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The Molecular Logic of Smell Msmmals can recognize thousands ofodors, some of which prompt powerful responses. Recent experiments illuminate how the nose and brain may perceive scents by Richard Axel mell is perhaps our most evocative sense. In Marcel Proust's novel Remembrance of Things Pasc, the nostalgic flavor and fragra nce of a madeleine, a delicate pastry, evokes a description of taste and smell, the senses that "alone. more fragile but more enduring, more unsubstantial, more persistent. .. bear unflinchingly, in the tiny and almost impalpable drop of their essence, th e vast structure of recollection." Humans often view smell as an aestheti c sense, yet for most animals smell is the primal sense. one they rely on to iden tify food, predators and mates. Indeed, for many organ- S isms, odors arc their most cfficient means of communicating wi th others and interpreting their surroundings. Innate behavior in response to smell is essential to these organisms' survi val and most likely result s from nonconscious perception of odors. Each individual has a unique, genetically deter- mined scent. This olfactory identiry is coupled with a remarkable ability to distinguish a diversity of odors. Humans. for instance, canrecognize approximate- ly 10,000 scents , ranging from the pleasurable scent of freshly cut Dowers to the aversive smell of an angry skunk. Many animals have an even greater sensitivity to odors than humans do: bloodhounds, for example, are legendary for their extraordinary abiliry to dlscrimlnatescents. The wide spectru m of odors that humans consciously detect prompt varied emotional and cognitive responses. But do humans recognize other smells without a conscious awareness of this perception, and do such odo rs elicit innate behavioral responses? How does the perception of specific odors lead to appropriate thoughts, memories and behaviors? Whether smell is primal or aesthetic to a species, all organisms must have developed in the cour se of evolution mechanisms to recogni ze various odors and transmit this olfactory information from the nose to the brain, where it is decoded to provide an inter- ...:1:-•~ 4~ g,v' /BRAIN OLFAClORY BULB nal representation o f the external world. As molecular biologists stu dying perceptio n, my colleagues and I have reduced these questions to the level of genes and prot eins. We have used these molerules to examine how animals recognizc such a diverse array o f scents and how the recognition of odors in the nose is translated into a map of odo r qu ality in the brain. The ba sic anato my of the nose and olfactory system has been underst ood for so me time. In mammals, for example, the initial detection of odo rs takes place at the posterior of the nose, In the small region known as the olfactory epithelium. A scanni ng electro n micrograph of the area reveals two interest ing types of cells. In this region, millions of neuron s, the signaling cells of se nso ry sys tems, provide a direct physical connec tion between the exte rnal world and the brain. From o ne end of each neuron , hairlike sensors called cilia extend o utward and are in direct co ntact wi th the air. At the o ther end of the cell, a fiber known as a n axon run s into the brain. In additlon, the olfactory epithelium co ntains neuron al stem cells, which genera te olfacto ry BRAIN neurons throughout the life of the organism. Unlike mo st neurons, which die and are never repla ced , the olfactory sensory neurons are continually regenera ted. When an animal inhales odorous molecules , these st ruc tures hiod to specialize d proteins, knO\\TI as recep tor prorein s, that extend fro m the cilia . The bindin g of odors to these receptor s ininat es an electrical signal that travels along th e axons to the olfactory bul b, which is located in the front of the brain , right behind the nose Itself. The olfacto ry bulb serves as the first relay station for pro cessin g olfactory Infermalion in the brain; the bulb conn ects the nose wi th the olfac tory co rtex, which then projects to highe r sensory centers in the cerebral cortex , the area of the brain that controls though ts an d behavi ors . A Family of Receptors omewhere in this arrangement