NMDA Receptors in Retrosplenial Cortex Are Necessary for Retrieval of Recent and Remote Context Fear Memory

Over time, memory retrieval is thought to transfer from the hippocampus to a distributed network of neocortical sites. Of these sites, the retrosplenial cortex (RSC) is robustly activated during retrieval of remotely acquired, emotionally valenced memories. It is unclear, however, whether RSC is specifically involved in memory storage or retrieval, and which neurotransmitter receptor mechanisms serve its function. We addressed these questions by inhibiting NMDARs in RSC via infusions of APV before tests for context fear in mice. Anterior cingulate cortex (ACC) and dorsal hippocampus (DH), which have been implicated in the retrieval of remote and recent memory, respectively, served as neuroanatomical controls. Surprisingly, infusion of APV only into RSC, but not ACC or DH, abolished retrieval of remote memory, as revealed by lack of freezing to the conditioning context. APV infused into RSC also impaired retrieval of recent memory, but had no effect on conditioning or memory storage. Within-subject experiments confirmed that the role of RSC in memory retrieval is not time limited. RSC-dependent context fear memory retrieval was mediated by NR2A, but not NR2B, subunit-containing NMDARs. Collectively, these data are the first demonstration that NMDARs in RSC are necessary for the retrieval of remote and recent memories of fear-evoking contexts. Dysfunction of RSC may thereby contribute significantly to the reexperiencing of traumatic memories in patients with posttraumatic stress disorder.

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

[2]  Richard G M Morris,et al.  Distinct Contributions of Hippocampal NMDA and AMPA Receptors to Encoding and Retrieval of One-Trial Place Memory , 2005, The Journal of Neuroscience.

[3]  G. Winocur,et al.  “I have often walked down this street before”: fMRI Studies on the hippocampus and other structures during mental navigation of an old environment , 2004, Hippocampus.

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

[5]  April E Hebert,et al.  A role for the prefrontal cortex in recall of recent and remote memories , 2006, Neuroreport.

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

[7]  B. Sacchetti,et al.  Role of Secondary Sensory Cortices in Emotional Memory Storage and Retrieval in Rats , 2010, Science.

[8]  Martina Piefke,et al.  The Neurofunctional Mechanisms of Traumatic and Non-Traumatic Memory in Patients with Acute PTSD Following Accident Trauma , 2008, Neurocase.

[9]  Michael J. Jutras,et al.  Perirhinal and Postrhinal Contributions to Remote Memory for Context , 2004, The Journal of Neuroscience.

[10]  M. Fanselow,et al.  Temporally Graded Retrograde Amnesia of Contextual Fear after Hippocampal Damage in Rats: Within-Subjects Examination , 1999, The Journal of Neuroscience.

[11]  Min Zhuo,et al.  Roles of NMDA NR2B Subtype Receptor in Prefrontal Long-Term Potentiation and Contextual Fear Memory , 2005, Neuron.

[12]  Eric Halgren,et al.  Ecphory of autobiographical memories: An fMRI study of recent and remote memory retrieval , 2006, NeuroImage.

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

[14]  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.

[15]  N. Tronson,et al.  Hippocampal NMDA receptor subunits differentially regulate fear memory formation and neuronal signal propagation , 2010, Hippocampus.

[16]  M. Fanselow,et al.  Dorsal hippocampus NMDA receptors differentially mediate trace and contextual fear conditioning , 2005, Hippocampus.

[17]  Karim Nader,et al.  Engagement of the PFC in consolidation and recall of recent spatial memory. , 2010, Learning & memory.

[18]  J. W. Rudy,et al.  The role of dorsal hippocampus and basolateral amygdala NMDA receptors in the acquisition and retrieval of context and contextual fear memories. , 2007, Behavioral neuroscience.

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

[20]  J. Sweatt,et al.  Cortical DNA methylation maintains remote memory , 2010, Nature Neuroscience.

[21]  I. Izquierdo,et al.  Sequential Role of Hippocampus and Amygdala, Entorhinal Cortex and Parietal Cortex in Formation and Retrieval of Memory for Inhibitory Avoidance in Rats , 1997, The European journal of neuroscience.

[22]  John P. Aggleton,et al.  Understanding retrosplenial amnesia: Insights from animal studies , 2010, Neuropsychologia.

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

[24]  Z. Solomon,et al.  The longitudinal course of posttraumatic stress disorder symptom clusters among war veterans. , 2009, The Journal of clinical psychiatry.

[25]  R. Clark,et al.  The medial temporal lobe. , 2004, Annual review of neuroscience.

[26]  I. Izquierdo,et al.  Molecular signalling pathways in the cerebral cortex are required for retrieval of one-trial avoidance learning in rats , 2000, Behavioural Brain Research.

[27]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .

[28]  Anterograde and retrograde amnesia of place discrimination in retrosplenial cortex and hippocampal lesioned rats. , 2008, Learning & memory.