Initiated by CREB: Resolving Gene Regulatory Programs in Learning and Memory

Consolidation of long‐term memory is a highly and precisely regulated multistep process. The transcription regulator cAMP response element‐binding protein (CREB) plays a key role in initiating memory consolidation. With time processing, first the cofactors are changed and, secondly, CREB gets dispensable. This ultimately changes the expressed gene program to genes required to maintain the memory. Regulation of memory consolidation also requires epigenetic mechanisms and control at the RNA level. At the neuronal circuit level, oscillation in the activity of CREB and downstream factor define engram cells. Together the combination of all regulation mechanisms allows correct memory processing while keeping the process dynamic and flexible to adjust to different contexts. Also see the video abstract here https://youtu.be/BhSCSmorpEc.

[1]  Eric R Kandel,et al.  The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB , 2012, Molecular Brain.

[2]  G. Anand,et al.  Phosphodiesterases Catalyze Hydrolysis of cAMP-bound to Regulatory Subunit of Protein Kinase A and Mediate Signal Termination* , 2010, Molecular & Cellular Proteomics.

[3]  Marc Montminy,et al.  Transcriptional regulation by the phosphorylation-dependent factor CREB , 2001, Nature Reviews Molecular Cell Biology.

[4]  K. Martin,et al.  The Cell Biology of Synaptic Plasticity , 2011, Science.

[5]  N. L. La Thangue,et al.  p300/CBP proteins: HATs for transcriptional bridges and scaffolds. , 2001, Journal of cell science.

[6]  P. Castillo,et al.  Closing the gap: long-term presynaptic plasticity in brain function and disease , 2017, Current Opinion in Neurobiology.

[7]  N. Perrimon,et al.  A Drosophila CREB/CREM homolog encodes multiple isoforms, including a cyclic AMP-dependent protein kinase-responsive transcriptional activator and antagonist , 1995, Molecular and cellular biology.

[8]  I. Mori,et al.  Behavioral plasticity, learning, and memory in C. elegans , 2013, Current Opinion in Neurobiology.

[9]  Dheeraj S. Roy,et al.  Memory engram storage and retrieval , 2015, Current Opinion in Neurobiology.

[10]  T. Abel,et al.  The role of NR4A transcription factors in memory formation , 2011, Brain Research Bulletin.

[11]  P. Lazarovici,et al.  cAMP Response Element-Binding Protein (CREB): A Possible Signaling Molecule Link in the Pathophysiology of Schizophrenia , 2018, Front. Mol. Neurosci..

[12]  Richard G. Jenner,et al.  Genome-wide analysis of cAMP-response element binding protein occupancy, phosphorylation, and target gene activation in human tissues. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[13]  M. Greenberg,et al.  Membrane depolarization and calcium induce c-fos transcription via phosphorylation of transcription factor CREB , 1990, Neuron.

[14]  H. Okuno,et al.  Role of Immediate-Early Genes in Synaptic Plasticity and Neuronal Ensembles Underlying the Memory Trace , 2016, Front. Mol. Neurosci..

[15]  D. Ginty,et al.  Function and Regulation of CREB Family Transcription Factors in the Nervous System , 2002, Neuron.

[16]  Masatoshi Hagiwara,et al.  Phosphorylated CREB binds specifically to the nuclear protein CBP , 1993, Nature.

[17]  T. Miyashita,et al.  Long-Term Memory Engram Cells Are Established by c-Fos/CREB Transcriptional Cycling. , 2018, Cell reports.

[18]  Mala Murthy,et al.  Cell-Type-Specific Transcriptome Analysis in the Drosophila Mushroom Body Reveals Memory-Related Changes in Gene Expression. , 2016, Cell reports.

[19]  E. Schuman,et al.  mRNA transport & local translation in neurons , 2017, Current Opinion in Neurobiology.

[20]  U. Heberlein,et al.  Lmo4 in the Basolateral Complex of the Amygdala Modulates Fear Learning , 2012, PloS one.

[21]  C. Schmauss.  The roles of class I histone deacetylases (HDACs) in memory, learning, and executive cognitive functions: A review , 2017, Neuroscience & Biobehavioral Reviews.

[22]  A. F. Stewart,et al.  KMT2A and KMT2B Mediate Memory Function by Affecting Distinct Genomic Regions. , 2017, Cell reports.

