Functional integrity of the retrosplenial cortex is essential for rapid consolidation and recall of fear memory.

Memory storage is a temporally graded process involving different phases and different structures in the mammalian brain. Cortical plasticity is essential to store stable memories, but little is known regarding its involvement in memory processing. Here we show that fear memory consolidation requires early post-training macromolecular synthesis in the anterior part of the retrosplenial cortex (aRSC), and that reversible pharmacological inactivation of this cortical region impairs recall of recent as well as of remote memories. These results challenge the generally accepted idea that neocortical areas are slow encoding systems that participate in the retrieval of remote memories only.

[1]  E. Maguire,et al.  What does the retrosplenial cortex do? , 2009, Nature Reviews Neuroscience.

[2]  Seralynne D Vann,et al.  Extensive cytotoxic lesions of the rat retrosplenial cortex reveal consistent deficits on tasks that tax allocentric spatial memory. , 2002, Behavioral neuroscience.

[3]  John H. Martin.  Autoradiographic estimation of the extent of reversible inactivation produced by microinjection of lidocaine and muscimol in the rat , 1991, Neuroscience Letters.

[4]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[5]  L. Squire.  "Memory and the hippocampus: A synthesis from findings with rats, monkeys, and humans": Correction. , 1992 .

[6]  B. Levine,et al.  The functional neuroanatomy of autobiographical memory: A meta-analysis , 2006, Neuropsychologia.

[7]  Julie R. Dumont,et al.  Fornix and retrosplenial contribution to a hippocampo-thalamic circuit underlying conditional learning , 2010, Behavioural Brain Research.

[8]  J. Baron,et al.  Relationships between Hippocampal Atrophy, White Matter Disruption, and Gray Matter Hypometabolism in Alzheimer's Disease , 2008, The Journal of Neuroscience.

[9]  S. Robinson,et al.  Identification of Functional Circuitry between Retrosplenial and Postrhinal Cortices during Fear Conditioning , 2012, The Journal of Neuroscience.

[10]  D. Storm,et al.  Type 1 Adenylyl Cyclase Is Essential for Maintenance of Remote Contextual Fear Memory , 2008, The Journal of Neuroscience.

[11]  E R Kandel,et al.  Different training procedures recruit either one or two critical periods for contextual memory consolidation, each of which requires protein synthesis and PKA. , 1998, Learning & memory.

[12]  I. Izquierdo,et al.  On brain lesions, the milkman and Sigmunda , 1998, Trends in Neurosciences.

[13]  Dorothy Tse,et al.  References and Notes Supporting Online Material Materials and Methods Figs. S1 to S5 Tables S1 to S3 Electron Impact (ei) Mass Spectra Chemical Ionization (ci) Mass Spectra References Schemas and Memory Consolidation Research Articles Research Articles Research Articles Research Articles , 2022 .

[14]  R. Sutherland,et al.  Contributions of cingulate cortex to two forms of spatial learning and memory , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[15]  E Valenstein,et al.  Retrosplenial amnesia. , 1987, Brain : a journal of neurology.

[16]  I. Izquierdo,et al.  Infusion of protein synthesis inhibitors in the entorhinal cortex blocks consolidation but not reconsolidation of object recognition memory , 2009, Neurobiology of Learning and Memory.

[17]  I. Whishaw,et al.  Impaired place navigation in place and matching‐to‐place swimming pool tasks follows both retrosplenial cortex lesions and cingulum bundle lesions in rats , 2004, Hippocampus.

[18]  E. Kandel.  The Molecular Biology of Memory Storage: A Dialogue Between Genes and Synapses , 2001, Science.

[19]  B. Vogt,et al.  Form and distribution of neurons in rat cingulate cortex: Areas 32, 24, and 29 , 1981, The Journal of comparative neurology.

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

[21]  Y. Ichitani,et al.  Dissociable anterograde amnesic effects of retrosplenial cortex and hippocampal lesions on spontaneous object recognition memory in rats , 2012, Hippocampus.

[22]  C. Ranganath,et al.  Two cortical systems for memory-guided behaviour , 2012, Nature Reviews Neuroscience.

[23]  Edith Lesburguères,et al.  Early Tagging of Cortical Networks Is Required for the Formation of Enduring Associative Memory , 2011, Science.

[24]  J. D. McGaugh.  Memory--a century of consolidation. , 2000, Science.

[25]  Y. Dudai,et al.  Rites of Passage of the Engram Reconsolidation and the Lingering Consolidation Hypothesis , 2004, Neuron.

[26]  Y. Dudai.  Molecular bases of long-term memories: a question of persistence , 2002, Current Opinion in Neurobiology.

[27]  N. Foster,et al.  Metabolic reduction in the posterior cingulate cortex in very early Alzheimer's disease , 1997, Annals of neurology.

[28]  C. Alberini.  The role of protein synthesis during the labile phases of memory: Revisiting the skepticism , 2008, Neurobiology of Learning and Memory.

[29]  S. Mizumori,et al.  Temporary Inactivation of the Retrosplenial Cortex Causes a Transient Reorganization of Spatial Coding in the Hippocampus , 2001, The Journal of Neuroscience.

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

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

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

[33]  David J. Bucci,et al.  Involvement of the retrosplenial cortex in processing multiple conditioned stimuli. , 2008, Behavioral neuroscience.

[34]  B. Bontempi,et al.  Sites of Neocortical Reorganization Critical for Remote Spatial Memory , 2004, Science.

[35]  R. Morris,et al.  Elements of a neurobiological theory of hippocampal function: the role of synaptic plasticity, synaptic tagging and schemas , 2006, The European journal of neuroscience.

[36]  Jelena Radulovic,et al.  NMDA Receptors in Retrosplenial Cortex Are Necessary for Retrieval of Recent and Remote Context Fear Memory , 2011, The Journal of Neuroscience.

[37]  Dorothy Tse,et al.  Schema-Dependent Gene Activation and Memory Encoding in Neocortex , 2011, Science.

[38]  M. Bear,et al.  A molecular correlate of memory and amnesia in the hippocampus , 1999, Nature Neuroscience.

[39]  I. Izquierdo,et al.  Memory Formation: The Sequence of Biochemical Events in the Hippocampus and Its Connection to Activity in Other Brain Structures , 1997, Neurobiology of Learning and Memory.

[40]  Joseph E LeDoux,et al.  De novo mRNA synthesis is required for both consolidation and reconsolidation of fear memories in the amygdala. , 2008, Learning & memory.

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

[42]  J. Hodges,et al.  Focal posterior cingulate atrophy in incipient Alzheimer's disease , 2010, Neurobiology of Aging.

[43]  Craig J. Brozinsky,et al.  Functional connectivity with the hippocampus during successful memory formation , 2005, Hippocampus.

[44]  John P. Aggleton,et al.  Testing the importance of the retrosplenial guidance system: effects of different sized retrosplenial cortex lesions on heading direction and spatial working memory , 2004, Behavioural Brain Research.

[45]  I. Izquierdo,et al.  Two Time Periods of Hippocampal mRNA Synthesis Are Required for Memory Consolidation of Fear-Motivated Learning , 2002, The Journal of Neuroscience.

[46]  Roberto Cabeza,et al.  Effects of healthy aging on hippocampal and rhinal memory functions: an event-related fMRI study. , 2005, Cerebral cortex.

[47]  I. Izquierdo,et al.  Persistence of Long-Term Memory Storage Requires a Late Protein Synthesis- and BDNF- Dependent Phase in the Hippocampus , 2007, Neuron.