Synapse-specific plasticity governs the identity of overlappingmemory engrams
Kareem Abdou1,2, Mohammad Shehata1,2, Kiriko Choko1,2, Hirofumi Nishizono2,3, Mina Matsuo3, Shin-ichi Muramatsu4, Kaoru Inokuchi1,2
1 Department of Biochemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan. 2 Japan Science and Technology Agency, CREST, University of Toyama, Japan
3 Division of Animal Experimental Laboratory, Life Science Research Center, University of Toyama, Toyama, Japan. 4 Division of Neurology, Department of Internal Medicine, Jichi Medical University, Tochigi, JapanAbstractThroughout the life, we form several memories that are encoded in specific neuronal ensemble, called engram cells. Some ofthese memories are associated and stored in shared ensemble. However, brain machinery that underlies memory storage anddefines certain memory identity amidst numerous number of memories stored in the same ensemble is poorly understood.
Here we show that when two associative memories are encoded in shared ensemble, engram-specific synaptic plasticity
delineates specific memory entity and that specific plasticity is both sufficient and crucial for information storage. Using auditory
fear conditioning and c-fos-TetTag system, optogenetic stimulation of the activated ensemble terminals of auditory cortex (AC) andmedial geniculate nucleus (MGm) in lateral amygdala (LA) after complete retrograde amnesia -accomplished by autophagy
induction with protein synthesis inhibition- failed to induce memory recall at recent and remote time points, indicating that memory
engram no longer exists in that circuit. This result was correlated with the resetting of plasticity and functional connectivity between
the engram assemblies. Furthermore, potentiating or depotentiating the plasticity at synapses specific to a given memory did notaffect the linked memory that is encoded in the same ensemble, suggesting that memories are stored in specific synapses.
These findings unravel how the brain organizes and stores multiple associative memories in shared ensemble, underpinninga causal relationship between synaptic input-specific plasticity and memory identity and storage. Moreover, our study sheds lighton the capability of selective and integral erasure of memory trace from the engram network, suggesting a potential way to treatpost-traumatic stress disorder (PTSD).

③ Functional connectivity between engram cells is disrupted after complete amnesia
AC

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Introduction
Autophagy enhances synaptic and memory destabilization

Associated memories are stored in shared ensembles④ Synapse-specific plasticity within engram circuit denotes memory trace identity
Two memory engrams overlap in LA, but not in AC, with 5 h interval

ACB

Aim of the work

What is the fundamental substrate for memory storage ?
ACHow are multiple associated memories identified in the shared ensemble ?

①Engram circuit loses the memory after complete amnesia
LASparse labelling of AC & MGm engram cells

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Synapse-specific erasure of fear memory trace

CDE

Optogenetic activation of AC & MGm engram terminals in LA fails to induce memory recall

GF

DE
FGH

H

I

Synaptic plasticity is sufficient and crucial for memory storageHD②

Resetting of synaptic plasticity after complete retrograde amnesia
Capacity to induce LTP is recovered after complete amnesia

EI

FGJA
BConclusionC▪ LTP protocol: 5 trains (each train 100 pulses, 100 Hz) at 3 min intertrain intervals.

- Engram network no longer stores the memory after complete retrograde amnesia.
- Resetting of synaptic plasticity and functional connectivity between engram assemblies asneural correlates of complete amnesia.
- Memories, stored in engram cells, are synapse specific.
- Synapse-specific plasticity guarantees the storage of specific fear memory identity.

Shared ensemble