[23]  R. Duman,et al.  CREB Binding and Activity in Brain: Regional Specificity and Induction by Electroconvulsive Seizure , 2008, Biological Psychiatry.

[24]  Sankar Ghosh,et al.  NF-κB, the first quarter-century: remarkable progress and outstanding questions. , 2012, Genes & development.

[25]  S. Haggarty,et al.  HDAC2 negatively regulates memory formation and synaptic plasticity , 2009, Nature.

[26]  B. Sabatini,et al.  Dopaminergic Modulation of Synaptic Transmission in Cortex and Striatum , 2012, Neuron.

[27]  G. Schafe,et al.  Identification of plasticity‐associated genes regulated by Pavlovian fear conditioning in the lateral amygdala , 2010, Journal of neurochemistry.

[28]  T. Abel,et al.  Differential transcriptional response to nonassociative and associative components of classical fear conditioning in the amygdala and hippocampus. , 2006, Learning & memory.

[29]  Jamie M. Kramer,et al.  Mushroom Body Specific Transcriptome Analysis Reveals Dynamic Regulation of Learning and Memory Genes After Acquisition of Long-Term Courtship Memory in Drosophila , 2018, G3: Genes, Genomes, Genetics.

[30]  Eric R Kandel,et al.  In search of general mechanisms for long-lasting plasticity: Aplysia and the hippocampus. , 2003, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[31]  C. Gallego,et al.  Recruitment of Staufen2 Enhances Dendritic Localization of an Intron-Containing CaMKIIα mRNA. , 2017, Cell reports.

[32]  M. Blanchette,et al.  Regulated Intron Removal Integrates Motivational State and Experience , 2017, Cell.

[33]  C. Stevens,et al.  Of mice and memory. , 1999, Learning & memory (Cold Spring Harbor, N.Y.).

[34]  J. Arthur,et al.  Targeted deletion of miR-132/-212 impairs memory and alters the hippocampal transcriptome , 2016, Learning & memory.

[35]  C. Murphy,et al.  Genome-wide Functional Analysis of CREB/Long-Term Memory-Dependent Transcription Reveals Distinct Basal and Memory Gene Expression Programs , 2015, Neuron.

[36]  T. Préat,et al.  Upregulated energy metabolism in the Drosophila mushroom body is the trigger for long-term memory , 2017, Nature Communications.

[37]  Gail Mandel,et al.  Defining the CREB Regulon A Genome-Wide Analysis of Transcription Factor Regulatory Regions , 2004, Cell.

[38]  C. Saura,et al.  Emerging Roles of CREB-Regulated Transcription Coactivators in Brain Physiology and Pathology , 2017, Trends in Neurosciences.

[39]  M. Montminy,et al.  Identification of a cyclic-AMP-responsive element within the rat somatostatin gene. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[40]  Alcino J. Silva,et al.  CREB regulates excitability and the allocation of memory to subsets of neurons in the amygdala , 2009, Nature Neuroscience.

[41]  Andrew I Su,et al.  Genome-wide analysis of CREB target genes reveals a core promoter requirement for cAMP responsiveness. , 2003, Molecular cell.

[42]  S. Iguchi-Ariga,et al.  CpG methylation of the cAMP-responsive enhancer/promoter sequence TGACGTCA abolishes specific factor binding as well as transcriptional activation. , 1989, Genes & development.

[43]  D. Inta,et al.  Inducible forebrain-specific ablation of the transcription factor Creb during adulthood induces anxiety but no spatial/contextual learning deficits , 2014, Front. Behav. Neurosci..

[44]  T. Préat,et al.  Delayed dopamine signaling of energy level builds appetitive long-term memory in Drosophila. , 2015, Cell reports.

[45]  Prahlad T. Ram,et al.  G Protein Pathways , 2002, Science.

[46]  Daniel N. Barry,et al.  The time course of systems consolidation of spatial memory from recent to remote retention: A comparison of the Immediate Early Genes Zif268, c-Fos and Arc , 2016, Neurobiology of Learning and Memory.

[47]  Tsonwin Hai,et al.  Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[48]  Steven Finkbeiner,et al.  Ca2+ Influx Regulates BDNF Transcription by a CREB Family Transcription Factor-Dependent Mechanism , 1998, Neuron.

[49]  A. Barco,et al.  CREB's control of intrinsic and synaptic plasticity: implications for CREB-dependent memory models , 2010, Trends in Neurosciences.