lies S an intricate logic that the brain uses to ident ify the odor detected in the nose, dis tinguish it from others and trigger an emotional or behavi oral respo nse. To pro be the organization of the brain, my co-workers and I began where an odor is first physically perceived-e-at the odor recep tor proteins, Inst ead of examlnlng odo r recepto rs directly, Li nda Buck, then a postdoctor al fellow in my labora tory and now a professo r at Harva rd University, and I se t out to find the genes encod ing odo r receptors. Genes provide the template for pro teins, the molecu les that carry out the function s o f cells , Once we isolat e the genes that e ncode a protein, \",' C can usc them as tool s to study the structu re and function of the odor reo cep tors them selves. Furthermore, using gene s to invest igate pro teins is mu ch simpler and fast er than studying the recept ors di· rectly. By arttttdalty manipulating genes, we can easily alter odo r receptors in ways that help us un derstand how the molecules enable the nose and brain to perceive smell. Afte r we understand how the recep tors work, we can then study how olfacto ry information is transmitted to the brain and processed to permi t the discrimination of smells. Using the technique of gene clonin g, we were able to isolate the genes encoding the odo r recept ors. This family of receptor ge nes exhibited several properties that su ited it to its role in odor recognition. First , the genes encoded prot eins that SCENT OF A FLOWER is translated from a sniff to a smile by the olfactory se nsory system. An odor is first detected in the upper region of the nose , at the ol- factory epithelium. Wilhln this area. odor molecules bind to receptors on hairlike projections, or cilia . The receptors are part of neuron s lhat can extend three to four centimeters from the inside of the nose to the brain. Structures known as axo ns run from the neuronal cell bod y to the olfactory hulb In the brain. In the bulb, ax' ons converge at sites called glomeruli; from there signals are relayed to other regions of the brain, including the olfactory cortex . The v omerona sal organ is part of a separa te se nsory system that gov erns innate responses tn some mammals. lis role in human behavior Is not well Imown. gions of the vi sibl e spectrum, so the brain can compa re Input from aU three types of detectors " to identify a color. OUr j data sugges t that a small number of odo r recepI tors would not be able to i recogni ze and di scrimi~ Ii nate the full arr ay of J sce nts that can be perceived by mamm als . i i Mamm als can detect at lea st 10,000 od ors; con~ sequen tlv, each of the 1,000 different receptors I mu s t respond to several i. odor molecules, and each .I odo r must bind to sever- i ! l al ~ b f receptors . Scie ntis ts b eli eve that various recep tors respond to dis- cre te parts of an odor's and that an odo r ~onsists o f se veral chemical gro ups that 8 structure SENSORY NEURON in the human olfactory epithelium (Iell) is surround. ed by s uppo rt cells and sits over a layer of neuronal s tem cell s, wh ich generate new olfactory neurons duro ea~h .actlvate a charactensn c rece ptor. For e.xam ple, the mo lecu les reo Ing an organism's life. Hairlike cilia sp on sible for the scents protrude from the tip of an individual neuron (above), shown magnifled 17,500 times; receptors located on cilia bind to odor mole cule s. These images were taken by R. M. C~~tanzo and Eo Eo Morr~ son ?f Vir' guua Commonwealth Unlversitv. faU squar ely within a pr evi ou sly described group of receptors that pass th rough the cell membran e of the neuron seven times; these receptors acttvate signaling proteins knO\\TI as G protein s. Early studies by D oron Lancet of the wetzm ann Institute of Science and Rand all R. Reed of the John s IIupkins Sd lOOI of Medicine have established that complementary stran d In the chro moso me \...