So, the idea that mem­o­ry is stored in the brain and per­sis­tent phys­i­cal changes goes back to Plato. But the mod­ern for­mu­la­tion of this hypoth­e­sis had to wait until the turn of the 20th cen­tu­ry, when Richard Semon coined the word engram” for these per­sis­tent changes. 

We have now iden­ti­fied a pop­u­la­tion of brain cells that hold a spe­cif­ic mem­o­ry. Not only that, we can now engi­neer these cells with light, so that ani­mals’ mem­o­ries, emo­tions, and even thoughts can be manip­u­lat­ed. This is an idea that has exist­ed only in the realm of sci­ence fic­tion until recent­ly.

An x-ray-like representation of a side view of the brain, with a narrow strip near the center highlighted

When you encounter an episode, a pop­u­la­tion of cells deep inside your brain fires. And then this will be fol­lowed by per­sis­tent changes in these cells. You can recall this mem­o­ry only when exter­nal stim­uli reac­ti­vate these cells. So, these hypothe­ses have now been proven to be cor­rect by using a tech­nol­o­gy called opto­ge­net­ics. The key mol­e­cule of opto­ge­net­ics is a light-sensitive pro­tein called chan­nel­rhodopsin, which is extract­ed from green algae. Scientists can insert chan­nel­rhodopsin into mem­o­ry cells. Subsequently, sci­en­tists can even acti­vate these with blue light which they deliv­er deep inside the brain with optic fibers. 

Now, mem­o­ry is usu­al­ly quite reli­able. But under cer­tain con­di­tions, humans make incred­i­ble false mem­o­ries. For instance, after arrest­ing John Doe #1, or Timothy McVeigh, fol­low­ing the Oklahoma City bomb­ing in 1995, which some of you may remem­ber, the tes­ti­mo­ny based on the false mem­o­ry caused a nation­wide man­hunt for a sec­ond, John Doe #2, who nev­er exist­ed.

We can implant false mem­o­ry in the brain of mice. For that pur­pose, you let mice stay in a blue box, and the let the mice form a mem­o­ry of the blue box. And then you can label these cells with chan­nel­rhodopsin. Subsequently, when the mice are asleep, they are [giv­en] a mild foot shock in a red box, which is very dif­fer­ent from a blue box. At the same time, the ani­mal is forced to recall the mem­o­ry of the blue box. Then, if let the ani­mal return to the blue box, they will be scared. This is a demon­stra­tion of for­ma­tion of false mem­o­ry, because this mouse has nev­er been shocked in the blue box.

Depression is a ter­ri­ble brain dis­or­der which afflicts 350 mil­lion peo­ple world­wide. Depression is often caused by chron­ic stress which pre­cip­i­tates a series of neg­a­tive mem­o­ries. We know now that the neg­a­tive and the pos­i­tive mem­o­ries com­pete with each oth­er in the brain net­work. Using this prin­ci­ple, we have recent­ly made a very excit­ing dis­cov­ery, that is to cure depres­sion with opto­ge­net­ic tech­nol­o­gy.

For this pur­pose, we made a mouse form [plea­sur­able] mem­o­ries by play­ing with a female mouse, and then sub­ject­ed it to chron­ic stress treat­ment and fall into depres­sion. We could cure the depres­sion of this male mouse by acti­vat­ing the pos­i­tive mem­o­ry engram cells with light. 

Scientists can also cure the prob­lem of mice with the ear­ly stages of Alzheimer’s dis­ease. These mice can form mem­o­ries, but can­not retrieve the mem­o­ries. But we could restore the mem­o­ry recall of these mice by using opto­ge­net­ic tech­nol­o­gy.

So, opto­ge­net­ics has demon­strat­ed proof of con­cept for pos­si­ble ther­a­py for a vari­ety of dis­eases. The big ques­tion is now, can we con­vert or trans­late these find­ings made with ani­mal mod­els into ther­a­py for human patients?

Further Reference

Tonegawa Lab, MIT


Help Support Open Transcripts

If you found this useful or interesting, please consider supporting the project monthly at Patreon or once via Square Cash, or even just sharing the link. Thanks.