LIGHT­ING UP MEM­ORY LANE

The cen­tury-old idea of en­grams – mem­ory traces in our brains – turns out to be cor­rect. EL­IZ­A­BETH FINKEL re­ports.

Cosmos - - Feature - EL­IZ­A­BETH FINKEL is ed­i­tor-in-chief of Cos­mos. IMAGES 01 Sci­ence Photo Li­braby / Getty Images

WHAT IS A MEM­ORY? In 1904 Ger­man bi­ol­o­gist Richard Se­mon came up with the idea of a mem­ory trace held to­gether by the con­nec­tion of a dis­crete group of brain cells. He named that imaginary phys­i­cal cir­cuit an en­gram. En­grams went on to have a ro­bust life in sci­ence fic­tion and scien­tol­ogy.

But as far as proving their ex­is­tence in the brain, that had to await the de­vel­op­ment of light-ac­ti­vated tweez­ers to dis­sect out the fine cir­cuitry. Em­ploy­ing these so called “op­to­ge­netic” tweez­ers in 2012, Susumu Tone­gawa’s lab at MIT first showed that an en­gram was real.

Now in a pa­per pub­lished in Sci­ence last April, the same group has re­vealed the de­tails of how en­grams are made in one part of the brain, the hip­pocam­pus, and then up­loaded for stor­age in the cor­tex, the out­er­most layer.

Un­pick­ing these de­tails of mem­ory stor­age opens the door to find­ing new ways to tweak mem­ory ei­ther when it fails or be­comes hy­per­ac­tive.

“In prin­ci­ple this study shows how we might treat these cells that be­come over­ac­tive in PTSD,” says Pankaj Sah, di­rec­tor of the Queens­land Brain In­sti­tute. “In some ways it’s a sur­prise to find these very com­plete mem­o­ries can be so dis­crete.”

The first ex­per­i­men­tal ev­i­dence of how hu­man mem­o­ries are formed and stored goes back to just 1953. That’s when 27-year-old Amer­i­can Henry Mo­lai­son had his hip­pocampi re­moved as a means to cure his seizures. To the hor­ror of his sur­geons, the op­er­a­tion also de­stroyed his abil­ity to make new mem­o­ries. Yet his old mem­o­ries were fine.

The un­in­tended ex­per­i­ment re­vealed the hip­pocam­pus is needed to weave new mem­o­ries – par­tic­u­larly the con­text-rich “episodic” mem­o­ries made ev­ery day, like what you saw when you walked your dog in the park this morn­ing.

These de­tailed mem­o­ries aren’t stored in the hip­pocam­pus, though. Over time they are trans­ferred to the brain’s outer shell – the cor­tex. We know this from pa­tients who, when these parts of their brain have been elec­tri­cally stim­u­lated, re­call par­tic­u­lar mem­o­ries.

The up­load­ing of these mem­o­ries gen­er­ally in­volves com­press­ing in­for­ma­tion, some­what like the way we com­press com­puter files for long-term stor­age. It was also be­lieved to take place over sev­eral days.

This coarse-grained pic­ture was largely how things stood un­til five years ago. That’s when Tone­gawa’s lab, a col­lab­o­ra­tion be­tween Ja­pan’s RIKEN Brain Sci­ence In­sti­tute and MIT, re­duced a cou­ple of near-myth­i­cal ideas to prac­tice by us­ing a state-of-the-art tech­nol­ogy known as op­to­ge­net­ics. One of the ideas was that of Se­mon’s en­gram. A mem­ory, he posited, would leave a phys­i­cal trace in the brain; and the brain, when stim­u­lated, would re­play the mem­ory.

Se­mon pro­posed this idea decades be­fore re­searchers un­der­stood neu­rons sent sig­nals via elec­tri­cal impulses. Re­searchers have since de­coded much of the elec­tri­cal sig­nalling that passes be­tween neu­rons; and shown how learn­ing and mem­ory cor­re­spond to the strength­en­ing of con­nec­tions, or synapses, be­tween in­di­vid­ual neu­rons.

Yet no-one had ever been able to match a par­tic­u­lar ensem­ble of neu­rons in the brain to a par­tic­u­lar mem­ory. In 1999 Fran­cis Crick, a Nobel prize win­ner who turned his tal­ents to un­pack­ing the mys­ter­ies of the brain, mused that, to make progress, pulses of light might be em­ployed to ac­ti­vate in­di­vid­ual neu­rons in a liv­ing an­i­mal.

“This seems rather far-fetched,” he wrote, “but it is con­ceiv­able that molec­u­lar bi­ol­o­gists could en­gi­neer

The first ex­per­i­men­tal ev­i­dence of how hu­man mem­o­ries are formed and stored goes back to just 1953.

a par­tic­u­lar cell type to be sen­si­tive to light.” Just six years later Stan­ford neu­ro­sci­en­tists Ed­ward Boy­den and Karl Deis­seroth, much to their own sur­prise, made it a re­al­ity with their pi­o­neer­ing work in op­to­ge­net­ics. They co-opted a light switch used by green al­gae – the chan­nel­rhodopsin protein.