·c can loca te a gen e and determin e both the number and position o f a gene or gene family. Specifically, by exa mining DNA from a variety of mamm als, including humans, we determin ed that around 1,000 o f jasmine and freshly baked bread are made up o f different structural gro ups, and each group activates a dis tinct set of recep tors; to distinguish the s mell, the brain must the n determin e the precise combinatio n of receptors activated by a particular odo r. Ilow does the brain identify which of the 1,000 typ es of receptors have been turned on? Severa l scenarios are possi ble, If every neuron carries all 1,000 types , every neuron would sen d a sig- gen es encode 1,000 differcn t o do r re- nal to the brain eve ry time an odor was sensed. All the engaged recepto rs would in the transmission of an electrical im- ceptors. (Each type of recept or is expr essed in thousand s of ncuron s.) Gtven that mammalian DNA probably contams around 100,000 genes, this find ing pulse along the o lfacto ry se nsory axon. indicates that I percen t of all our genes Second, the genes encoding the odo r are devot ed to the detection of odors, making this the largest gene family thu s signals to deciph er the identit y o f the smel l. Ahe rna tively, if eac h neu ron fea- odor receptors, too, usc G prote ins to initiate the casca de of events resulting receptor prot ein s arc active onl y in olfactory neurons. Allhough nearly every cell of the body carries a copy of every gene, many genesarc expressed only in s pecia lize d cells. Finally. a broad range o f odo r recep tor genes app ears to mirror the striking range of odors. The technique known as mol ecular hvbrtdi zati on allowed us 10 det ermin e th e numb er of these ge nes in the chro mosome . This proce- dure works because genes consist of two s trands of DNA that come together to create a doubl e helix. We can label o ne s trand so that wh en it finds its 156 far identifi ed in mamm als . The enormou s amo unt of ge ne tic informa tion devot ed to smell perh ap s reflects the s ignificance of this se nsory sys tem fo r the survival and repro duction o f mos t mammalian species. The large fam ily of od or recep tor s then need t o co ntribute some distin cttve compone nt to the neuron' s s ignal; the brain could then compa re these tures only one type of receptor, the prob lem of distinguis hing which reccp tor was activated by a particular odor reduces to the probl em of Identifyi ng which neuro ns fired. Such a model woul d grea tly simplify the tas k of the brain in so rting out which of the numerous receptors have been activated. contrasts sharply with the far more res tricted rep ertoire of recept ors in the eye . Humans, for exa mple, can di scri rntnatc among severa l hundred hues using o nly three kinds o f receptors o n the retina , These photoreccptors detect light in different but overlapping rc- Scrrxmrtc AMr.RICAN Ocrober / 995 One Neuron, One Receptor o in vesti gate which of these two sc he mes occ urs in the detectio n of smells. we again loo ked at gene exp ressian in the olfactory neurons. Using the T procedure of molecular hybridization. Andrew Chess, John Ngai an d Robert Vassar, the n all at Columbia Umvers lty, and I observe d that in mammals, each of the 1,000 receptors is exp ressed in about 0.1 perce nt of the neuro ns. In fish, which have 100 odo r recep tor s, each recep tor can be found in about 1 percent of th e neurons. These resu lts suggest that , in both cases, eac h neu ron may express only one receptor gene. Furthermore, in recent experime nts, Catherine Dulac, also a t Colum bia, an d I have used th e polymerase chai n reaction, which a mplifies small pa rts of DNA. to clone th e odor recep tor genes th at arc expressed In Individual olfactoryneurons. when such receptor genes arc isolat ed fro m a single neuron , the y all appear 10 be ide nt ical. When th e same procedure is applied to a collection of neurons, however, hundreds of diffe rent receptor genes are ob tained. Taken togeth er, these observations indicate that each se nsory neuron expresses only one receptor and is therefor e fun ctionally disti nct. This simp le co rrelation between recepto rs and neurons docs not exp lain the much morc co mplex processing tha t the brain mus t em ploy 10 discrim· inate an odo r. For example. how does the brain determine which olfa ctory neurons have fired? In all othe r sensory systems. th e brain relies on defined spatial pa tt erns of neurons as well as th e position of th e neurons' ultimate targets to defin e th e qu ah ry of a sensation. Perhaps the brain applies