Tracking the Time-Dependent Role of the Hippocampus in Memory Recall Using DREADDs

PLoS One. 2016 May 4;11(5):e0154374. doi: 10.1371/journal.pone.0154374. eCollection 2016.


The hippocampus is critical for the storage of new autobiographical experiences as memories. Following an initial encoding stage in the hippocampus, memories undergo a process of systems-level consolidation, which leads to greater stability through time and an increased reliance on neocortical areas for retrieval. The extent to which the retrieval of these consolidated memories still requires the hippocampus is unclear, as both spared and severely degraded remote memory recall have been reported following post-training hippocampal lesions. One difficulty in definitively addressing the role of the hippocampus in remote memory retrieval is the precision with which the entire volume of the hippocampal region can be inactivated. To address this issue, we used Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), a chemical-genetic tool capable of highly specific neuronal manipulation over large volumes of brain tissue. We find that remote (>7 weeks after acquisition), but not recent (1-2 days after acquisition) contextual fear memories can be recalled after injection of the DREADD agonist (CNO) in animals expressing the inhibitory DREADD in the entire hippocampus. Our data demonstrate a time-dependent role of the hippocampus in memory retrieval, supporting the standard model of systems consolidation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Clozapine / analogs & derivatives
  • Clozapine / metabolism
  • Clozapine / pharmacology
  • Designer Drugs / metabolism
  • Fear / physiology
  • Hippocampus / drug effects
  • Hippocampus / physiology*
  • Humans
  • Memory, Long-Term / drug effects
  • Memory, Long-Term / physiology
  • Mental Recall / drug effects
  • Mental Recall / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Receptor, Muscarinic M4 / agonists
  • Receptor, Muscarinic M4 / genetics
  • Receptor, Muscarinic M4 / metabolism
  • Receptors, Drug / agonists
  • Receptors, Drug / genetics
  • Receptors, Drug / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Time Factors


  • Designer Drugs
  • Receptor, Muscarinic M4
  • Receptors, Drug
  • Recombinant Proteins
  • Clozapine
  • clozapine N-oxide