Exploring Memory Representations with Activity-Based Genetics.

The brain is thought to represent specific memories through the activity of sparse and distributed neural ensembles. In this review, we examine the use of immediate early genes (IEGs), genes that are induced by neural activity, to specifically identify and genetically modify neurons activated naturally by environmental experience. Recent studies using this approach have identified cellular and molecular changes specific to neurons activated during learning relative to their inactive neighbors. By using opto- and chemogenetic regulators of neural activity, the neurons naturally recruited during learning can be artificially reactivated to directly test their role in coding external information. In contextual fear conditioning, artificial reactivation of learning-induced neural ensembles in the hippocampus or neocortex can substitute for the context itself. That is, artificial stimulation of these neurons can apparently cause the animals to "think" they are in the context. This represents a powerful approach to testing the principles by which the brain codes for the external world and how these circuits are modified with learning.

[1]  C. Rankin,et al.  Nonassociative Learning in Invertebrates , 2017 .

[2]  Pablo E. Jercog,et al.  Large-Scale Fluorescence Calcium-Imaging Methods for Studies of Long-Term Memory in Behaving Mammals. , 2016, Cold Spring Harbor perspectives in biology.

[3]  E. Kandel,et al.  The Role of Functional Prion-Like Proteins in the Persistence of Memory. , 2016, Cold Spring Harbor perspectives in biology.

[4]  S. Siegelbaum,et al.  The Corticohippocampal Circuit, Synaptic Plasticity, and Memory. , 2015, Cold Spring Harbor perspectives in biology.

[5]  Edmund C Schwartz,et al.  Neural Representations of Unconditioned Stimuli in Basolateral Amygdala Mediate Innate and Learned Responses , 2015, Cell.

[6]  T. Abel,et al.  Molecular Genetic Strategies in the Study of Corticohippocampal Circuits. , 2015, Cold Spring Harbor perspectives in biology.

[7]  Paul W. Frankland,et al.  Whole-brain mapping of behaviourally induced neural activation in mice , 2015, Brain Structure and Function.

[8]  Michele Pignatelli,et al.  Engram cells retain memory under retrograde amnesia , 2015, Science.

[9]  Srinivas C. Turaga,et al.  Mapping social behavior-induced brain activation at cellular resolution in the mouse. , 2014, Cell reports.

[10]  Peyman Golshani,et al.  CREB Regulates Memory Allocation in the Insular Cortex , 2014, Current Biology.

[11]  Brian J. Wiltgen,et al.  Cortical Representations Are Reinstated by the Hippocampus during Memory Retrieval , 2014, Neuron.

[12]  P. Golshani,et al.  Direct Reactivation of a Coherent Neocortical Memory of Context , 2014, Neuron.

[13]  M. Woodin,et al.  Neurons Are Recruited to a Memory Trace Based on Relative Neuronal Excitability Immediately before Training , 2014, Neuron.

[14]  S. Tonegawa,et al.  Bidirectional switch of the valence associated with a hippocampal contextual memory engram , 2014, Nature.

[15]  Kenji F. Tanaka,et al.  Hippocampal Memory Traces Are Differentially Modulated by Experience, Time, and Adult Neurogenesis , 2014, Neuron.

[16]  Alcino J. Silva,et al.  Encoding and storage of spatial information in the retrosplenial cortex , 2014, Proceedings of the National Academy of Sciences.

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

[18]  Ji-Song Guan,et al.  In vivo imaging of immediate early gene expression reveals layer-specific memory traces in the mammalian brain , 2014, Proceedings of the National Academy of Sciences.

[19]  Mark Mayford,et al.  The search for a hippocampal engram , 2014, Philosophical Transactions of the Royal Society B: Biological Sciences.

[20]  R. Morris.  NMDA receptors and memory encoding , 2013, Neuropharmacology.

[21]  S. Tonegawa,et al.  Creating a False Memory in the Hippocampus , 2013, Science.

[22]  L. Luo,et al.  Permanent Genetic Access to Transiently Active Neurons via TRAP: Targeted Recombination in Active Populations , 2013, Neuron.

[23]  David C Rowland,et al.  Generation of a Synthetic Memory Trace , 2012, Science.

[24]  K. Deisseroth,et al.  Optogenetic stimulation of a hippocampal engram activates fear memory recall , 2012, Nature.