a simi· lar logic to the se nse of smell. There ar e a number of poten tial scenarios for arranging neurons and axons In the nose an d brain [see tIIusrra · tion below ). In one mod el, neuro ns tha t bear a given type of rece ptor wou ld be locali zed in the olfac tory epithelium. Activation of neurons at specific sites would th en define the quality of a n odo r. Altematively, neurons carrying one type of recep tor could be randomly positi on ed in th e epithe lium, bu t th eir axons would co nverge on discret e areas in the brain. In this case, exposure 10 a particular odor would result In defined patt erns of acttvity in the brain. In a th ird model, bo th the neurons and their projecti on s to the brain could be arranged randomly. To int erpre t the scent, the brain would have to use a sophisticated algorit hm to decod e the random signals. Some neurons In th e nose are spatially segregated according 10 th e sce nts Ihey d etect. Most manunals, including humans, possess a "sexual nose," or vomero nasal organ, Ihal is physically se pa rate from th e main olfactory epithelium. The vomeronasal organ detects the ph eromones that govern reproductive and social beh avi ors. Sexual acnvtty in male rodents, for example, is an inn ate res ponse , prompted by the detection at the vome ronasal organ o f ph eromones secreted by fema les. If the neuron s in the vomeronasal system in virgin mice are destroyed, the mice can still smell with their main olfac tory system, but the damage to their vomer' ona sal organ prevents the m from ever mating. Addit ionally, as Dulac an d I have shown by studying the genes enco ding pheromone recept ors, the sequence of amino acids (th e building block s of proteins) in the recep tors of the vorneronasal organ is completely different from that in th e receptors of the main olfactory epit helium. Th ese differences sug ges t that the two systems may have evolved independently of eac h ot he r. Finally , neu rons in the main olfa ctory epitheli um project Ihei r axo ns to an a rea of th e brain th at is distinct fro m the region where neurons in the \ '0meronasal organ se nd nerve impulses, Consequently, signals from these 1\\'0 c .. . ' AXON ·• ... ,- · " .. • ~ • • ..' . •. • . , •. . '" e- ~ .• .. • . • • ~ ~ ~""'-""'------_-'=I PATITRNS OF NEURONScan help the brain Interpret a smell. Seve ral arrangements are possible. In one scenario ( a ), neurons that contain a particular type of receptor (I ndicated here by color) would be locali zed In the olfactory epilbeIlwn; In thi s way, th e brain could identify an odor by determining what area of the olfactory epith elium was activated by the smell. Alternatively (b), neurons may be arranged randomly throughout the epithelium. but lheir axons may conve rge on localized regions of the olfactory bulh known a s glomeru lL An odor would therefore be identified by a characteristic pattern of acti vlrv In the glomeruli. Finally (e), both the neurons and their axons may be arranged randomly. scrorrmc AMI:JUCAN Oerober 1995 I S7 BLUE NEURONS rev eal the pathway of sensory infonnation from the olfactory ep ithe lium in th e nose 10 th e olfa ctory regions of the nose prod uce \"(.'. r)' dif- bulb in the brain (a) . By ge netica lly modifying th e od or rece p tor gen es in mice. th e au th or and his collea gues dyed ga nization, th e most impo rta nt fea tur e of this arra ngemen t is th e ran do m distri bution of recept ors wi thin each region . Recause we were unable to de tect a more precise spa tial pa ttern o f neuron s In the epithelium, we searched for a pa tt ern in th e proj ection s o f' axons into th e brain. If such a patt ern is ind eed employed, neurons expres sing a given receptor, thoug h randomly dist ribut ed throughout a region of the epitheliu m, must project th eir axons to a small number of glomeruli. Several pieces of evi dence suppo rt this model. First , th e number of glomeruli is roug hly the same as the nu mb er of typ es of recepto rs; becau se each neu- ron exp resses only one recep tor, each type of neu ron may connec t to a characteristic glomerulus. Second, physiological experiment s have revealed that d ifferent odors elicit distinct pattern s of ac tivi ty in the brain. For example, Gordo n M . She