[42]  S. Ribeiro,et al.  Brain gene expression during REM sleep depends on prior waking experience. , 1999, Learning & memory.

[43]  Christine M. Walsh,et al.  Cognitive neuroscience of sleep. , 2010, Progress in brain research.

[44]  G. Bi,et al.  Synaptic Modifications in Cultured Hippocampal Neurons: Dependence on Spike Timing, Synaptic Strength, and Postsynaptic Cell Type , 1998, The Journal of Neuroscience.

[45]  E. Kandel,et al.  Control of Memory Formation Through Regulated Expression of a CaMKII Transgene , 1996, Science.

[46]  Bruno Bozon,et al.  How necessary is the activation of the immediate early gene zif268 in synaptic plasticity and learning? , 2003, Behavioural Brain Research.

[47]  Marco Idiart,et al.  A Second Function of Gamma Frequency Oscillations: An E%-Max Winner-Take-All Mechanism Selects Which Cells Fire , 2009, The Journal of Neuroscience.

[48]  M. Steriade,et al.  Neuronal Plasticity in Thalamocortical Networks during Sleep and Waking Oscillations , 2003, Neuron.

[49]  W. R. Adey,et al.  Spontaneous activity of cat hippocampal neurons in sleep and wakefulness. , 1969, Experimental neurology.

[50]  S. Ribeiro,et al.  Induction of Hippocampal Long-Term Potentiation during Waking Leads to Increased Extrahippocampal zif-268 Expression during Ensuing Rapid-Eye-Movement Sleep , 2002, The Journal of Neuroscience.

[51]  G. Lawton.  Why do we sleep? , 2000, Nature Neuroscience.

[52]  G. Tononi,et al.  Sleep-Dependent Synaptic Down-Selection (I): Modeling the Benefits of Sleep on Memory Consolidation and Integration , 2013, Front. Neurol..

[53]  Ryohei Yasuda,et al.  Local, persistent activation of Rho GTPases during plasticity of single dendritic spines , 2011, Nature.

[54]  C. Mello,et al.  Song-induced ZENK gene expression in auditory pathways of songbird brain and its relation to the song control system , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[55]  J. Born,et al.  Learning increases human electroencephalographic coherence during subsequent slow sleep oscillations. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[56]  Manuel Schabus,et al.  Sleep spindle‐related activity in the human EEG and its relation to general cognitive and learning abilities , 2006, The European journal of neuroscience.

[57]  D. Johnston,et al.  Regulation of Synaptic Efficacy by Coincidence of Postsynaptic APs and EPSPs , 1997 .

[58]  Robert Stickgold,et al.  Sleep Preferentially Enhances Memory for Emotional Components of Scenes , 2008, Psychological science.

[59]  S. Datta,et al.  Spatio‐temporal activation of cyclic AMP response element‐binding protein, activity‐regulated cytoskeletal‐associated protein and brain‐derived nerve growth factor: a mechanism for pontine‐wave generator activation‐dependent two‐way active‐avoidance memory processing in the rat , 2005, Journal of neurochemistry.

[60]  M. Ferrara,et al.  Sleep spindles: an overview. , 2003, Sleep medicine reviews.

[61]  Miguel A L Nicolelis,et al.  Reverberation, storage, and postsynaptic propagation of memories during sleep. , 2004, Learning & memory.

[62]  Mark C. W. van Rossum,et al.  Stable Hebbian Learning from Spike Timing-Dependent Plasticity , 2000, The Journal of Neuroscience.

[63]  J. Lisman,et al.  A mechanism for the Hebb and the anti-Hebb processes underlying learning and memory. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[64]  C. Gottesmann,et al.  The Transition from Slow-wave Sleep to Paradoxical Sleep: Evolving Facts and Concepts of the Neurophysiological Processes Underlying the Intermediate Stage of Sleep , 1996, Neuroscience & Biobehavioral Reviews.

[65]  A. Giuditta,et al.  The sequential hypothesis of the function of sleep , 1995, Behavioural Brain Research.

[66]  J. Csicsvari,et al.  Communication between neocortex and hippocampus during sleep in rodents , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[67]  R. Stickgold.  Sleep-dependent memory consolidation , 2005, Nature.

[68]  Vincenzo Russo,et al.  Memory Consolidation and Forgetting During Sleep: A Neural Network Model , 2004, Neural Processing Letters.

[69]  G. Tononi,et al.  Sleep and synaptic homeostasis: a hypothesis , 2003, Brain Research Bulletin.

[70]  Geoffrey E. Hinton,et al.  A Learning Algorithm for Boltzmann Machines , 1985, Cogn. Sci..

[71]  Seok-Jin R. Lee,et al.  Activation of CaMKII in single dendritic spines during long-term potentiation , 2009, Nature.

[72]  J. Csicsvari,et al.  Replay and Time Compression of Recurring Spike Sequences in the Hippocampus , 1999, The Journal of Neuroscience.

[73]  I. Wilhelm,et al.  Sleep Selectively Enhances Memory Expected to Be of Future Relevance , 2011, The Journal of Neuroscience.

[74]  Bruce L. McNaughton,et al.  Environment-specific expression of the immediate-early gene Arc in hippocampal neuronal ensembles , 1999, Nature Neuroscience.

[75]  T. Bliss,et al.  A requirement for the immediate early gene Zif268 in the expression of late LTP and long-term memories , 2001, Nature Neuroscience.

[76]  Al Mahdy Hamieh,et al.  Paradoxical sleep: A vigilance state to gate long-term brain plasticity? , 2015, Neurobiology of Learning and Memory.

[77]  W. Abraham,et al.  Memory retention – the synaptic stability versus plasticity dilemma , 2005, Trends in Neurosciences.

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

[79]  C. Law,et al.  Sleep-Dependent Plasticity Requires Cortical Activity , 2005, The Journal of Neuroscience.

[80]  J. D. McGaugh,et al.  Experience-Dependent Gene Expression in the Rat Hippocampus after Spatial Learning: A Comparison of the Immediate-Early GenesArc, c-fos, and zif268 , 2001, The Journal of Neuroscience.

[81]  J. Born,et al.  Odor Cues During Slow-Wave Sleep Prompt Declarative Memory Consolidation , 2007, Science.

[82]  Alcino J. Silva,et al.  Deficient hippocampal long-term potentiation in alpha-calcium-calmodulin kinase II mutant mice. , 1992, Science.