[25]  Erin M. Wissink,et al.  Rapid activity-induced transcription of Arc and other IEGs relies on poised RNA polymerase II , 2011, Nature Neuroscience.

[26]  Alison L. Barth,et al.  An Embedded Subnetwork of Highly Active Neurons in the Neocortex , 2010, Neuron.

[27]  J. Staiger,et al.  The Somatosensory Cortex of reeler Mutant Mice Shows Absent Layering But Intact Formation and Behavioral Activation of Columnar Somatotopic Maps , 2010, The Journal of Neuroscience.

[28]  Thomas G. Oertner,et al.  Temporal Control of Immediate Early Gene Induction by Light , 2009, PloS one.

[29]  Alcino J. Silva,et al.  Molecular and Cellular Approaches to Memory Allocation in Neural Circuits , 2009, Science.

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

[31]  Ewelina Knapska,et al.  Reciprocal patterns of c-Fos expression in the medial prefrontal cortex and amygdala after extinction and renewal of conditioned fear. , 2009, Learning & memory.

[32]  M. Nicolelis,et al.  Remote Control of Neuronal Activity in Transgenic Mice Expressing Evolved G Protein-Coupled Receptors , 2009, Neuron.

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

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

[35]  Roberto Malinow,et al.  Synaptic AMPA Receptor Plasticity and Behavior , 2009, Neuron.

[36]  David J Bucci,et al.  Neurotoxic lesions of retrosplenial cortex disrupt signaled and unsignaled contextual fear conditioning. , 2008, Behavioral neuroscience.

[37]  K. Koshibu,et al.  Control of the establishment of aversive memory by calcineurin and Zif268 , 2008, Nature Neuroscience.

[38]  M. Mayford,et al.  Spine-Type-Specific Recruitment of Newly Synthesized AMPA Receptors with Learning , 2008, Science.

[39]  D. Bucci,et al.  Contributions of the retrosplenial and posterior parietal cortices to cue-specific and contextual fear conditioning. , 2008, Behavioral neuroscience.

[40]  K. Svoboda,et al.  Sparse optical microstimulation in barrel cortex drives learned behaviour in freely moving mice , 2008, Nature.

[41]  Mark Mayford,et al.  Localization of a Stable Neural Correlate of Associative Memory , 2007, Science.

[42]  T. Bliss,et al.  Arc/Arg3.1 Is Essential for the Consolidation of Synaptic Plasticity and Memories , 2006, Neuron.

[43]  Jonathan R. Whitlock,et al.  Learning Induces Long-Term Potentiation in the Hippocampus , 2006, Science.

[44]  Susumu Tonegawa,et al.  In Vivo Two-Photon Imaging Reveals a Role of Arc in Enhancing Orientation Specificity in Visual Cortex , 2006, Cell.

[45]  David J. Foster,et al.  Reverse replay of behavioural sequences in hippocampal place cells during the awake state , 2006, Nature.

[46]  K. Deisseroth,et al.  Millisecond-timescale, genetically targeted optical control of neural activity , 2005, Nature Neuroscience.

[47]  C. Koch,et al.  Invariant visual representation by single neurons in the human brain , 2005, Nature.

[48]  Joseph E LeDoux,et al.  Postsynaptic Receptor Trafficking Underlying a Form of Associative Learning , 2005, Science.

[49]  Richard C Gerkin,et al.  Alteration of Neuronal Firing Properties after In Vivo Experience in a FosGFP Transgenic Mouse , 2004, The Journal of Neuroscience.

[50]  Alcino J. Silva,et al.  The Involvement of the Anterior Cingulate Cortex in Remote Contextual Fear Memory , 2004, Science.

[51]  A. Grinvald,et al.  Spontaneously emerging cortical representations of visual attributes , 2003, Nature.

[52]  E. Wagner,et al.  Impaired Long-Term Memory and NR2A-Type NMDA Receptor-Dependent Synaptic Plasticity in Mice Lacking c-Fos in the CNS , 2003, The Journal of Neuroscience.

[53]  M. R. Mehta,et al.  Role of experience and oscillations in transforming a rate code into a temporal code , 2002, Nature.

[54]  T. Bliss,et al.  Subfield‐specific immediate early gene expression associated with hippocampal long‐term potentiation in vivo , 2001, The European journal of neuroscience.

