Susumu Tonegawa: 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

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