[50]  C. Alberini,et al.  A Positive Autoregulatory BDNF Feedback Loop via C/EBPβ Mediates Hippocampal Memory Consolidation , 2014, The Journal of Neuroscience.

[51]  I. Izquierdo,et al.  BDNF Activates mTOR to Regulate GluR1 Expression Required for Memory Formation , 2009, PloS one.

[52]  W. Lu,et al.  Distinct Roles of PKCι/λ and PKMζ in the Initiation and Maintenance of Hippocampal Long-Term Potentiation and Memory. , 2016, Cell reports.

[53]  Transcriptional correlates of memory maintenance following long-term sensitization of Aplysia californica. , 2017, Learning & memory.

[54]  A. Chiang,et al.  Visualizing Long-Term Memory Formation in Two Neurons of the Drosophila Brain , 2012, Science.

[55]  S. Waddell,et al.  Rapid Consolidation to a radish and Protein Synthesis-Dependent Long-Term Memory after Single-Session Appetitive Olfactory Conditioning in Drosophila , 2008, The Journal of Neuroscience.

[56]  P. Lasko,et al.  Cytoplasmic polyadenylation element binding proteins in development, health, and disease. , 2014, Annual review of cell and developmental biology.

[57]  S. Josselyn,et al.  4.27 – Transcription Regulation of Memory: CREB, CaMKIV, Fos/Jun, CBP, and SRF , 2008 .

[58]  S. Mooney,et al.  The Role of CREB, SRF, and MEF2 in Activity-Dependent Neuronal Plasticity in the Visual Cortex , 2017, The Journal of Neuroscience.

[59]  Richard L. Huganir,et al.  Arc/Arg3.1 Interacts with the Endocytic Machinery to Regulate AMPA Receptor Trafficking , 2006, Neuron.

[60]  S. Waddell,et al.  Remembering Nutrient Quality of Sugar in Drosophila , 2011, Current Biology.

[61]  Ann-Shyn Chiang,et al.  The staufen/pumilio Pathway Is Involved in Drosophila Long-Term Memory , 2003, Current Biology.

[62]  John F. Guzowski,et al.  Neuronal Competition and Selection During Memory Formation , 2006, Science.

[63]  Alcino J. Silva,et al.  CREB and memory. , 1998, Annual review of neuroscience.

[64]  Stanislav S Zakharenko,et al.  CRTC1 Nuclear Translocation Following Learning Modulates Memory Strength via Exchange of Chromatin Remodeling Complexes on the Fgf1 Gene. , 2017, Cell reports.

[65]  R. Goodman,et al.  Deacetylase Activity Is Required for cAMP Activation of a Subset of CREB Target Genes* , 2003, Journal of Biological Chemistry.

[66]  Huilin Li,et al.  The Postsynaptic Density Proteins Homer and Shank Form a Polymeric Network Structure , 2009, Cell.

[67]  O. Steward,et al.  Localization and local translation of Arc/Arg3.1 mRNA at synapses: some observations and paradoxes , 2015, Front. Mol. Neurosci..

[68]  H. Kaphzan,et al.  Neuronal CTCF Is Necessary for Basal and Experience-Dependent Gene Regulation, Memory Formation, and Genomic Structure of BDNF and Arc. , 2016, Cell reports.

[69]  Hélène Marie,et al.  Genetic Approaches to Investigate the Role of CREB in Neuronal Plasticity and Memory , 2011, Molecular Neurobiology.

[70]  C. Alberini,et al.  CCAAT Enhancer Binding Protein δ Plays an Essential Role in Memory Consolidation and Reconsolidation , 2013, The Journal of Neuroscience.

[71]  B. Howard,et al.  The Transcriptional Coactivators p300 and CBP Are Histone Acetyltransferases , 1996, Cell.

[72]  H. Okuno,et al.  Region-Specific Activation of CRTC1-CREB Signaling Mediates Long-Term Fear Memory , 2014, Neuron.

[73]  T. H. Ch’ng,et al.  Activity-dependent synapse to nucleus signaling , 2017, Neurobiology of Learning and Memory.

[74]  L. Fradkin,et al.  Retrovirus-like Gag Protein Arc1 Binds RNA and Traffics across Synaptic Boutons , 2018, Cell.