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

[56]  B. Bontempi,et al.  Time-dependent reorganization of brain circuitry underlying long-term memory storage , 1999, Nature.

[57]  K. Svoboda,et al.  Rapid spine delivery and redistribution of AMPA receptors after synaptic NMDA receptor activation. , 1999, Science.

[58]  R. L. Marie,et al.  Spatial representation of frequency in the rat dorsal nucleus of the lateral lemniscus as revealed by acoustically induced c-fos mRNA expression , 1999, Hearing Research.

[59]  J. Radulovic,et al.  Relationship between Fos Production and Classical Fear Conditioning: Effects of Novelty, Latent Inhibition, and Unconditioned Stimulus Preexposure , 1998, The Journal of Neuroscience.

[60]  U. Frey,et al.  Synaptic tagging: implications for late maintenance of hippocampal long-term potentiation , 1998, Trends in Neurosciences.

[61]  O. Stiedl,et al.  Production of the Fos protein after contextual fear conditioning of C57BL/6N mice , 1998, Brain Research.

[62]  E. Kandel,et al.  Synapse-Specific, Long-Term Facilitation of Aplysia Sensory to Motor Synapses: A Function for Local Protein Synthesis in Memory Storage , 1997, Cell.

[63]  M. McKERNAN,et al.  Fear conditioning induces a lasting potentiation of synaptic currents in vitro , 1997, Nature.

[64]  Joseph E LeDoux,et al.  Fear conditioning induces associative long-term potentiation in the amygdala , 1997, Nature.

[65]  U. Frey,et al.  Synaptic tagging and long-term potentiation , 1997, Nature.

[66]  Richard J Smeyne,et al.  Regulation of c-fos expression in transgenic mice requires multiple interdependent transcription control elements , 1995, Neuron.

[67]  Carol A Barnes,et al.  Arc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites , 1995, Neuron.

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

[69]  M E Greenberg,et al.  Calcium regulation of gene expression in neuronal cells. , 1994, Journal of neurobiology.

[70]  M. Greenberg,et al.  The destabilizing elements in the coding region of c-fos mRNA are recognized as RNA , 1993, Molecular and cellular biology.

[71]  Carol A. Barnes,et al.  Expression of a mitogen-inducible cyclooxygenase in brain neurons: Regulation by synaptic activity and glucocorticoids , 1993, Neuron.

[72]  Elly Nedivi,et al.  Numerous candidate plasticity-related genes revealed by differential cDNA cloning , 1993, Nature.

[73]  Eric R. Kandel,et al.  Tissue-plasminogen activator is induced as an immediate–early gene during seizure, kindling and long-term potentiation , 1993, Nature.

[74]  M. Gossen,et al.  Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[75]  M. Fanselow,et al.  Modality-specific retrograde amnesia of fear. , 1992, Science.

[76]  Richard J Smeyne,et al.  Fos-IacZ transgenic mice: Mapping sites of gene induction in the central nervous system , 1992, Neuron.

[77]  P. Worley,et al.  Constitutive expression of zif268 in neocortex is regulated by synaptic activity. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[78]  T. Curran,et al.  Mapping patterns of c-fos expression in the central nervous system after seizure. , 1987, Science.

[79]  A. Schönthal,et al.  Posttranscriptional regulation of c-fos mRNA expression. , 1987, Nucleic acids research.

[80]  M. Greenberg,et al.  Effect of protein synthesis inhibitors on growth factor activation of c-fos, c-myc, and actin gene transcription , 1986, Molecular and cellular biology.

[81]  R. Hawkins,et al.  Associative learning in invertebrates. , 2015, Cold Spring Harbor perspectives in biology.

[82]  M. Wilson,et al.  Coordinated memory replay in the visual cortex and hippocampus during sleep , 2007, Nature Neuroscience.

[83]  Richard J Smeyne,et al.  fos-lacZ transgenic mice: mapping sites of gene induction in the central nervous system. , 1992, Neuron.

[84]  D. Hubel,et al.  Receptive fields, binocular interaction and functional architecture in the cat's visual cortex , 1962, The Journal of physiology.

[85]  Alcino J. Silva,et al.  Supporting Online Material Materials and Methods Som Text Figs. S1 to S5 Tables S1 to S3 References Neuronal Competition and Selection during Memory Formation , 2022 .