Optogenetic Stimulation of a Hippocampal Engram Activates Fear

Optogenetic Stimulation of a Hippocampal Engram Activates Fear Memory Recall Xu Liu 1, Steve Ramirez 1, Petti T. Pang 1, Corey B. Puryear 1, Arvind Govindarajan 1, Karl Deisseroth 2, & Susumu Tonegawa 1 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 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 Ch. R 2 EYFP Ch. R 2 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 Ch. R 2, but not EYFP, as shown by c-Fos signal. Verification by Electrophysiology 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 in vivo head-fixed recordings from anesthetized animals show light response in Ch. R 2 -expressing animals. 0 T 1 T 2 day 1 T 3 E 1 day 2 E 3 E 4 E 5 Retest day 3 day 4 day 5 day 6 day 7 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 R 01 MH 078821, P 50 -MH 58880 to S. T. and RIKEN Brain Science Institute.