[75]  J. Briggs,et al.  The Neuronal Gene Arc Encodes a Repurposed Retrotransposon Gag Protein that Mediates Intercellular RNA Transfer , 2018, Cell.

[76]  Colleen M. Doyle,et al.  Acetylation of cAMP-responsive Element-binding Protein (CREB) by CREB-binding Protein Enhances CREB-dependent Transcription* , 2003, The Journal of Biological Chemistry.

[77]  C. Vorhees,et al.  Assessing spatial learning and memory in rodents. , 2014, ILAR journal.

[78]  S. Kida,et al.  Functional roles of CREB as a positive regulator in the formation and enhancement of memory , 2014, Brain Research Bulletin.

[79]  Zhiping Weng,et al.  A systems level approach to temporal expression dynamics in Drosophila reveals clusters of long term memory genes , 2017, PLoS genetics.

[80]  David P. Wolfer,et al.  Does cAMP Response Element-Binding Protein Have a Pivotal Role in Hippocampal Synaptic Plasticity and Hippocampus-Dependent Memory? , 2003, The Journal of Neuroscience.

[81]  P. Scheiffele,et al.  Beyond proteome diversity: alternative splicing as a regulator of neuronal transcript dynamics , 2017, Current Opinion in Neurobiology.

[82]  E. Kandel,et al.  The Molecular and Systems Biology of Memory , 2014, Cell.

[83]  F. Wendler,et al.  Extracellular vesicles round off communication in the nervous system , 2016, Nature Reviews Neuroscience.

[84]  E. Olson,et al.  The many roles of histone deacetylases in development and physiology: implications for disease and therapy , 2009, Nature Reviews Genetics.

[85]  Paul W. Frankland,et al.  Competition between engrams influences fear memory formation and recall , 2016, Science.

[86]  Giulia Antonazzo,et al.  FlyBase 2.0: the next generation , 2018, Nucleic Acids Res..

[87]  Jianhua Shi,et al.  O-GLCNACYLATION MODULATES PKA-CREB SIGNALING IN A MANNER SPECIFIC TO PKA CATALYTIC SUBUNIT ISOFORMS , 2018, Alzheimer's & Dementia.

[88]  F. Drabløs,et al.  Gene regulation in the immediate-early response process. , 2016, Advances in biological regulation.

[89]  M. Montminy,et al.  Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133 , 1989, Cell.

[90]  Evan L Ardiel,et al.  An elegant mind: learning and memory in Caenorhabditis elegans. , 2010, Learning & memory.

[91]  Wade G. Regehr,et al.  The calcium sensor synaptotagmin 7 is required for synaptic facilitation , 2015, Nature.

[92]  N. Birnberg,et al.  A cyclic AMP- and phorbol ester-inducible DNA element , 1986, Nature.

[93]  R. Goodman,et al.  Adenoviral ElA-associated protein p300 as a functional homologue of the transcriptional co-activator CBP , 1995, Nature.

[94]  E. Galea,et al.  CREB Regulates Distinct Adaptive Transcriptional Programs in Astrocytes and Neurons , 2017, Scientific Reports.

[95]  D. A. Baxter,et al.  Computational model of a positive BDNF feedback loop in hippocampal neurons following inhibitory avoidance training , 2016, Learning & memory.

[96]  M E Greenberg,et al.  Calcium signaling in neurons: molecular mechanisms and cellular consequences. , 1995, Science.

[97]  S. Sprecher,et al.  Regulators of Long-Term Memory Revealed by Mushroom Body-Specific Gene Expression Profiling in Drosophila melanogaster , 2018, Genetics.

[98]  P. Sassone-Corsi,et al.  Signaling routes to CREM and CREB: plasticity in transcriptional activation. , 1999, Trends in biochemical sciences.

[99]  T. Préat,et al.  Genetic dissection of consolidated memory in Drosophila , 1994, Cell.

[100]  R. Shaw,et al.  AMPK: guardian of metabolism and mitochondrial homeostasis , 2017, Nature Reviews Molecular Cell Biology.

[101]  Bruno Bontempi,et al.  Selective Erasure of a Fear Memory , 2009, Science.

[102]  J. Baker,et al.  The Orphan Steroid Receptor Nur77 Family Member Nor-1 Is Essential for Early Mouse Embryogenesis* , 2003, Journal of Biological Chemistry.

