What a Memory Looks Like
Posted on by Dr. Francis Collins
Your brain has the capacity to store a lifetime of memories, covering everything from the name of your first pet to your latest computer password. But what does a memory actually look like? Thanks to some very cool neuroscience, you are looking at one.
The physical manifestation of a memory, or engram, consists of clusters of brain cells active when a specific memory was formed. Your brain’s hippocampus plays an important role in storing and retrieving these memories. In this cross-section of a mouse hippocampus, imaged by the lab of NIH-supported neuroscientist Steve Ramirez, at Boston University, cells belonging to an engram are green, while blue indicates those not involved in forming the memory.
When a memory is recalled, the cells within an engram reactivate and turn on, to varying degrees, other neural circuits (e.g., sight, sound, smell, emotions) that were active when that memory was recorded. It’s not clear how these brain-wide connections are made. But it appears that engrams are the gatekeepers that mediate memory.
The story of this research dates back several years, when Ramirez helped develop a system that made it possible to image engrams by tagging cells in the mouse brain with fluorescent dyes. Using an innovative technology developed by other researchers, called optogenetics, Ramirez’s team then discovered it could shine light onto a collection of hippocampal neurons storing a specific memory and reactivate the sensation associated with the memory .
Ramirez has since gone on to show that, at least in mice, optogenetics can be used to trick the brain into creating a false memory . From this work, he has also come to the interesting and somewhat troubling conclusion that the most accurate memories appear to be the ones that are never recalled. The reason: the mammalian brain edits—and slightly changes—memories whenever they are accessed.
All of the above suggested to Ramirez that, given its tremendous plasticity, the brain may possess the power to downplay a traumatic memory or to boost a pleasant recollection. Toward that end, Ramirez’s team is now using its mouse system to explore ways of suppressing one engram while enhancing another .
For Ramirez, though, the ultimate goal is to develop brain-wide maps that chart all of the neural networks involved in recording, storing, and retrieving memories. He recently was awarded an NIH Director’s Transformative Research Award to begin the process. Such maps will be invaluable in determining how stress affects memory, as well as what goes wrong in dementia and other devastating memory disorders.
 Optogenetic stimulation of a hippocampal engram activates fear memory recall. Liu X, Ramirez S, Pang PT, Puryear CB, Govindarajan A, Deisseroth K, Tonegawa S. Nature. 2012 Mar 22;484(7394):381-385.
 Creating a false memory in the hippocampus. Ramirez S, Liu X, Lin PA, Suh J, Pignatelli M, Redondo RL, Ryan TJ, Tonegawa S. Science. 2013 Jul 26;341(6144):387-391.
 Artificially Enhancing and Suppressing Hippocampus-Mediated Memories. Chen BK, Murawski NJ, Cincotta C, McKissick O, Finkelstein A, Hamidi AB, Merfeld E, Doucette E, Grella SL, Shpokayte M, Zaki Y, Fortin A, Ramirez S. Curr Biol. 2019 Jun 3;29(11):1885-1894.
The Ramirez Group (Boston University, MA)
Ramirez Project Information (Common Fund/NIH)
NIH Director’s Early Independence Award (Common Fund)
NIH Director’s Transformative Research Award (Common Fund)
NIH Support: Common Fund
Dr. Collins, I deeply appreciate your on-going leadership at NIH. Thank you for taking the time to pass on your updates about the latest science. Have a wonderful Holiday Season. mark
An attractive and visually-appealing optogenetics’-hippocampal-engram-based memory/brain-neuronal-networks’ circuitary depiction for eventual public health-oriented patient-friendly neuropharmacological therapeutically significant research in ethnically distinct population-subsets!
Being a conscientious research scientist/clinical research expert with professional achievements in translational/biomedical/public health research spanning both the Western world/USA and my homecountry/India, I wish to congratulate the entire team of experts for bridging the existing scientific knowledge-gap in emerging concepts of high-quality medical research; the expert take-home message provided by the internationally-acclaimed NIH Director, Dr. Collins, further enhanced my scientific intellect triggering my inherent interest for future meaningful public hralth oriented clinical research excellence by collaboratively developing cost-effective public health research models for eventual patient-friendly immunotherapeutically-significant treatment modalities/regimens in the complex neurophysiology field.
The authors of the present study may further design genetic association-pharmacogenetics’ research coupled with brain-cells’ derived neuronal primary cell cultures coupled with optogenetics-engrams-simulations with whole-cell-patch-clamping/electrophysiology and record neuronal-current-spikes with short-term and long-term memory patterns; further, the impressive findings may be extrapolated in both healthy volunteers from random populations/controls and borderline to symptomatic cases of pooled population-subsets/cohorts for dissecting the cellular/molecular/genetic intricacies associated with the initiation, progression and clinical manifestation of neurological disorders, including memory-recall, loss of memory, and/or dementia, migraine, neurodegeneration or Alzheimers’ disease.
An innovative idea may be further explored by the study group by therapeutically targeting the complex Ceramide/Sphingolipid signaling pathways (Pandey S, Experimental Molecular Pathology/Elsevier-publishing, 2006/Pubmed) coupled with ion-channel physiology/receptors/Wnt-Fzd-TLRs-Autophagy-Apoptosis-signaling networks for unraveling the mysteries underlying optogenetics-memory biases in age-/ethnicity-specific populations.
Once again, a thought-provoking research endeavor certainly deserving a critical applause; the NIH Directpr’s crisp expert intellectual inputs and article-highlights tremendously aided in comprehending the excellent research study in the physiology-public health research arena!
Exciting research! Reaping the full harvest depends, however, on linkage to relevant behavioral work with humans. Such work is possible, but has been neglected in some of the fascination with cellular work.