CEPHALOPOD – OC­TO­PUS

Cosmos - - Octopus Intelligence -

They were still able to change colour and body pat­terns but in a seem­ingly ran­dom fash­ion. Anatom­i­cal ev­i­dence also shows that nerves in the lower brain con­nect di­rectly to mus­cles sur­round­ing the pig­ment sacs or chro­matophores.

Like an artist spread­ing pig­ment on a pal­let, ac­ti­vat­ing the mus­cles pulls the sacs apart spread­ing the chro­matophore pig­ments into thin discs of colour. But the oc­to­pus is not com­pos­ing a pic­ture. Han­lon’s ex­per­i­ments with cut­tle­fish show they are de­ploy­ing one of three pre-ex­ist­ing pat­terns – uni­form, mot­tled or dis­rup­tive – to achieve cam­ou­flage on di­verse back­grounds.

As far as de­tailed brain cir­cuitry goes, re­searchers have made lit­tle progress since the 1970s when leg­endary Bri­tish neu­ro­sci­en­tist J.Z Young worked out the gross anatomy of the dis­trib­uted coleoid brain. Es­cap­ing Bri­tain’s dis­mal win­ter for the Stazione Zoo­log­ica in balmy Naples, Young’s re­search was part of an Amer­i­can Air Force funded project to search for the the­o­ret­i­cal mem­ory cir­cuit, the ‘en­gram’.

“They were ahead of their time,” says Han­lon, who ex­pe­ri­enced a stint with Young in Naples. Nev­er­the­less they were limited by the paucity of brain-record­ing tech­niques that were suited to the oc­to­pus.

It’s a prob­lem that has continued to hold back the understanding of how their brain cir­cuits work. “Is it the same as the way mam­mals process in­for­ma­tion? We don’t know,” says Rags­dale.

UN­WILL­ING SUB­JECTS

It’s not for want of try­ing, as Kuba will tell you. In the 1990s, he joined the lab of neu­ro­sci­en­tist Binyamin Hochner at the He­brew Univer­sity of Jerusalem. Hochner was a grad­u­ate of Eric Kan­del’s lab, the No­bel lau­re­ate who pi­o­neered stud­ies on how the sea slug Aplysia learns.

All the ac­tion takes place in the gaps be­tween in­di­vid­ual neu­rons, the ‘synapse’. The synapse may look like an empty gap un­der the mi­cro­scope but it’s a crowded place. It’s packed with over 1,000 pro­teins that as­sem­ble into a pin­point-size mi­cro­pro­ces­sor. If each neu­ron is like a wire, it’s up to this mi­cro­pro­ces­sor to de­cide whether the sig­nal crosses over from one wire to the next. When the sea slug learns a les­son, for in­stance with­draw­ing its gill in re­sponse to a tail shock, that’s be­cause new com­pu­ta­tions at the synapse rerouted the connections.

Kuba, how­ever, found an oc­to­pus to be far less oblig­ing than a sea slug. What­ever elec­tri­cal probe he stuck into its brain was rapidly re­moved thanks to all those op­pos­able thumbs. Rags­dale also had his share of frus­tra­tion. “We have a tech­ni­cal prob­lem with sharp elec­trodes. For ex­am­ple, if you put an elec­trode into the op­tic lobe, the neu­rons will fire for about 10 to 20 min­utes and then be­come silent.”

Kuba, who is now based at the Ok­i­nawa In­sti­tute of Science and Tech­nol­ogy, hopes that a new kind of minia­ture brain log­ger that sits on the sur­face of the brain, hope­fully out of reach of pry­ing suck­ers, will kick-start the era of oc­to­pus brain-cir­cuit map­ping.

“There’s a lot of tech­ni­cal chal­lenges, but they are sur­mount­able,” agrees Rags­dale.

The irony is that the first in­sights into how the oc­to­pus brain sends sig­nals came from a squid. In 1934 Young iden­ti­fied a gi­ant squid nerve cell that con­trolled the mas­sive con­trac­tions of its man­tle, the bul­bous mus­cu­lar sac be­hind the eyes that both houses the or­gans and squeezes wa­ter through the siphon with such great ef­fect!

Like mam­malian neu­rons, the most dis­tinc­tive fea­ture of the squid cell was its wire-like axon, but with a di­am­e­ter of around one mil­lime­tre, it was 1,000 times fat­ter than those of mam­mals. The colos­sal size al­lowed re­searchers to in­sert a metal elec­trode and mea­sure the chang­ing elec­tri­cal volt­age as a nerve im­pulse trav­elled along the axon.

All this foun­da­tional knowl­edge shed light on ver­te­brate brains, but the de­tailed cir­cuitry of the squid brain was largely left in the dark.

BREAK­ING THE CEN­TRAL DOGMA

It was an­other frus­trated neu­ro­sci­en­tist who opened the lat­est front into the understanding of soft in­tel­li­gence.

In the early 1990s, Josh Rosen­thal, based at Wil­liam Gilly’s lab at Stan­ford, was mak­ing use of the time­honoured gi­ant squid mo­tor axon. But with a new pur­pose. Rather than mea­sure its elec­tri­cal prop­er­ties, Rosen­thal wanted to iso­late one of its key com­po­nents: the ‘off’ switch. It is a protein called the potas­sium chan­nel.

The squid neu­ron made this protein ac­cord­ing to a recipe car­ried by its DNA blueprint, which is cached in the cell’s nu­cleus. To ac­cess the recipe, the cell makes a MRNA tran­script, rather like tran­scrib­ing a sin­gle recipe from a recipe book. Rosen­thal wanted to iso­late th­ese tran­scripts and read the code se­quence for the protein chan­nels.

But he had a prob­lem. Ev­ery time he read the se­quence for the potas­sium chan­nel, it was slightly dif­fer­ent. Was it just an er­ror? If so, it was highly con­sis­tent. The changes were not ran­dom. They al­ways oc­curred at one or more pre­cise po­si­tions in the code. And, in­vari­ably, the let­ter A was al­ways changed to the let­ter G.

For in­stance, imag­ine a recipe for ap­ple pie was sup­posed to read: Place the crust around the pie.

In­stead it was be­ing edited to: Place the crust ground the pie. Such a change might in­struct the modern-day de­con­structed ap­ple pie rather than the tra­di­tional crusted ver­sion.

Un­be­knownst to Rosen­thal, Peter See­burg at the Univer­sity of Hei­del­berg was puz­zling over a sim­i­lar glitch in a recipe for a hu­man brain protein, the glu­ta­mate re­cep­tor. When See­burg’s pa­per was pub­lished in 1991, Rosen­thal re­calls, “ev­ery­one got excited”.

Clearly edit­ing brain recipes was im­por­tant for hu­mans and squid. But why?

In the hu­man (or mouse), edit­ing the glu­ta­mate re­cep­tor changed how much cal­cium could flow into brain cells. In mice, fail­ure to edit was lethal, as it al­lowed toxic lev­els of cal­cium to stream in. There’s also ev­i­dence that fail­ure to edit the same re­cep­tor in hu­mans is as­so­ci­ated with the neu­rode­gen­er­a­tive dis­ease Amy­otrophic Lat­eral Scle­ro­sis.

An enzyme called ADAR2 car­ried out th­ese cru­cial ed­its to the RNA recipe. Just why evo­lu­tion hasn’t gone ahead and ‘fixed’ the DNA source code of the glu­ta­mate re­cep­tor re­mains a mys­tery.

As for the squid potas­sium chan­nel, Rosen­thal had a hunch. Af­ter an elec­tri­cal sig­nal has passed through a neu­ron, it needs a ‘re­set’ for the next sig­nal. The potas­sium chan­nel plays a cru­cial part. In cold tem­per­a­tures, the re­set might take longer, mak­ing the an­i­mal a bit slug­gish. Could RNA edit­ing be a way of fine tun­ing the sys­tem in re­sponse to tem­per­a­ture? Rosen­thal tested his idea by spend­ing sev­eral years col­lect­ing oc­to­puses that live in ei­ther trop­i­cal, tem­per­ate or po­lar cli­mates. It was in­deed the po­lar oc­to­puses that were the most avid ed­i­tors of their potas­sium chan­nels.

Potas­sium chan­nels turned out to be just the tip of the ice­berg. Rosen­thal teamed up with com­pu­ta­tion geek Eli Eisen­berg at Tel Aviv Univer­sity to trawl through MRNA data­bases and find out just how much recipe tweak­ing was go­ing on with squid genes. In hu­mans, tweak­ing is rare – re­stricted to a hand­ful of brain gene recipes. In the squid, the ma­jor­ity of brain recipes re­ceived this treat­ment. Many of them were re­lated to pro­teins found at the synapses, the mi­cro­pro­ces­sors for mem­ory and learn­ing.

Could this ex­tem­po­ris­ing with brain protein recipes be im­por­tant for soft in­tel­li­gence? It’s a tan­ta­lis­ing idea. “Coleoids show it. Nau­tilus – the stupid cousin does not, it’s like any other mol­lusc,” says Eisen­berg.

“Coleoids are edit­ing the same pro­teins that we

know are in­volved in learn­ing and mem­ory. By edit­ing them or not, it’s not a stretch to hy­poth­e­sise that they are adding flex­i­bil­ity and com­plex­ity to the sys­tem,” says Rosen­thal.

CLUES FROM THE BLUEPRINT

Over in Chicago, Cliff Rags­dale, an­other frus­trated oc­to­pus neu­ro­sci­en­tist, was also turn­ing his in­ter­est to oc­to­pus DNA.

In 2015, work­ing with Daniel Rokhsar and Oleg Si­makov of OIST, the Rags­dale lab­o­ra­tory man­aged to read the genome of the Cal­i­for­nia two-spot oc­to­pus.

It turns out that the oc­to­pus has more genes that we do: 33,000 com­pared to our 21,000. But gene num­ber per se doesn’t bear much re­la­tion to brain power: wa­ter fleas also have about 31,000. In fact most of the genes in the oc­to­pus cat­a­logue were not all that dif­fer­ent to those of its close rel­a­tive – the limpet, a type of sea snail. But there were two gene fam­i­lies that stood out like a sore thumb. One was a fam­ily of genes called pro­to­cad­herins. This fam­ily of ‘ad­he­sion’ pro­teins are known to build brain cir­cuits. Like la­bels on the tips of grow­ing neu­rons, they al­low the cor­rect types of neu­rons to wire to each other — so neu­ron 370 con­nects up to neu­ron 471 at the right time and the right place. Lim­pets and oys­ters have be­tween 17-25 types of pro­to­cad­herins. Ver­te­brates have 70 types of pro­to­cad­herins plus over 100 dif­fer­ent types of re­lated cad­herins. Th­ese cir­cuit builders have long been thought to be the key to ver­te­brate brain­i­ness.

So it was stun­ning to find that the oc­to­pus has a su­per­fam­ily of 168 pro­to­cad­herins. Rags­dale says the squid genome, also now be­ing se­quenced, shows it is sim­i­larly equipped with hun­dreds of cir­cuit-build­ing genes.

THE OTHER STAND- OUT

in the oc­to­pus genome was a fam­ily of genes called ‘zinc fin­gers’. They get their name be­cause the en­coded pro­teins have a chain struc­ture that is cinched by zinc atoms into a se­ries of fin­gers. Th­ese fin­gers poke into the coils of DNA to reg­u­late the tran­scrip­tion of genes.

Lim­pets have about 413 of th­ese zinc fin­gers. Hu­mans have 764. Oc­to­puses have 1,790! Per­haps this pro­fu­sion of oc­to­pus zinc fin­gers is in­volved in reg­u­lat­ing the net­work of brain genes?

So far, the oc­to­pus has re­vealed three big clues as to how it gen­er­ates brain com­plex­ity: it has mul­ti­plied its set of cir­cuit-build­ing pro­to­cad­herin genes and its net­work-reg­u­lat­ing zinc fin­gers. It has also un­leashed RNA edit­ing to gen­er­ate more com­plex­ity on the fly. There may also be a fourth mech­a­nism at work. Genes are sup­posed to stay put. But ‘jump­ing genes’, which are closely re­lated to viruses, have a ten­dency to up an­chor and in­sert them­selves into dif­fer­ent sec­tions of the DNA code. That can scram­ble or oth­er­wise change its mean­ing. Imag­ine if the words ‘jump­ing gene’ just started ap­pear­ing ran­domly in this text. Fred Gage’s group at the Salk In­sti­tute in San Diego has found that dur­ing the devel­op­ment of the ner­vous sys­tem in mice and hu­mans, jump­ing genes start jump­ing.

