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New Neurons: Good News, Bad News

Over the last year we have glad­ly seen an avalanche of news on adult neu­ro­ge­n­e­sis (the cre­ation of new neu­rons in adult brains), fol­low­ing recent research reports. Fur­ther, we have seen how the news that phys­i­cal exer­cise can enhance neu­ro­ge­n­e­sis is becom­ing com­mon knowl­edge among many health sys­tems we work with.

Now, the obvi­ous ques­tion that doesn’t always get asked is, “What good are new neu­rons if they don’t sur­vive?”. And that’s where learn­ing, enrich­ment, men­tal exer­cise, are crit­i­cal.

We are glad to intro­duce a new Expert Con­trib­u­tor, Dr. Bill Klemm, a pro­fes­sor of Neu­ro­science at Texas A&M Uni­ver­si­ty, who sum­ma­rizes much research on how new neu­rons are born-and what they need to live long hap­py lives.

- Alvaro

New Neu­rons: Good News, Bad News

– By Dr. Bill Klemm

In the last few years, researchers have dis­cov­ered that new nerve cells (neu­rons) are born, pre­sum­ably from resid­ual stem cells that exist even in adults. That should be good news for all of us as we get old­er and fear men­tal decline. The bad news is that these new neu­rons die, unless our minds are active enough.

Ever since the neu­ron doc­trine was firm­ly estab­lished by the inde­pen­dent his­to­log­i­cal stud­ies of Gol­gi and Ramon y Cajal, the pre­vail­ing dog­ma was that the after birth, no new neu­rons appear. We now know that pre­vail­ing dog­ma was wrong. In 1965, Joseph Alt­man and Goapl Das doc­u­ment­ed neu­ro­ge­n­e­sis in adult rat hip­pocam­pus. Then, in 1977, Michael Kaplan and James Hinds used radioac­tive thymi­dine incor­po­ra­tion to show that neu­ro­ge­n­e­sis occurred in the olfac­to­ry bulb and hip­pocam­pal den­tate gyrus of the rat. In these areas, new neu­rons seem to appear through­out life.

Anoth­er appar­ent excep­tion is in a group of neu­rons asso­ci­at­ed with singing in song­birds. In 1983, Fer­nan­do Not­te­bohm doc­u­ment­ed neu­ro­ge­n­e­sis in the cor­tex of adult canaries. Here, birth and death of neu­rons seems to change with sea­sons of the weath­er. In Spring, when birds are court­ing with songs and mat­ing, the neu­rons in this nucle­us pro­lif­er­ate notice­ably, only to regress after the mat­ing sea­son.

In 1977, Eliz­a­beth Gould showed that new neu­rons appeared in adult tree shrews and that stress decreased the num­ber of neu­rons in the hip­pocam­pal den­tate gyrus. Ten in 1998, Rusty Gage used the divid­ing cell mark­er, bro­mod­eoxyuri­dine, to show that new neu­rons occur in adult humans.

There have been claims of adult neu­ro­ge­n­e­sis in sev­er­al regions of neo­cor­tex, but these fnd­ings are in dis­pute because of method­olog­i­cal issues. Orig­i­nal demon­stra­tions of adult neu­ro­ge­n­e­sis were based on the rea­son­able approach of inject­ing radi­o­la­beled cell-divi­sion mark­ers and then check­ing for incor­po­ra­tion in the nucle­us of cells, indica­tive of new­ly formed DNA. Advanced tech­nol­o­gy using car­bon-14 dat­ing shows that in the human cor­tex, new neu­rons do not seem to appear in the adult, though it is clear that they appear in the hip­pocam­pus.

Neu­ro­ge­n­e­sis in adults may be manip­u­la­ble, but research in this area is just begin­ning. Recent­ly, one study demon­strat­ed that new neu­rons could be trig­gered by direct injec­tion of a chem­i­cal that stim­u­lates neu­ro­ge­n­e­sis into the feed­ing cen­ter area of the hypo­thal­a­mus of rodents. Sur­vival of these new neu­rons in the adult depends on their abil­i­ty to make func­tion­al con­tacts with exist­ing neu­rons. Typ­i­cal­ly, about half of new neu­rons failed to inte­grate into exist­ing net­works, and they died.