[103]  G L Johnson,et al.  Nuclear protein phosphatase 2A dephosphorylates protein kinase A-phosphorylated CREB and regulates CREB transcriptional stimulation , 1993, Molecular and cellular biology.

[104]  C. Alberini,et al.  Transcription factors in long-term memory and synaptic plasticity. , 2009, Physiological reviews.

[105]  M. Saitoe,et al.  Shifting transcriptional machinery is required for long-term memory maintenance and modification in Drosophila mushroom bodies , 2016, Nature Communications.

[106]  D. Ginty,et al.  A Dominant-Negative Inhibitor of CREB Reveals that It Is a General Mediator of Stimulus-Dependent Transcription of c-fos , 1998, Molecular and Cellular Biology.

[107]  Shanshan Zou,et al.  Research progress on the roles of microRNAs in governing synaptic plasticity, learning and memory. , 2017, Life sciences.

[108]  M. Schumacher,et al.  Consensus and Variant cAMP-regulated Enhancers Have Distinct CREB-binding Properties* , 2001, The Journal of Biological Chemistry.

[109]  N. Sonenberg,et al.  Regulation of translation via TOR signaling: insights from Drosophila melanogaster. , 2001, The Journal of nutrition.

[110]  Robin Fropf,et al.  dCREB2-Mediated Enhancement of Memory Formation , 2013, The Journal of Neuroscience.

[111]  W. Huber,et al.  cAMP Response Element-Binding Protein Is a Primary Hub of Activity-Driven Neuronal Gene Expression , 2011, The Journal of Neuroscience.

[112]  Ronald L. Davis,et al.  Thirty years of olfactory learning and memory research in Drosophila melanogaster , 2005, Progress in Neurobiology.

[113]  E. Kandel,et al.  Gene Expression Profiling of Facilitated L-LTP in VP16-CREB Mice Reveals that BDNF Is Critical for the Maintenance of LTP and Its Synaptic Capture , 2005, Neuron.

[114]  U. Moens,et al.  What turns CREB on? , 2004, Cellular signalling.

[115]  J. Lisman,et al.  Memory Erasure Experiments Indicate a Critical Role of CaMKII in Memory Storage , 2017, Neuron.

[116]  S. B. Baltaci,et al.  Molecular Mechanisms of Early and Late LTP , 2018, Neurochemical Research.

[117]  C. Kaltschmidt,et al.  NF-KappaB in Long-Term Memory and Structural Plasticity in the Adult Mammalian Brain , 2015, Front. Mol. Neurosci..

[118]  Zheng Li,et al.  miRNAs in synapse development and synaptic plasticity , 2017, Current Opinion in Neurobiology.

[119]  Kelsey C. Martin,et al.  RNA Trafficking and Local Protein Synthesis in Dendrites: An Overview , 2006, The Journal of Neuroscience.

[120]  C. Molina,et al.  Inducibility and negative autoregulation of CREM: An alternative promoter directs the expression of ICER, an early response repressor , 1993, Cell.

[121]  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.

[122]  B. Mensh,et al.  Synaptic Orb2A Bridges Memory Acquisition and Late Memory Consolidation in Drosophila , 2015, Cell reports.

[123]  Tony D. Southall,et al.  Cell-Type-Specific Profiling of Gene Expression and Chromatin Binding without Cell Isolation: Assaying RNA Pol II Occupancy in Neural Stem Cells , 2013, Developmental cell.

[124]  Andrew J. Bannister,et al.  The CBP co-activator is a histone acetyltransferase , 1996, Nature.

[125]  Amar N. Kar,et al.  MicroRNAs in the axon and presynaptic nerve terminal , 2013, Front. Cell. Neurosci..

[126]  J. Morys,et al.  BDNF: A Key Factor with Multipotent Impact on Brain Signaling and Synaptic Plasticity , 2017, Cellular and Molecular Neurobiology.

[127]  L. Squire,et al.  Protein synthesis and memory: a review. , 1984, Psychological bulletin.

[128]  U. Heberlein,et al.  A Selective Role for Lmo4 in Cue–Reward Learning , 2015, The Journal of Neuroscience.

[129]  Loren Miraglia,et al.  TORCs: transducers of regulated CREB activity. , 2003, Molecular cell.

[130]  M. Hagiwara,et al.  Transcriptional attenuation following cAMP induction requires PP-1-mediated dephosphorylation of CREB , 1992, Cell.