Synapse-specific representation of the identity of overlapping memory engrams
Memories are integrated into interconnected networks; nevertheless, each memory has its own identity. How the brain defines specific memory identity out of intermingled memories stored in a shared cell ensemble has remained elusive. We found that after complete retrograde amnesia of auditory fear conditioning in mice, optogenetic stimulation of the auditory inputs to the lateral amygdala failed to induce memory recall, implying that the memory engram no longer existed in that circuit. Complete amnesia of a given fear memory did not affect another linked fear memory encoded in the shared ensemble. Optogenetic potentiation or depotentiation of the plasticity at synapses specific to one memory affected the recall of only that memory. Thus, the sharing of engram cells underlies the linkage between memories, whereas synapse-specific plasticity guarantees the identity and storage of individual memories.
© 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. This is an article distributed under the terms of the Science Journals Default License. http://www.sciencemag.org/about/science-licenses-journal-article-reuse Received for publication February 21, 2018. Accepted for publication April 26, 2018. From the University of Toyama, we thank N. Ohkawa for his help in providing c-Fos::tTA mice, Y. Saitoh and M. Nomoto for their help with electrophysiology, and S. Tsujimura for maintenance of mice. We thank all members of the Inokuchi laboratory for discussion and suggestions. We also thank M. Ito and N. Takino (Jichi Medical University, Japan) for their help with production of the AAV vectors. This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas ("Memory dynamism"; JP25115002) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT); JSPS KAKENHI grant number 23220009; the Core Research for Evolutional Science and Technology (CREST) program (JPMJCR13W1) of the Japan Science and Technology Agency (JST); the Mitsubishi Foundation; the Uehara Memorial Foundation; and the Takeda Science Foundation (to K.I.). Additional support was provided by a Grant-in-Aid for young scientists from JSPS KAKENHI (grant number 25830007) to M.S. The Otsuka Toshimi Scholarship Foundation supported K.A. Author contributions: K.A., M.S., and K.I. designed the experiments. K.A., M.S., and K.I. wrote the manuscript. K.A., M.S., and K.C. performed the experiments. K.A., M.S., and K.I. analyzed the data. H.N. and M.M. produced and maintained transgenic mice. S.M. prepared AAVs. Competing interests: S.M. owns equity in a company, Gene Therapy Research Institution, that commercializes the use of AAV vectors for gene therapy applications. To the extent that the work in this manuscript increases the value of these commercial holdings, S.M. has a conflict of interest. Data and materials availability: All data are available in the main text or the supplementary materials.
Supplemental Material - aat3810_Abdou_SM.pdf