Heroes of the Engram

In 1904, Richard Semon introduced the term “engram” to describe the neural substrate responsible for (or at least important in) storing and recalling memories (i.e., a memory trace). The recent introduction of a vast array of powerful new tools to probe and manipulate memory function at the cell and neuronal circuit level has spurred an explosion of interest in studying the engram. However, the present “engram renaissance” was not borne in isolation but rather builds on a long tradition of memory research. We believe it is important to acknowledge the debts our current generation of scientists owes to those scientists who have offered key ideas, persevered through failed experiments and made important discoveries before us. Examining the past can also offer a fresh perspective on the present state and future promise of the field. Given the large amount of empirical advances made in recent years, it seems particularly timely to look back and review the scientists who introduced the seminal terminology, concepts, methodological approaches, and initial data pertaining to engrams. Rather than simply list their many accomplishments, here we color in some details of the lives and milestone contributions of our seven personal heroes of the engram (Richard Semon, Karl Lashley, Donald Hebb, Wilder Penfield, Brenda Milner, James McConnell, and Richard Thompson). In reviewing their historic role, we also illustrate how their work remains relevant to today's studies.

[1]  A. Jacobson,et al.  The effects of regeneration upon retention of a conditioned response in the planarian. , 1959, Journal of comparative and physiological psychology.

[2]  M. Rilling The mystery of the vanished citations: James McConnell's forgotten 1960s quest for planarian learning, a biochemical engram, and celebrity. , 1996 .

[3]  T. Bliss,et al.  Long‐lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path , 1973, The Journal of physiology.

[4]  Fred H. Gage,et al.  What is memory? The present state of the engram , 2016, BMC Biology.

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

[6]  R. F. Thompson,et al.  Hippocampus and trace conditioning of the rabbit's classically conditioned nictitating membrane response. , 1986, Behavioral neuroscience.

[7]  L. Squire,et al.  Retrograde amnesia and memory consolidation: a neurobiological perspective , 1995, Current Opinion in Neurobiology.

[8]  D. Hebb MAN'S FRONTAL LOBES: A CRITICAL REVIEW , 1945 .

[9]  Erminio Costa,et al.  RNAi and brain function: was McConnell on the right track? , 2001, Trends in Neurosciences.

[10]  Theodore W. Berger,et al.  Hippocampal unit-behavior correlations during classical conditioning , 1980, Brain Research.

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

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

[13]  S. Josselyn Continuing the search for the engram: examining the mechanism of fear memories. , 2010, Journal of psychiatry & neuroscience : JPN.

[14]  Alcino J. Silva,et al.  Molecular and Cellular Mechanisms for Trapping and Activating Emotional Memories , 2016, PloS one.

[15]  Kaia L. Vilberg,et al.  Brain Networks Underlying Episodic Memory Retrieval This Review Comes from a Themed Issue on Macrocircuits Memory Signals within the Mtl , 2022 .

[16]  L. Squire,et al.  The History of Neuroscience in Autobiography , 1998 .

[17]  E. Tulving,et al.  Richard Semon's Theory of Memory , 1978 .

[18]  R. F. Thompson,et al.  Neuronal responses of the rabbit cerebellum during acquisition and performance of a classically conditioned nictitating membrane-eyelid response , 1984, The Journal of neuroscience : the official journal of the Society for Neuroscience.

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

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

[21]  Hongkeun Kim,et al.  Neural activity that predicts subsequent memory and forgetting: A meta-analysis of 74 fMRI studies , 2011, NeuroImage.

[22]  G. Winocur,et al.  Memory formation and long-term retention in humans and animals: Convergence towards a transformation account of hippocampal–neocortical interactions , 2010, Neuropsychologia.

[23]  I. Mansuy,et al.  Epigenetic codes in cognition and behaviour , 2008, Behavioural Brain Research.

[24]  James R. Bloedel,et al.  ‘Involvement in’ versus ‘Storage of’ , 1993, Trends in Neurosciences.

[25]  G. Winocur,et al.  Episodic Memory and Beyond: The Hippocampus and Neocortex in Transformation. , 2016, Annual review of psychology.

[26]  Daniel L. Schacter,et al.  Stranger Behind the Engram: Theories of Memory and the Psychology of Science , 1982 .

[27]  W. Scoville,et al.  LOSS OF RECENT MEMORY AFTER BILATERAL HIPPOCAMPAL LESIONS , 1957, Journal of neurology, neurosurgery, and psychiatry.

[28]  Paul W. Frankland,et al.  Neurons Are Recruited to a Memory Trace Based on Relative Neuronal Excitability Immediately before Training , 2014, Neuron.

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

[30]  A. McIntosh,et al.  Mapping cognition to the brain through neural interactions. , 1999, Memory.

[31]  W. Penfield,et al.  SOMATIC MOTOR AND SENSORY REPRESENTATION IN THE CEREBRAL CORTEX OF MAN AS STUDIED BY ELECTRICAL STIMULATION , 1937 .

[32]  L. Nadel,et al.  Memory consolidation, retrograde amnesia and the hippocampal complex , 1997, Current Opinion in Neurobiology.

[33]  H. Eichenbaum Still searching for the engram , 2016, Learning & Behavior.

[34]  I. Fried,et al.  Internally Generated Reactivation of Single Neurons in Human Hippocampus During Free Recall , 2008, Science.

[35]  Michael Levin,et al.  An automated training paradigm reveals long-term memory in planarians and its persistence through head regeneration , 2013, Journal of Experimental Biology.

[36]  K. S. Lashley,et al.  INTEGRATIVE FUNCTIONS OF THE CEREBRAL CORTEX , 1933 .

[37]  R. Yuste,et al.  Imprinting and recalling cortical ensembles , 2016, Science.

[38]  Dheeraj S. Roy,et al.  Memory retrieval by activating engram cells in mouse models of early Alzheimer’s disease , 2016, Nature.

[39]  T W Berger,et al.  Identification of pyramidal cells as the critical elements in hippocampal neuronal plasticity during learning. , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[40]  Natasa Kovacevic,et al.  Identification of a Functional Connectome for Long-Term Fear Memory in Mice , 2013, PLoS Comput. Biol..

[41]  Brian D. Slaughter,et al.  A Putative Biochemical Engram of Long-Term Memory , 2016, Current Biology.

[42]  D. Hebb,et al.  HUMAN BEHAVIOR AFTER EXTENSIVE BILATERAL REMOVAL FROM THE FRONTAL LOBES , 1940 .

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

[44]  B. Kaang,et al.  Which Neurons Will Be the Engram - Activated Neurons and/or More Excitable Neurons? , 2016, Experimental neurobiology.

[45]  S. Tonegawa,et al.  Memory Engram Cells Have Come of Age , 2015, Neuron.

[46]  Jonas Schreiber,et al.  The Analysis of Mind , 1935, Nature.

[47]  M. Moscovitch Memory before and after H.M.: an impressionistic historical perspective , 2012 .

[48]  G. Winocur,et al.  Functional neuroanatomy of remote episodic, semantic and spatial memory: a unified account based on multiple trace theory , 2005, Journal of anatomy.

[49]  M. G. Faulkner,et al.  Engram cells retain memory under retrograde amnesia , 2015, Science.

[50]  Daniel D. McGarry The metalogicon of John of Salisbury : a twelfth-century defense of the verbal and logical arts of the trivium , 1955 .

[51]  D. Forsdyke Heredity as transmission of information: Butlerian 'Intelligent Design.'. , 2006, Centaurus; international magazine of the history of science and medicine.

[52]  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.

[53]  P. Frankland,et al.  The organization of recent and remote memories , 2005, Nature Reviews Neuroscience.

[54]  W. B. Orr,et al.  Hippocampectomy selectively disrupts discrimination reversal conditioning of the rabbit nictitating membrane response , 1983, Behavioural Brain Research.

[55]  W. Penfield,et al.  THE FRONTAL LOBE IN MAN: A CLINICAL STUDY OF MAXIMUM REMOVALS , 1935 .

[56]  D. Glanzman,et al.  Reinstatement of long-term memory following erasure of its behavioral and synaptic expression in Aplysia , 2014, eLife.

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

[58]  D. Hebb,et al.  The McGill Adult Comprehension Examination: "Verbal Situation" and "Picture Anomaly" Series. , 1943 .

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

[60]  W. Feindel No Man Alone. A Neurosurgeon's Life. , 1978 .

[61]  L. T. Robertson Memory and the brain. , 2002, Journal of dental education.

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

[63]  Karl J. Friston,et al.  PHRENOLOGY : What Can Neuroimaging Tell Us About Distributed Circuitry ? , 2005 .

[64]  G. Mcrobert Biographical Memoirs of Fellows of the Royal Society , 1976 .

[65]  J. Harvey,et al.  Pavlovian conditioning in the rabbit during inactivation of the interpositus nucleus. , 1991, The Journal of physiology.

[66]  James L Olds,et al.  Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain. , 1954, Journal of comparative and physiological psychology.

[67]  K. Lashley STUDIES OF CEREBRAL FUNCTION IN LEARNING: IV. Vicarious Function after Destruction of the Visual Areas , 1922 .

[68]  B. Dias,et al.  Parental olfactory experience influences behavior and neural structure in subsequent generations , 2013, Nature Neuroscience.

[69]  G. Majno,et al.  PREPARATION OF TISSUE SLICES FOR METABOLIC STUDIES: A HAND‐MICROTOME ESPECIALLY SUITABLE FOR BRAIN , 1957, Journal of neurochemistry.