What this means is that each in­di­vid­ual brain cell ends up with slightly dif­fer­ent ver­sions of its DNA code. Gage spec­u­lates that this may be a way to gen­er­ate di­ver­sity in the way neu­rons wire up. Per­haps it goes some way to ex­plain­ing why twins, born with the same DNA, nev­er­the­less end up with dif­fer­ent be­hav­iours.

“If you be­lieve that the­ory,” says Rags­dale, “you’ll be struck by the fact that we also found a high num­ber of jump­ing genes ac­tive in the brain tis­sues of the oc­to­pus.”

TEST­ING THE THE­ORY

Un­rav­el­ling the de­tails of how oc­to­pus and squid are us­ing and abus­ing the ge­netic code is gen­er­at­ing icon­o­clas­tic hy­pothe­ses about how they gen­er­ate their com­plex brain cir­cuitry.

And re­searchers are not blind to the prob­lems of dogma-break­ing. For one thing, play­ing fast and free with the ge­netic code cre­ates an astro­nom­i­cal num­ber of pos­si­ble pro­teins, most of which would be toxic to the an­i­mal, says Eisen­berg. “It’s very trou­bling; one hy­poth­e­sis is that this may ex­plain their short life­span of one to three years.”

Trou­bling or not, Rosen­thal and col­leagues at Woods Hole are moving full speed ahead to test the role of RNA edit­ing in the coleoids by bring­ing to­gether re­searchers with dif­fer­ent ex­per­tise. “There’s a lot of moving pieces,” says Rosen­thal.

For starters, their Woods Hole team is cul­ti­vat­ing four species of small squid and cut­tle­fish that reach sex­ual ma­tu­rity in two to three months. The goal is to ma­nip­u­late the squid’s genes us­ing the ge­netic en­gi­neer­ing tool, CRISPR. To see if they can get CRISPR work­ing, they will try to ‘knock-out’ the pig­ment genes. If they’re suc­cess­ful they should see the re­sult on the squid bod­ies. “It’s a beau­ti­ful in-built test,” says Rosen­thal.

If that works, they will try the big ex­per­i­ment. Does im­pair­ing the abil­ity to edit pro­teins at the synapse (by knock­ing out the ADAR2 gene re­spon­si­ble for RNA edit­ing) tam­per with learn­ing and mem­ory?

Mean­while, col­lab­o­ra­tor Alex Sch­nell, a be­havioural bi­ol­o­gist based at the Univer­sity of Cam­bridge in the UK, is de­vel­op­ing rig­or­ous tests for com­plex learn­ing and mem­ory in cut­tle­fish. In par­tic­u­lar, she is test­ing their ca­pac­ity for “episodic mem­ory”, a de­tailed weav­ing to­gether of mem­o­ries once thought to be a strictly hu­man at­tribute.

For in­stance, it’s thanks to your episodic mem­ory that you re­call ex­actly where you were and what you were do­ing on 11 Septem­ber 2001. Since the late 1990s, we know that an­i­mals like great apes, crows and jays also have that ca­pac­ity. Maybe cut­tle­fish do too. Sch­nell’s ini­tial re­sults show that cut­tle­fish can learn and mem­o­rise com­plex in­for­ma­tion about their favourite food, such as when and where it is likely to be found.

With other teams around the world pur­su­ing sim­i­lar strate­gies, it seems likely that af­ter decades of awe and won­der, the mys­tery of soft in­tel­li­gence may soon yield to hard science.

| Oc­to­pus are body artists that use skin colour, tex­ture and arm con­tor­tions for their dis­ap­pear­ing acts.

07 | Cut­tle­fish have an im­pres­sive ca­pac­ity to learn. Th­ese Aus­tralian gi­ants are learn­ing about the birds and the bees at Whyalla, South Aus­tralia.

mil­lions of neu­rons

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