In anoth­er study, expos­ing mice to enriched envi­ron­ments (run­ning wheels, col­ored tun­nels, and play­mates) increased the sur­vival per­cent­age of new neu­rons up to about 80%. “Use it or lose it” seems to be the mot­to for new neu­rons.

Exer­cise has been found impor­tant for human brain. Researchers have stud­ied MRI images of exer­cis­ing humans and found that the blood vol­ume increased in the hip­pocam­pus in those sub­jects that under­went a three-month aer­o­bic exer­cise pro­gram. Those sub­jects also per­formed bet­ter than con­trols on mem­o­ry tasks. Such results indi­cat­ed that new blood ves­sels had grown into the brain area. The infer­ence is that this new blood sup­ply was need­ed to sup­port new neu­rons, and although there are oth­er expla­na­tions, this is a rea­son­able spec­u­la­tion.

The Hip­pocam­pus and Mem­o­ry.

The brain area known as the hip­pocam­pus is the one area where every­one agrees new neu­rons are born in the adult. The hip­pocam­pus is cru­cial for the for the con­ver­sion of cer­tain short-term, scratch pad, mem­o­ries into per­ma­nent form. Ani­mal exper­i­ments have shown that the pro­duc­tion of new neu­rons in the hip­pocam­pus is stim­u­lat­ed by enriched envi­ron­ments and by learn­ing expe­ri­ences. But do these new cells func­tion nor­mal­ly? Do they sup­port learn­ing? And do these new neu­rons sur­vive? Some ani­mal obser­va­tions indi­cate that new neu­rons in the hip­pocam­pus only live about one month.

An answer has come from some recent ani­mal exper­i­ments that exam­ined the role of new neu­rons in adults in learn­ing of a water maze and the effect of the maze learn­ing on sur­vival of these new cells. The water maze involved train­ing rats to find a sub­merged safe plat­form in a tub of water made opaque so that the plat­form could not be seen. Train­ing was per­formed under one of two con­di­tions: 1) loca­tion of the plat­form was cued by an over­head black and white striped rod, or 2) loca­tion was indi­cat­ed by the spa­tial rela­tion­ship of the plat­form to objects out­side the tub, such as objects on the room walls, that could be seen by the rat.

The exist­ing pop­u­la­tion of den­tate cells was killed by low-lev­el irra­di­a­tion. Rats so treat­ed could not form long-term mem­o­ries for the safe loca­tion in the spa­tial­ly cued task. How­ev­er, if they were trained after new neu­rons were born, then they learned the task. This effect was spe­cif­ic to spa­tial cues, because new cells were not need­ed to learn the task when the plat­form was indi­cat­ed by the ver­ti­cal rod point­er. By irra­di­at­ing cer­tain groups of rats at dif­fer­ent times before and after train­ing, the researchers found that new neu­rons 4–28 days old at the time of train­ing were impor­tant for the spa­tial learn­ing. Thus, these new neu­rons were func­tion­al. They knew what to do and how to do it.

So, it would seem that new neu­rons not only can be born in adult hip­pocam­pus, but that they per­form the learn­ing job that was done by their pre­de­ces­sors, at least as regard­ing learn­ing that involves spa­tial rela­tion­ships. A learn­ing-rich envi­ron­ment helps these new neu­rons live longer.

New Neu­rons. Use Them or Lose Them.

In rodents, the num­ber of new neu­rons in the hip­pocam­pus is on the order of thou­sands per day. These new neu­rons may not sur­vive and become use­ful in mem­o­ry for­ma­tion if they are not need­ed. Need seems to be estab­lished by ongo­ing require­ments to form more mem­o­ries. Learn­ing not only stim­u­lates new neu­rons to pro­lif­er­ate the mem­brane “sprouts” that make con­nec­tions with oth­er neu­rons but also increas­es the sur­vival of neu­rons born up to a week before the learn­ing. In oth­er words, use them or lose them..

A recent study of aged rodent learn­ing of spa­tial rela­tion­ships in a water maze has revealed that in “smart” rats that were good at learn­ing a water maze, maze learn­ing increased the sur­vival of new cells born before the learn­ing. An ear­li­er study had shown that in young rats, increased sur­vival of new neu­rons occurred in all rats, irre­spec­tive of their pre­vi­ous mem­o­ry abil­i­ties.