phe rd and his colleagues at Yale Univers ity es tablished that exposure of newbo rn rod ents 10 their mother' s milk led to ac tivi ty in res tri cted regions of the olfactory bulb. SimiOrgani zed Axons larly, John s. Kauer of Tuft s Univers ity u sed voltagc-scns inve dyes to show he ana to mic segrega tion of th ese that the pattern of activity in th e olfacto ry bulb is d istinct for various odo rs. two functionally distinct olfartory systems imme dia tely prompte d us to Furthermore, clcct rcphysiologtcal studexam ine wheth er neurons wit hin the ies by Kcn saku Mori of the Osaka Biomain olfacto ry system itse lf also exscience Institute dire ctly demonstrated that distinct glomeruli arc ploit spa tial seg rega tion to define th e qu ality of an activated by differe nt odors. odo r. Some of this spatial My colleagues and 1 have orga nization is well known : d evised two mo lecul ar apeach neu ron proj ects a sinpr oach es to stu dy the spagle, unb ra nched a xon totial segrega tion of neurons ward th e brain. As the co land axo ns. First, Vassa r, lection of axons eme rges Steve K. Chao a nd Leslie B. fro m th e olfactory epitheVosshall , working in my lium, abo ut 10 million axlab orat ory, mo dified the on s come toget her to form technique of molecular hyth e olfa ctory nerve, which bridiza tion used in p revithen ente rs th e brain. Once 3 ou s wor k so tha t we could inside the brain, groups of i exa mine receptor RNA in 10,00 0 axo ns converge at § th e lips of the axcns, where site s called glom erul i in th e . the y co nverge in the olfacolfac tory bulb. In the glo- ~>' lory bulb. These exp ertrncru li the axons comm uniments, as well as indepencate with neu ron s tha t pro- ... dent work by Buck, ind ica tjeer to higher centers in the c~ ed that neu ron s express ing brain. ~ a given recept or project to Expcnments done by Vas- ~ one or, at most , a few glosar in my labo ra tory at Col- '" meruli am ong the thouumbia, as well as ind ep en- ~ sa nds wi thin the olfactory dent research carrie d out :;; bu lb. Moreover, the posi by Buck, showed that the OI.FACTORY BULB of a ra t is see n in cross section in this mi- tions of the glomeru li arc olfactory epithelium is di - cro grap h. The two white s po ts indi cat e wher e axons that be ar fixed, as suring thai a given vided int o four broad re- a speci fic rece ptor gene conve rge. Becau se eac h axon projects odor will elicit the same patgions according 10 the types 10 a charac teristlc location in th e olfactory bulb, th e bulb p ro- tern of activi ty in th e brains of receptors foun d in each vides a two-dimensional map of odor quality, which the olfac- of all animals in a species. zone. Despite this coarse or- lory corte x employs to decipher a n odor. In ano the r approac h, l'cferent behavioral resp onses. The neurons of the vomeronasa l orga n bypass the cognitive cente rs of the brain and send signa ls directly to those areas that control innate beh avioral and emotional respons es. In contrast, th e main epithelium sends signal s to higher centers in the olfacto ry co rte." th at elicit mo re measured responses. T • • 15 8 SCIINTlrI C AMERICAN Octoher 1995 deep blue the neurons thaI bear a partlcular type of receplor-and are therefore sensitive to a limited number of odors. ler Mombaerts and Fan Wang, also at Columbia, and I have genetically altered mice, breeding experimental animals in which neurons that activate a sp ecific recepto r were dyed blue. Our procedure involves isola ting a gene for one of the odor receptors and th en attaching to it a second. marker ge ne. This marker gene, which will become active whenever th e odor rece p tor gene Is exp ressed , triggers a che mica l rea ction th at turns th e neuron and Its axon blue. Th e modIfied gene is inserted into cells th at are th en int roduced into a mou se embryo. In th e resulting mice that develop, neuro ns that make thi s particular recept or a ppear blu e, allowing us to see where th e cells are located . We examined th e olfac to ry epithelia an d brains of the mice and observed that about one In 1,000 neuron s were blu e, Most impo rtant, tndlvidual axons stretching fro m th e neurons coul d be Identified an d followed loto the brain. Th e blue axons projected to