Engram cells retain memory under retrograde amnesia

Abstract

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...

Memory retrieval by activating engram cells in mouse models of early Alzheimer’s disease

“…The retrieval deficit in early AD models is similar to memory deficits observed in amnesia induced by impairing memory consolidation via protein synthesis inhibitors 14 . The underlying mechanism of memory failure in early AD patients may not necessarily parallel the molecular and circuit impairments observed in mouse models of early AD.…”

“…In addition, our recent study of protein synthesis inhibitor-induced amnesia found reduced engram-cell specific dendritic spine density 14 . We detected an age-dependent (Extended Data Fig.…”

“…Using this technology, several groups have demonstrated that DG neurons activated during CFC learning are both sufficient 11 -14 and necessary 15 for subsequent memory retrieval. In addition, our recent study found that engram cells under protein synthesis inhibitor-induced amnesia were capable of driving acute memory recall if they are directly activated optogenetically 14 . In the present study, we have applied this memory engram cell identification and manipulation technology to 7-month old AD mice to determine whether memories could be retrieved in early stages of the disease.…”

“…1l-q). We recently proposed that the persistent cellular connectivity between multiple engram cell ensembles is a fundamental mechanism of memory information retention 14 . We labeled putative CFC memory engram cells in both medial EC (MEC) and lateral EC (LEC) with oChIEF 20 (a variant of ChR2) and simultaneously labeled CFC memory engram cells in the DG with EYFP (Fig.…”

“…Brains were transferred to PBS and 50 μm coronal slices were prepared using a vibratome. For immunostaining 14 , each slice was placed in PBS + 0.2% Triton X-100 (PBS-T), with 5% normal goat serum for 1 hr and then incubated with primary antibody at 4°C for 24 hr. Slices then underwent three wash steps for 10 min each in PBS-T, followed by 1 hr incubation with secondary antibody.…”