Time Is Crit­i­cal

A crit­i­cal win­dow of time deter­mines whether or not the new neu­rons sur­vive. In an exper­i­men­tal test of this time win­dow, mice were housed for one week in an envi­ron­men­tal­ly rich envi­ron­ment (toys, activ­i­ty wheels, etc.), or for con­trols in reg­u­lar cages, begin­ning one week after injec­tion with a new-neu­ron DNA-syn­the­sis mark­er. Results showed that last­ing increase was restrict­ed to new neu­rons that appeared between one and three weeks before liv­ing in an enriched envi­ron­ment. This cor­re­sponds to the time when new neu­rons are extend­ing their neu­rons in search of tar­gets and their den­drites are devel­op­ing synap­tic con­tacts to the neu­ro­trans­mit­ters nor­mal­ly used in the hip­pocam­pus. The new neu­rons that devel­oped dur­ing this time win­dow sur­vived up to the four months of mon­i­tor­ing, even when removed the enriched envi­ron­ment. It would seem that the learn­ing expe­ri­ences encoun­tered in a rich envi­ron­ment pro­vide the stim­u­lus need­ed to help new neu­rons get estab­lished into mem­o­ry-form­ing cir­cuits, but there is a lim­it­ed crit­i­cal time when this effect occurs.

Bill Klemm— W. R. (Bill) Klemm, D.V.M., Ph.D. Sci­en­tist, pro­fes­sor, author, speak­er As a pro­fes­sor of Neu­ro­science at Texas A&M Uni­ver­si­ty, Bill has taught about the brain and behav­ior at all lev­els, from fresh­men, to seniors, to grad­u­ate stu­dents to post-docs. His recent books include Thank You Brain For All You Remem­ber and Core Ideas in Neu­ro­science.

Ref­er­ences

- Dra­peau, E. et al. 2007. Learn­ing-induced sur­vival of new neu­rons depends on the cog­ni­tive sta­tus of aged rats. J. Neu­ro­science. 27 (22): 6037–6044.

- Fin­ger, S. et al. 1988. Brain Injury and Recov­ery. Plenum Press, N.Y.,N.Y.

- Good­man, C. S., and Spitzer, N. C. 1979. Embry­on­ic devel­op­men­to f iden­ti­fied neu­rons: difer­en­ti­a­tion from neu­rob­last to neu­ron. Nature. 280: 208–213.

- Gorio, Alfre­do, Ed. 1993. Neu­rore­gen­er­a­tion. Raven Press, N.Y., N.Y.

- Koko­e­va„ M. V., Yin, H., and Fli­er, J. S. 2005. Neu­ro­ge­n­e­sis in the hypo­thal­a­mus of adult mice: poten­tial role in ener­gy bal­ance. Sci­ence. 310: 679–683.

- Mack­lis, J. D., and Kem­per­mann, G. 2006. Adult neu­ro­ge­n­e­sis and neur­al pre­cur­sors, prog­en­i­tors, and stem cells in the adult CNS, p. 303–325. In Text­book of Neur­al Repair and Reha­bil­i­ta­tion, edit­ed by M. Selz­er et al. Cam­bridge Univ. Press, Cam­bridge, U.K.

- Pereira, A. C. et al. 2007. An in vivo cor­re­late of exer­cise-induced neu­ro­ge­n­e­sis in the adult den­tate gyrus. Proc Natl Acad Sci U S A. 104(13): 5638–5643.

- Sny­der, J. S. et al. 2005. A role for adult neu­ro­ge­n­e­sis in spa­tial long-term mem­o­ry. Neu­ro­science. 130: 843–852.

- Tashiro, A., Maki­no, H., and Gage, F. H. 2007. Expe­ri­ence-spe­cif­ic func­tion­al mod­i­fi­ca­tion of the den­tate gyrus through adult neu­ro­ge­n­e­sis: A crit­i­cal peri­od dur­ing an imma­ture stage. J. Neu­rosci. 27: 3252–3259.

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