only two of the 2,000 glomeruli lo th e olfactory bulb. The se experim ent s provide convincing visu al evidence that neuro ns that activate one type of receptor -and th ere for e res po nd to a limited number of odors- project their axons to a small number of glo meruli in the brain. Because the glom eruli In the olfactory bulb are differentially sensitive to specific odors, and th e po sitions of th e individua l glomeruli are topologically defined, the olfac tory bulb provide s a two-dimen sional map th at ide ntifies which of the num erous receptors have been activa ted lo th e nose. We believe a given odor wi ll activate a characteristic combination of glomeruli In the olfactory bulb; signals from the glomeruli are th en transmitted to the olfactory cortex , where they mu st be processed to allow odo r discrtmlnation. Decoding th e Signal A ccording to thi s mod el of sme ll, J-\. mammals sbould, In theo ry, be able to detect an ext rao rdina rily large number of od ors. Becau se odors int eract with multiple recep tors ra ther than with individual ones, th e possible cornbinations exceed by severa l orders of magnitude th e nu mber of odors a nimals can actu ally de tec t, Consequently, just as with ot her senses, th e olfactory system offers a meager represen ta tion of the environment . Presumably, animals dis crtmlnate only th ose odors that are biologically Important to their survival and reproduction. TItis vi ew of olfactory perception shares several bas ic features with perception In other sensory systems, For example, In vi ston the brai n analyzes The Author RICHARD AXEl Is professor of Randomly positioned neurons on the olfactory ep ithelium (bl converge at one location In the olfactory bulb ( c~ an Image by lot erpretlng the Individual compo nents: form, location, movement, color. The unity of an Image is accomplished by reconstructing the signals In th e visual centers of the higher cortex. in compari son, th e brain analyzes an odo r by dissectin g th e struc tu ra l features of th e scent. The odor is the n recons tructed by the olfactory cortex . But how does th e olfac to ry co rtex , which receives signals fro m the olfactory bulb, decod e th e map provided by the olfactory bulb? TItis qu esti on is one of the central and m ost elu sive problem s in neurobiology. It see ms likely that some form of spatial seg regation, similar to that se en in the olfactory bulb but undoubtedly far m ore co mplex , "ill be malntained as th e signals project Into th e cortex . This arran gemen t, however, merely places th e problem of Interpreting spatlallnforrnatlon one level beyond the olfactory bulb, In the cortex. How does the cortex prompt the range of emotional or behavioral res ponses that smells often provoke? To wha t extent is th e recogni tion of od ors in humans consdous or nonconsdous, an d how much of behavior or mood is governed by th e perception of odors lo our environment? We have only begun to exp lore the logic of smell and how It can evoke the "vas t structu re of reco llection.' Further Reading CO!'lfffiIBU1l0NS or T OPOGRAI'HY AN U PARA1lH. PROCESSING TO OOOR CODING IN TI lE VI:R.TI:BRATE biochemistryandmolecular biophvs- OUACTORY PATIfWAY. J. S. Kauer In TrendsIn Neurosciences; Vol. 14 , No.2, pages 79 -85; February ics at Columbia Unfverslty, where he 1991. is also an Investigator \..1th the How- A Nova MULTIGENE FN-ULY MAY ENCODE ODORANT RECIPTORS: A MOILCUl AR BASIS fOR OOOR Rrard Hughes Medlcal lnstttute, Axel Is CIPTION. Unda Buck and RIchard Axel In Cell , Vol. 65, No. I , pages 175-t 87; April 5, 1991. a molecular biol ogist who now ap- SIGNAllNG PATIfWAYS IN OOORANT nrrrcnos. R. R. Reed in Neuron, Vol. 8. No.2, pages 20 5- 209 ; plles the tcchntqu cs of reco mbinan t February t992. DNA and m olecul ar genetics to prob- lems In ncuroblology. Most recentl y he has focu sed o n the molecular biology of perception. D ISCRIMINATION OFMOl..ICULAR SIGNALS BY TIlE OlfACTORY RrcFnoR NruRON. G. M. Shepherd tn Neuron. Vol. 13, No. 4, pages 771-790: OCtober 1994. MOlLCUlAR RICOGNTI10 N AND OUA(.I ORY PROCESSING IN nu: MAMMA.1JAN OlfACTORY SVSlT.M. K. Mort and Y. Yoshthara In Progress in Neurobiology, Vol. 45, No.6, pages 585-619: April 1995. SCIENTIFICAMi:RJCAN Ocrober 1995 159