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Optogenetic Stimulation of a Hippocampal Engram Activates Fear Memory Recall Xu Liu1, Steve Ramirez1, Petti T. Pang1, Corey B. Puryear1, Arvind Govindarajan1, Karl Deisseroth2, & Susumu Tonegawa1 1. RIKEN-MIT Center for Neural Circuit Genetics and The Picower Institute for Learning and Memory, MIT, Cambridge, MA 2. Department of Bioengineering and Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA Abstract The memory engram theory proposes that a specific memory is encoded and stored in a defined population of neurons. In order to test this hypothesis directly, one needs to show that the activation of such a population of neurons can cause the recall of that specific memory. We constructed an activity-dependent, doxycycline-regulatable labeling system by combing a transgenic mouse expressing tetracycline transactivator (tTA) driven by the cfos promoter and an adeno-associated virus (AAV) encoding channelrhodopsin-2 (ChR2) under the control of the tetracycline response element (TRE). In the experimental group, we labeled a population of cells in the dentate gyrus (DG) that were active during fear conditioning with ChR2. Control groups consisted of animals with either ChR2 labeling a DG cell population active during a non-fear memory learning task, or EYFP labeling a DG cell population active during fear conditioning, followed by light stimulation. Our study tests the hypothesis that a DG cell population active during fear memory learning is sufficient for fear memory recall upon activation, and thus may provide direct evidence for the cellular basis of a memory engram. Labeling and Activating a Memory Engram Optical Stimulation of Engram-bearing Cells Induces Post-training Freezing Verified Implant Placements Expected behavior Labeling and Activating Engram-bearing Cells with ChR2 ChR2 EYFP ChR2 Crosses mark the tip of optic fiber as verified by histology. EYFP Conclusions Optical activation of DG cells active during fear learning is sufficient for fear memory recall. Experimental Mice Show Reduced Freezing during Context, but not Tone, Probe Trials Light preferentially activated cells expressing ChR2, but not EYFP, as shown by c-Fos signal. Verification by Electrophysiology Combining Transgenics and Optogenetics a Five sessions of light-induced fear memory recall elicit a decrease in freezing to the original training context. Here we have shown that optical activation of hippocampal cells that were active during fear conditioning is sufficient to elicit freezing behavior. Our results argue that defined cell populations can form a cellular basis for fear memory engrams. The memory engram that we selectively labeled and manipulated is likely contextual in nature, as previous studies have demonstrated that hippocampal interventions affect conditioned freezing responses to a context, but not a tone, which is consistent with our finding that only experimental groups showed decreased freezing during context, but not tone, probe trials. The approach and methods described here will be a powerful tool for mapping multiple component engrams, each contributing to an overall memory. Extinction by Light or Context 0.6 Freezing 0.5 Acknowledgements Light N=6 Context 0.4 0.3 0.2 0.1 When an animal is kept off Dox diet, only active c-Fos expressing cells will become labeled by ChR2. in vivo head-fixed recordings from anesthetized animals show light response in ChR2-expressing animals. 0 T1 T2 day1 T3 E1 day2 E2 E3 E4 E5 Retest day3 day4 day5 day6 day7 The Tonegawa Lab @ MIT Grace Lin Xiaoning Zhou Shu Huang Mike Ragion Tomas Ryan Roger Redondo Alex Rivest Jennie Young This work is supported by NIH grants R01MH078821, P50-MH58880 to S.T. and RIKEN Brain Science Institute.