Brain: So­cial mem­ory and ag­gres­sion

Sunday Trust - - VIEWPOINT - Source:www.sci­

Columbia sci­en­tists have iden­ti­fied a brain re­gion that helps tell an an­i­mal when to at­tack an in­truder and when to ac­cept it into its home. This brain area, called CA2, is part of the hip­pocam­pus, a larger brain struc­ture known to be crit­i­cal for our mem­ory of peo­ple, places, things and events.

CA2 was al­ready known to spe­cial­ize in so­cial mem­ory, the abil­ity to re­mem­ber en­coun­ters with oth­ers. Sur­pris­ingly, to­day’s find­ings re­veal that a sin­gle brain re­gion can con­trol both higher-or­der cog­ni­tion, like so­cial mem­ory, and an in­nate, in­stinc­tual be­hav­iour like so­cial ag­gres­sion. And be­cause CA2 dys­func­tion has been im­pli­cated in psy­chi­atric dis­eases, such as schizophre­nia and bipo­lar dis­or­der, these re­sults pro­vide fur­ther sup­port that al­tered CA2 func­tion may con­trib­ute to ab­nor­mal so­cial be­hav­iours as­so­ci­ated with such ill­nesses.

“Hu­mans and mice are so­cial crea­tures. We both en­gage in learned and in­nate so­cial in­ter­ac­tions that some­times fos­ter co­op­er­a­tion, and other times drive com­pe­ti­tion for mates, food and dom­i­nance. How the brain me­di­ates these con­flict­ing im­pulses has been a puz­zling ques­tion,” said Steven A. Siegel­baum, PhD, the Ger­ald D. Fis­chbach, MD Pro­fes­sor and Chair of Neu­ro­science at Columbia Univer­sity Irv­ing Med­i­cal Cen­ter, prin­ci­pal in­ves­ti­ga­tor at Columbia’s Zuck­er­man In­sti­tute and the pa­per’s se­nior au­thor.

“To­day’s study in mice shows us that diminu­tive CA2, which is made up of just a few thou­sand cells, acts as a nexus of so­cial be­hav­iours, al­low­ing mem­ory to in­flu­ence the de­ci­sion to en­gage in so­cial ag­gres­sion,” he con­tin­ued.

Al­though a great deal is known about the other re­gions of the hip­pocam­pus, the small size of CA2, cou­pled with its in­ac­ces­si­ble lo­ca­tion sand­wiched be­tween larger, neigh­bour­ing ar­eas, make it chal­leng­ing to study. But in 2014, the Siegel­baum lab de­vel­oped a ge­netic ap­proach for turn­ing CA2 on or off and dis­cov­ered that this re­gion is es­sen­tial for so­cial mem­ory.

As a first step to de­ter­mine whether CA2 may reg­u­late other so­cial be­hav­iours, the re­searchers ex­am­ined the brain re­gions that re­ceive in­for­ma­tion from CA2. They found that CA2 sends a strong con­nec­tion to the lat­eral sep­tum, a brain re­gion that had been known for some time to play an im­por­tant role in lim­it­ing ag­gres­sion. In­deed, both clas­sic and more re­cent stud­ies have shown that brain le­sions to the lat­eral sep­tum in sev­eral species, in­clud­ing hu­mans, pro­mote a hy­per-ag­gres­sive state.

“CA2’s close ties to the lat­eral sep­tum made us won­der whether it also played a role in this type of ag­gres­sion,” said Felix Leroy, PhD, an as­so­ciate re­search sci­en­tist in the Siegel­baum lab and the pa­per’s first au­thor.

To find out, the re­searchers tem­po­rar­ily turned off CA2 in a mouse liv­ing alone in its home cage. They then in­tro­duced an in­truder into the cage and ob­served the re­sult­ing be­hav­iour.

When CA2 was switched off, there was a marked de­crease in the ten­dency of the res­i­dents to at­tack, com­pared to what would nor­mally oc­cur. This dif­fer­ence strongly sug­gested that CA2 nor­mally acts to drive ag­gres­sive be­hav­iour, in ad­di­tion to reg­u­lat­ing so­cial mem­ory.

But why would a brain re­gion that con­trols mem­ory also be used to reg­u­late ag­gres­sion? One clue comes from the fact that male mice de­velop a so­cial hi­er­ar­chy when housed to­gether; a dom­i­nant al­pha male sits atop this hi­er­ar­chy, fol­lowed by a suc­ces­sion of in­creas­ingly sub­mis­sive males. When a new mouse is in­tro­duced into a colony, there are bouts of fights be­tween the stranger and the other mice until the so­cial hi­er­ar­chy is re-es­tab­lished.

“It ap­pears that, at the be­gin­ning of a so­cial in­ter­ac­tion -- such as when the res­i­dent mouse meets an in­truder -- the an­i­mal’s CA2 forms a so­cial mem­ory, a sort of so­cial ID tag, of the other mouse,” Dr. Leroy con­tin­ued. “Fur­ther along in the in­ter­ac­tion be­tween the two mice, a sig­nal gen­er­ated in CA2 is sent to the lat­eral sep­tum, which fa­cil­i­tates ag­gres­sive be­hav­iour.”

A hor­mone called va­so­pressin may also be at work, says the re­search team. When re­leased in the brain, va­so­pressin reg­u­lates a num­ber of so­cial be­hav­iours, so the team asked whether va­so­pressin might help de­ter­mine whether a mouse de­cides to at­tack.

“We found that the abil­ity of CA2 cells to ef­fi­ciently ac­ti­vate the lat­eral sep­tum is greatly en­hanced when va­so­pressin is re­leased in the lat­eral sep­tum,” said Dr. Siegel­baum. “Pre­vi­ous re­search had re­vealed a link be­tween va­so­pressin and ag­gres­sion, and CA2 ap­pears to lie at the cen­ter of this ef­fect.”

As va­so­pressin lev­els are al­tered in peo­ple with schizophre­nia and autism, the re­searchers hope to fur­ther ex­plore whether and how such dis­or­ders are tied to CA2 dys­func­tion.

In 2016, Dr. Siegel­baum and fel­low Zuck­er­man In­sti­tute Prin­ci­pal In­ves­ti­ga­tor Joseph Go­gos, MD, PhD, found that mice car­ry­ing a hu­man mu­ta­tion linked to schizophre­nia have a dys­func­tional CA2. This pro­vided strik­ing ev­i­dence that so­cial mem­ory deficits, a key fea­ture of schizophre­nia, may have their ori­gins in CA2.

“Peo­ple with schizophre­nia ex­hibit a wide range of be­havioural al­ter­ations, in­clud­ing im­paired so­cial mem­ory and al­tered lev­els of ag­gres­sion,” said Dr. Siegel­baum. “Might this re­sult from a loss or change in CA2 ac­tiv­ity? And could these deficits be al­le­vi­ated by ar­ti­fi­cially boost­ing CA2 ac­tiv­ity? That is some­thing that our re­search, and that of oth­ers, hopes to re­veal.”

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