When zapped by blue light, the protein opens a pore, al­low­ing pos­i­tively charged ions to flow across the cell mem­brane. This flow of cur­rent sig­nals the fla­gella at the op­po­site end of the al­gal cell to beat, pro­pel­ling it to­wards the light.

Re­searchers found they could in­sert a sin­gle chan­nel­rhodopsin gene into in­di­vid­ual neu­rons by us­ing an in­fect­ing virus as the courier. They also en­sured only cells that had re­cently made a mem­ory pro­duced the light switch gene; mem­ory-mak­ing cells pro­duce a protein called c-fos, so the gene was en­gi­neered to only be made in cells pro­duc­ing c-fos.

In 2012, Tone­gawa’s group used this op­to­ge­netic tech­nique to demon­strate the ex­is­tence of a fear en­gram. A mouse was placed in a box with dis­tinc­tive wall pat­terns and floor tex­tures. When­ever it was placed in that box, it re­ceived an elec­tric shock. Sub­se­quently just plac­ing it in the shock box was enough to make it cringe.

The re­searchers also iden­ti­fied a group of cells in the hip­pocam­pus ac­tively mak­ing the light switch, the smok­ing gun in­di­cat­ing those cells had been in­volved in mak­ing a mem­ory.

To prove that was the case, the sci­en­tists then threaded an op­ti­cal fi­bre through the brain to the hip­pocam­pus to tar­get these cells. When they zapped the hip­pocam­pus with rhyth­mic flashes of blue light, the mouse froze as if were re­liv­ing the mem­ory of be­ing placed in the shock box. It was the first ev­i­dence for an en­gram – a col­lec­tion of a few hun­dred cells that, when stim­u­lated, re­played the mem­ory.

In this new study, the re­searchers wanted to see what hap­pened to the hip­pocam­pus en­gram in the mice over time. Other stud­ies had sug­gested it was a par­tic­u­lar small patch of the cor­tex – the pre­frontal cor­tex – where fear mem­o­ries ap­peared to be stored. So the re­searchers in­fected the cells of the pre­frontal cor­tex with the virus con­tain­ing the light switch.

They found some­thing cu­ri­ous. As be­fore, once the mice learnt to fear the shock room, the mem­ory could be re­played by di­rect­ing flashes of light at the hip­pocam­pus. The sur­prise was the mem­ory could also be pro­voked by flash­ing lights at the pre­frontal cor­tex cells. So the en­gram, it seemed, was si­mul­ta­ne­ously up­loaded to the pre­frontal cor­tex. “This was sur­pris­ing,” notes Tone­gawa, “be­cause it in­di­cated that the cor­ti­cal mem­ory was likely cre­ated on the very first day, and not grad­u­ally as has been as­sumed.”

How­ever, when the mice were placed in the shock room, cring­ing at the mem­ory, those same cells of the pre­frontal cor­tex were silent (as ev­i­denced by check­ing the chem­i­cal ac­tiv­ity in iso­lated brain tis­sue). It was only a cou­ple of weeks af­ter the ex­pe­ri­ence that the cells of the pre­frontal cor­tex fired when the mouse was placed in the shock room. Con­versely, the en­gram in the hip­pocam­pus be­gan to fade.

So when it comes to long-term mem­ory stor­age, first a silent copy is made in the pre­frontal cor­tex; only grad­u­ally does it be­come ce­mented while the hip­pocam­pal en­gram is erased. Just what that long-term ce­ment is, though, re­mains to be de­ter­mined, says Takashi Ki­ta­mura, the first au­thor of the pa­per.

An­other key to ce­ment­ing the mem­ory was that the pre­frontal cor­tex needed to get in­puts from both the hip­pocam­pus and the amyg­dala, the emo­tional cen­tre of the brain. When the re­searchers blocked neu­ronal in­puts from ei­ther (again em­ploy­ing light switches), the cor­tex mem­ory failed to ce­ment.

How might this in­for­ma­tion help peo­ple? While we can’t im­plant light switches, it is nev­er­the­less pos­si­ble to switch par­tic­u­lar re­gions of the brain on or off by im­plant­ing fine elec­trodes us­ing a tech­nique known as deep brain stim­u­la­tion, al­ready used to treat dis­or­ders like Parkin­son’s dis­ease. Ki­ta­mura imag­ines it will one day be pos­si­ble to use a sim­i­lar tech­nique to ma­nip­u­late the en­grams in the brain. “But first we need to map them out in mice.”

Given the break­neck speed at which this field is pro­gress­ing, the era of ma­nip­u­lat­ing our en­grams might not be that far off.

It was the first ev­i­dence of an en­gram – a col­lec­tion of a few hun­dred cells that, when stim­u­lated, re­played the mem­ory.

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