[70]  W. Penfield,et al.  Memory deficit produced by bilateral lesions in the hippocampal zone. , 1958, A.M.A. archives of neurology and psychiatry.

[71]  David A. McCormick,et al.  Ipsilateral cerebellar lesions prevent learning of the classically conditioned nictitating membrane/eyelid response , 1982, Brain Research.

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

[73]  N. Matsuo,et al.  Pharmacogenetic reactivation of the original engram evokes an extinguished fear memory , 2017, Neuropharmacology.

[74]  M. Shermer,et al.  A new phrenology? , 2008, Scientific American.

[75]  S. Tonegawa,et al.  Activating positive memory engrams suppresses depression-like behaviour , 2015, Nature.

[76]  James J. Knierim,et al.  CA3 Retrieves Coherent Representations from Degraded Input: Direct Evidence for CA3 Pattern Completion and Dentate Gyrus Pattern Separation , 2014, Neuron.

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

[78]  R. Merton The Matthew Effect in Science , 1968, Science.

[79]  R. F. Thompson,et al.  Disruption of classical eyelid conditioning after cerebellar lesions: damage to a memory trace system or a simple performance deficit? , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[80]  Adam Santoro,et al.  Structural foundations of optogenetics: Determinants of channelrhodopsin ion selectivity , 2015, Proceedings of the National Academy of Sciences.

[81]  P. Frankland,et al.  Neuronal Allocation to a Hippocampal Engram , 2016, Neuropsychopharmacology.

[82]  James L. McClelland,et al.  Why there are complementary learning systems in the hippocampus and neocortex: insights from the successes and failures of connectionist models of learning and memory. , 1995, Psychological review.

[83]  The Neuropsychological Theories of Lashley and Hebb: Contemporary Perspectives Fifty Years After Hebb's the Organization of Behavior : Vanuxem Lectures and Selected Theoretical Papers of Lashley , 1998 .

[84]  P. Milner,et al.  The legacy of Donald O. Hebb: more than the Hebb Synapse , 2003, Nature Reviews Neuroscience.

[85]  G. A. Clark,et al.  The engram found? Role of the cerebellum in classical conditioning of nictitating membrane and eyelid responses , 1981 .

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

[87]  B. R. Gomulicki The development and present status of the trace theory of memory , 1953 .

[88]  N. Matsuki,et al.  Synaptic Plasticity Associated with a Memory Engram in the Basolateral Amygdala , 2014, The Journal of Neuroscience.

[89]  M. Glickstein,et al.  Classical conditioning of the nictitating membrane response of the rabbit , 2004, Experimental Brain Research.

[90]  J. Bower,et al.  Is the cerebellum sensory for motor's sake, or motor for sensory's sake: the view from the whiskers of a rat? , 1997, Progress in brain research.

[91]  Catching the engram: strategies to examine the memory trace , 2012, Molecular Brain.

[92]  J. McConnell,et al.  Classical conditioning in the planarian, Dugesia dorotocephala. , 1955, Journal of comparative and physiological psychology.

[93]  Retention and acquisition of classical trace conditioned responses by rabbits with hippocampal lesions. , 1986, Behavioral neuroscience.

[94]  E. Tulving Synergistic ecphory in recall and recognition. , 1982 .

[95]  Clement Hamani,et al.  Deep brain stimulation of the anterior nucleus of the thalamus: Effects of electrical stimulation on pilocarpine-induced seizures and status epilepticus , 2008, Epilepsy Research.

[96]  Daniel L. Schacter,et al.  Forgotten Ideas, Neglected Pioneers: Richard Semon and the Story of Memory , 2001 .

[97]  P. Milner,et al.  Donald Olding Hebb, 22 July 1904 - 20 August 1985 , 1996, Biographical Memoirs of Fellows of the Royal Society.

[98]  P. Frankland,et al.  Finding the engram , 2015, Nature Reviews Neuroscience.

[99]  S. Cooper Donald O. Hebb's synapse and learning rule: a history and commentary , 2005, Neuroscience & Biobehavioral Reviews.

[100]  K. S. Lashley,et al.  The retention of habits by the rat after destruction of the frontal portion of the cerebrum. , 1917 .

[101]  K. Deisseroth,et al.  Manipulating a “Cocaine Engram” in Mice , 2014, The Journal of Neuroscience.

[102]  D. Hebb,et al.  A method of rating animal intelligence. , 1946, The Journal of general psychology.

[103]  W. Penfield,et al.  THE BRAIN'S RECORD OF AUDITORY AND VISUAL EXPERIENCE. A FINAL SUMMARY AND DISCUSSION. , 1963, Brain : a journal of neurology.

[104]  Richard E. Brown The life and work of Donald Olding Hebb. , 2006, Acta neurologica Taiwanica.

[105]  F. Bartlett Karl Spencer Lashley, 1890-1958 , 1960, Biographical Memoirs of Fellows of the Royal Society.