Memories can be unreliable. We created a false memory in mice by optogenetically manipulating memory engram-bearing cells in the hippocampus. Dentate gyrus (DG) or CA1 neurons activated by exposure to a particular context were labeled with channelrhodopsin-2. These neurons were later optically reactivated during fear conditioning in a different context. The DG experimental group showed increased freezing in the original context, in which a foot shock was never delivered. The recall of this false memory was context-specific, activated similar downstream regions engaged during natural fear memory recall, and was also capable of driving an active fear response. Our data demonstrate that it is possible to generate an internally represented and behaviorally expressed fear memory via artificial means.

Memory consolidation is the process by which a newly formed and unstable memory transforms into a stable long-term memory. It is unknown whether the process of memory consolidation occurs exclusively by the stabilization of memory engrams. By employing learning-dependent cell labeling, we identified an increase of synaptic strength and dendritic spine density specifically in consolidated memory engram cells. While these properties are lacking in the engram cells under protein synthesis inhibitor-induced amnesia, direct optogenetic activation of these cells results in memory retrieval, and this correlates with the retained engram cell-specific connectivity. We propose that a specific pattern of connectivity of engram cells may be crucial for memory information storage and that strengthened synapses in these cells critically contribute to the memory retrieval process. Main TextMemory consolidation is the phenomenon whereby a newly formed memory transitions from a fragile state to a stable, long-term state (1-3). The defining feature of consolidation is a finite time window that begins immediately after learning, during which a memory is susceptible to disruption such as protein synthesis inhibition (4-6), resulting in retrograde amnesia. The stabilization of synaptic potentiation is the dominant cellular model of memory consolidation (7-10) because protein synthesis inhibitors disrupt late-phase longterm potentiation of in vitro slice preparations (11-13). Although much is known about the cellular mechanisms of memory consolidation it remains unknown whether these processes occur in memory engram cells. It may be possible to characterize cellular consolidation and empirically separate mnemonic properties in retrograde amnesia by directly probing and manipulating memory engram cells in the brain. The term memory engram originally † Correspondence to: tonegawa@mit.edu. * These authors contributed equally to this work. Supplemental reference: (41)Data and Materials: pAAV-TRE-ChR2-EYFP, pAAV-TRE-ChR2-mCherry, and pAAV-TRE-mCherry were developed by X.L., in the group of S.T., at the Massachusetts Institute of Technology; therefore, a materials transfer agreement (MTA) is required to obtain these virus plasmids. HHMI Author ManuscriptHHMI Author Manuscript HHMI Author Manuscript referred to the hypothetical learned information stored in the brain, which must be reactivated for recall (14)(15). Recently, several groups demonstrated that specific hippocampal cells that are activated during memory encoding are both sufficient (16)(17)(18) and necessary (19)(20) for driving future recall of a contextual fear memory, and thus represent a component of a distributed memory engram (21). Here, we applied this engram technology to the issue of cellular consolidation and retrograde amnesia.We employed the previously established method for tagging the hippocampal dentate gyrus (DG) component of a contextual memory engram with mCherry (see Materials and Methods, fig. S1,and (16,22)). To disrupt consolidation we systemicall...

SummaryAlzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory decline and subsequent loss of broader cognitive functions 1 . Memory decline in early stages of Alzheimer's is mostly limited to episodic memory, for which the hippocampus (HPC) plays a crucial role 2 . However, it has been uncertain whether the observed amnesia in early stages of Alzheimer's is due to disrupted encoding and consolidation of episodic information, or an impairment in the retrieval of stored memory information. Here we show that in transgenic mouse models of early Alzheimer's, direct optogenetic activation of hippocampal memory engram cells results in memory retrieval despite the fact that these mice are amnesic in long-term memory tests when natural recall cues are utilized, revealing a retrieval, rather than a storage impairment. Prior to amyloid plaque deposition, the amnesia in these mice is age-dependent 3 -5 , which correlates with a progressive reduction of spine density of hippocampal dentate gyrus (DG) engram cells. We show that optogenetic induction of long-term potentiation (LTP) at perforant path (PP) synapses of DG engram cells restores both spine density and long-term memory. We also demonstrate that an ablation of DG engram cells containing restored spine density prevents the rescue of long-term memory. Thus, selective rescue of spine density in engram cells may lead to an effective strategy for treating memory loss in early stages of Alzheimer's disease.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature