INS

IGHTREV
IEW NATURE|
Vo
l444|
16No
vemb
er2006
|do
i:
10.
1038/
natu
re05405

Sme
llimagesandthef
lavou
rsy
stem
inthe
humanbra
in
Go
rdon M
.Sh
eph
erd1

F
la vourperceptionisoneofthemo stcomplexo fhum anbehav
iours.
Itinvo
lvesalmo s
tal
lo fth es en
s e
s,
part
icular
lyth esenseofsm el
l,whichisin
vol
v edthroughodourimag esgenera
tedintheolfactor ypathway
.
Inth ehum anb ra
in,theperceptua
ls y
stemsar eclose
lyl
inkedtosystemsforlea
rning,m emo ry
,emo t
ion
and l
angu age
,sod istr
ibutedneura
lm e
chani
sm scont
ribu
t eto
foodp ref
erenceandfoodc r
a vings.Greate
r
recognit
iono ftheroleofthebrain
’sfla
voursystemand it
sconn e
ctionwitheat
ingb ehav
iou risn eededfo
ra
deep e
rund erstand
ingo fwhyp eop
l eeatwhatth eydo
,andtog ene
r a
teb et
terrecomm endation saboutdie
t
andnu tr
it
ion.

Man yhum ansr egardth ei

rs enseofsm ellt ob eo fm inorim portan ce. In fa ct
,b eh a v
iou r alt est
sshow th atp rim a
te sh av esu rp r
i s
in gl yg ood
5
Th edom in antr ol
eth atsm el
lh asins en sin gth efla voursofth ef oods sen sesofsm e
ll ,and ith asb eena rgued th atth ed ecl
in eino lfacto r y
- gene
wee atandin fluen c
in gwh atw el
i ketoe ati s l
ar gelyun recogn ized. num b eri
smo r eth ano f f
s etinhum an sb yth eirmu chen la rgedb rain s
Thisisunf ortun at
e,b e
c auseou rdietisc ausin gapu blichealthcrisisin with th e
irin c reasedc ap aci
ti esf oran aly s
isandcom plexp r oce ssin gof
6
man yw es
terncoun trie
s.Know ledgeo fth eim portan c
eo fsm e
llt oth e sm e
ll togu id ec rit
i calhum anb eha v
i ou rs .A sw esh a
lls ee,an ota b
le
per c
eptiono ff lavourandth ef orm a
tiono fco gnitiveandemo tion al sh areo fthi sen larg edb ra
inc apacity isin volv edin fla vou rp er ception
respon sest of oodsandb ev e
r agescou ldh elpt o im proveh ealthand andb eh aviou ralr espon sest ofla vours.
pre v
entch ron icconditionssu chasob esi
t yandd ia betes
. Th ea xon so fs en sor yn eu r ons inth eo lfact oryep ith el
iump roje ct
Theaimo fth i
sartic
le i
stor evi
ewr ecen tad v ancesin thebr a
inm ech a
- toth eo l
fa cto rybu lb,wh e reth eycon v ergeon to modu lesknowna s
nism sofsm ellperceptionand topu tf orw a rds ever a
lh ypothe sesf or glom erul
i(F ig.1 a)
.D irecte v
id en ceo fth eb rainm echan ism s in volved
int e
grat
in gth esem echanism s
in tocurr entth eo r
ieso fthen eura
lb as
isof insm el
lfir stem erg ed inth e1 9 70sw ith th ea pplic at
iono fth ee arl
i es
t
flavourasacomp lexmu lti
s y
stemp ercept.M yhop ei s
thatthisw il
lh e
lp brain -
im a gin gm ethod sto th eo lfactor ybu lb.Th isshow ed th atodou r
bridgethed i v
id ethatim ped e
sn eu roscientists,b eha v
iou r
alp sych olo- stimu liin th er atp rodu cesp atialp attern so fa ctiv
it yin th eglom erular
7
gists
,foods cientis
ts,nu tr
it
ionistsandpu b
lic-po licym aker
s fromcom - la yerth a
ta r eo verlapp in gbu t th a
tv ar yf ordifferen todou rs .F r om th i
s
mun ica
tinge ffect
ivelya cro
ssdi sc
iplinesa bou twh yw eeatwh atw edo wasd eri
ved the fund am en talp rin c
iple, f
i r
stsu ggestedb yA drian8, th a
t
andhow t oa chievehealthyd i
ets.Ifocu son th reecritica
lasp ec
t softh e differentodou rmo le culesa rer epr e
s entedb ydifferen tp a
tt ernso fsp atial
brainm ech anism sofsm el
l:howodou rmo l ecul e
sa rerepresented inth e activityin th eo l
f actor ybu lb.Ahomo lo gousch em ic a
ls eries —su cha s
formo f
‘odou rim ages
’a s
th ebasisforsm el
lp erception;theimpo rtance a
ld eh yd e
s —e licitsp atterns th atar eo verlappin gbu td ifferent,a sshown
ofr e
tronas a
lsm el
l forflavourp erception;and th ecloserelat
ion ship s by2 -d eoxy gluco se9 andh i gh -resolution fun ction alm agn eti
cr eson an c
e
10 11
betw eenth eb rainm e
ch anism sforfla vou rand th eb ra
ins ys
t em sf or im aging(fMR I) (Fi g
.1b )
.B eh aviou ralstud ie s hav econ firm ed th a
t
emo tionsandc ravings
. micec anr e adilyd iscrim in atesu chs in g
l e-carbond ifferen c e
sb etw een
mole cules
.
Odou
rmo
lecu
lesa
rer
epr
esen
tedb
yodou
rimag
es Th eolfact orys ystem thu sr es em bleso th ers enso ryp athw ays in th at
Odou rst
imu la
tiono folfactorys ensor ycel
lsinth eno seinv o
l vesodou r itu sesa c
ti vi
t yp at
t ern sintw o-dim ension aln eu ralsp ace tor epr esen tit
s
mo
l e
cu le
sinteractingw itho l
facto ry-receptorpro
t eins
.Th edisco ve
ryo f sen sor ymod al
ity.Andsu chp attern s
,an alog ou sto tho seo fo th ers en-
theg enesthaten cod eth e
s eproteins in1 991byR ich ardA xe
landL ind a so rys ys
tem s,con stitu te‘odou rim ages’
,o r‘odou rm aps
’.M uchr ese arch
Buck1 m ovedo lfaction intoth efr on trankam on gs c
ienti
fi cend eav- hascon fi
rm edande xtend ed thisb asic findin g inth eo lfacto rys yst em
ours
,no ton lyop enin gth ew ayt ound erst
andin go l
fa c
tory( andt as
te) (forar ev
i ews eer ef.1 2).Som er ecents tud iesh avef ocus edonch arac-
1
3
transductiona tth erec eptorlev e
l,bu talsop r
ovid in gnewg eneticand terizin ghow th eseim agese volv edu rin gar esp iratoryc ycle ,wh ere a
s
mo
l ecula
r tool
s forpu rsuin gtheo rg anizat
ionof th eolfactoryp athway oth ersh a
v ean a
l ysed th econ t r
i butiono ftempo r a
lfirin gp attern st oth e
14
inth ebrain. en cod ingp roc ess .W or kon tr ac
in g th econn ection sin theo lf actory
15
Th egen om ep ro
j ec
t ssh ow th a
t th efamilyofo lfactoryg enes to
tals bulb isreve aling thed i s
tribu tedc ircu i
ts thatp ro cessth eim ages .Th ese
morethan1 ,000— thela rges
tin them amm al
iang enom e2.In them a
jor- a
llow two -dim ension a
lim ag es(Fi g
.1b ) toen cod ethemu ltidim en s
ion al
it
yo fm amm a
ls,mo sto ftheg en esa refunct
ion al,bu tinp r
im at
esth e od ou rsp ac einh er ent in th ecom plexs tru ctu reso fod ourmo lecu les
.
num b e
roffun ct
ion algen esdec reases
, inhum anstoa bout3 50(archived Thisp rincip leo fodou r-mo l ecul erep resen ta
tionb yg lom erulara ct
i vi
t y
inth eO l
factor yR ecept orD a
t abas e
;s eeref
.3).Th i
sh asb een taken to pattern sapp liesa cr ossph yl a16.
confirm theb e
liefth a
thum an sha ved egenera
tes ensesofsm el
l.H ow- Despitethi sem ergin gcon s ensu s,the id eaofod ou rim ag esandod our
ever
,o l
factoryg enesdono tm apd irectlyontosm ellacuity;do gs,which ma psh asn oty etb een inc orpo rated int ocu rren tth eorieson th en eu ral
havesup er
iortr ackinga b
il
itie
s,h av eon lyabout8 5 0fun c
tion a
lg enes4. basiso fsm elland fla vou rp erception (bu ts eeref.1 7)
,o rinp sychoph ysical
1
Depa
rtmen
tofNeu
rob
io
logy
,Ya
leUn
ive
rsi
tyS
choo
lof Med
ic
ine
,333C
eda
rSt
ree
t,NewHa
ven
,Conne
cti
cut065
10,USA
.

3
16
©2006 Nat
urePubl
ishi
ngGr
oup
NATURE|
Vo
l444|
16No
vemb
er2006 INS
IGHTREV
IEW

a *O
lfa
cto
ry Thisis th er outeu sed tos enseodou rsin theen v
ironm ent(T able1).Th e
O
lfac
tory bu
lb resultan todou rim agesin theo l
fa c
to rybu lba resubj ecttop rocess
in gby
ep
ithe
lium
theo lf act oryco rtexanda rer elayed to th eprim ar yolfactor ycortexin
theo rb it o
fr ontalcort ex(OFC ),ap arto fth ep re
front allobe.Th i
sd irec
t
in put t oth eh ighestco gn it
i vec entr esof theb rainisasp ecialprop er
ty
Odou
r mo
lecu
les
ofsm el
l th atisc ri
ticalto thee xperien ceo fhum an flavou r
.
R e
tr on asalstimu lationo ccu rsdu rin gf ood ingestion,wh env olat
ile
molecu le srele a
s edfr om th efood in th emou tha repum ped,b ymo v
e-
O
lfa
cto
ry
ment so f th emou th,f rom theb ac ko fth eo ralcavityup thr ough the
s
ensor
y
n
eurons nasoph ar yn xtoth eolfacto ryep ithelium .O r
thon asalo l
f ac
tiondo esno t
G
lom
eru
l
i
con tr
i bu te to thissen sation.R e
tr on asalo l
fa c
t orystimu lationc anb e
20
Odou
r mo
lecu
les studi edb y introdu cin godou rs timu liat theb ackof th emou th orb y
21
theirr el easefr om ing es
ted food s .M arcelP roustvividl ydescribedhow
22
ate a-so a kedm ad e
lein eb rou ghtb ac kpow erfulchildhoodm emo r
i e
s ,
b and th isw ou ldh aveo ccu r
redp rim ar
ily thr ough th er e
tron asa
lp a
th-
way.Iti sa ctivatedon l ywh enb reathin gou tth rough th eno seb e
tw e
en
mastica tion so rsw a
llow in gs23 (F i g.2 b)
.B ecau seth emo le cul
e sari
s e
from th e food in themou th,th eya rer e
f e
r redt othemou th;th at
is,they
24
arep er c e
i veda sifth eya res en sedw i
thin themou th .Th isr et
r onasal
2
5
food -mo lecule-ladena irisjud ged tob ep ar
to fth e‘taste
’of thef ood
26
andh a sb eenshown tob en e cess aryf o
r flavou riden ti
ficat
ion .Thu s,
* a
lth ou gha largep arto fflavou risdu e tosm ell
,itisa t
tributed to‘tast
e’
,
and is th ereforea lmo sten tire
l yh idd enf romou rcon s c
iou sp erc
ep t
ion.
Toa voidg iving‘taste
’adoub lem eanin g
,w einco rporater et
ron asa
lsm e
ll
ason eo fth emod a
litiesco veredb y thet erm ‘flavour’
.

O O O R
etrona
salsme
llandtheb
rain
fla
vou
rsy
stem
Thet radition a
lv i ewinth eli
t eratureone atingb eh av
iou rinhum an
F
igu e1| Odou
r r imag e
sintheolfactoryg lomerularla ye.a
r ,D iagram cultu r2
e7
isth atth eflav ouro fp repar edf ood s ishum an ity
’sg re a
test
showingth erelationshipbetweenth eolf ac
toryre c
ep torce
llsh e
etinthe unive rs
alsh aredb eha v
iou r
,e xperienc edb yind ividu alsofa l
la g esin
noseandth eglom erul
iofth eol
factorybu lb53.
b,fMR Iimag e
softh e thecou rseo fd ailyli
fe.F lavou risa l
soam ongth e mo stcom plexand
dif
feren
tbu tove rlappingactiv
itypatternss e
eninth eg lom erula
rlayerof
pow erfulo fallhum ans en sat
ion s.Iten ga gesalm ostal
lo fth esen sor y
theolfac
tor ybulbo famou seexposedtom emb e
rso fth es
traight
-chain
aldehydeserie
s,v aryingfromfou rtosi xc a
rbona tom s.Th e
low erp a
rt mod a
litie
s.I talsoen gag e
s thecomp lexf ac
i a
l,sw a
llow ingandr e
sp ir
a-
oftheim a
ge inth eleftpanelcorre
spond stotheim ag eonth em edia
l torymo to rsystem s
.Flav ouristh ere
for eana ct
i ves ensation —w eu se
sideoftheolfacto ryglom e
rularlayerasshown ina( seeast
e r
isk)
.(Im a
ge ‘act
i vetaste’top alpateou rfoodw ithou rton guea sw eus e‘a
c t
ive touch’
inaad apted,wi thp ermiss
ion,fromr ef.5 3
;im agein bad apted,with top alpateanob j ectw ear eex amin ingw ithou rfin ge
rs.Som eo fth ese
permiss
ion,fromr ef.10.) system sare indicatedin th ediagramo fF ig
.2b .A bo vetheses ensor yand
motors ys
tem sare theco gnitivesyst emsf orm emo ry,emo tion,a bstract
thin kingand lan guag e
.Th eim portan ceo fr e
tr on asalsm e
l
l im a ge
s is
stud i
e sof ther ela
tionshipb etw eenodou rmo lecu les
tructureandp er c
ep - i
llust ra
tedb ythem ass
i vee x
ten ttowh i ch the y
in te rac
tw ithth eseb rain
tu a
lr espon se.Th isres
istanc ese ems tob edu e toa t
leasttw ofact
ors. system scomp aredw i
tho rthon asalsm ellim ages( comp ar eFig.2 awith
Fi r
st,un li kethecon sciousim agesw ep erceive through thevisualsys- Fig
.2b )
.B elow,w eb r
ieflycon side rthem ains en so rys y
stem s.
tem ,th eodou rpatternsthata ri
s einth eolfactor ybulba reun conscious. Tasteisth emo stob v
iou scompon entof food fl
a vou r
.Th er eceptorsthat
Wh enw ep e rceiveasm e
llw edon otthin ko f i
ta sasp atia
lim age
,e ven re
l a
t etosw eet
,s alt
,sou r
,b it
terandum am it as
tea r edescribed ind e
tail
thou ghita rose f
r omasp a
tialim agein theo lfact o
rybu lb.Thisun con - byZu ker
in thi
s i
s sue(pag e2 88)
.H ere
,I tou chon lyonc ertaina spectso f
sciou sn atu rem a
yr ef
lectthef ac
t thatthehum ano lfac
tor ypathwaydo e s tasterelevan ttoth ero
l eofsm e
llin fla
v our.Inhum ans,
th etastep a
thw ay
not includ eas i gnif
i c
antrelay in theth a
l amu s( seebelow )
. ascend sfr om th enu cleuso fth eso li
tar yt ractin th eb ra
in s
t em t oth e
S econd ,odou rp a
tternsa recom p
l e
xandh i ghlyirregular(Fig.1). hypo thal
amu sand toth etastea r
e aofth esom atos ensor ythalamu s,and
Reco gn i
tiono fodou rim agesisthu sane xamp leo fpat
t ernrecognition.
Weh av esu g gestedth a
tth i
sisan alo gou s
t ore cogn iz
ingcomp lexvisual
T
able1|Thedua
lol
fac
torys
yst
em
pattern ssu cha sth oseofhum an faces6.J usta sth e
id entit
yo faf aceis
en cod ed in itsvisu alim age
,so i sthe identityo fanodou rmo le
cu leor Op
era
tion
s O
rthon
asa
lol
fac
tion R
etron
asa
lol
fac
tion
com plexodou ro b
ject —su cha sth escento fa f
low ero rthea rom aof St
imula
tion Th
roughth
eex
tern
al Fromthebacko
fthemou
thth
rough
coffee —en coded inanodou rim age. rout
e na
res thenasoph
arynx
U ncon s ciou sp a
tt e
rnr eco gnitiono fod ou rim agesth e
r e
foreseem s S
timuli F
lor
als
cen
ts F
oodvo
lat
i
les
to lieat th eh earto fsm el
lp ercep t
ion .Th isv iew isbein gincorpor a
ted Per
fum es
by foods ci entist
s intoth e
ircon c
ep tsofth en euralbasiso ffl
avou r18. Smo ke
F oodaroma s
Neu ros c
i enti s
tsandp sych oph ysici
stsh ave th eoppo rtun it
y tofol
l ow Prey/
preda
torsmel
ls
suitandd e viseexp er
im ents that t
estthish ypo th es
is
,wh ichw ewillus e Soc
i a
lodors
tod escr
i b eth eroleofsm e
llin flavou rp er
c eption . Pheromones
MHCmo lecu
les
R
etrona
salsme
ll
ise
ssen
tia
lfo
rhuman
fla
vou
rpe
rcep
tion P
roc
ess
edb
y Ol
f a
cto
ryp a
thway Ol
fac
torypathw aycombinedwith
AsnotedbyP aulRozin19,sm el
lisuniqueinh a
vinga‘dualna
ture
’— in
fluencedbyth
e pathways
fo rta
ste,touch
,sound
visua
lpathway andact
ives ens
ingb yp
roprio
cept
ion
tha
tis,i
tcans ens
esignalsorig
inat
ingou t
side(or
thonasal
)andins
ide forma‘
flavoursystem’
(re
tronas
al)thebody(T ab
le1). Notethein
teres
tin gcont
rast
,thator
thonas
alol
facto
ryperc
ept
ion
in vo
lvesawider
angeoftyp
e s
O
rthonasa
lstimul
ationrefe
rstosni
ff
inginthroughtheext
ern
alnar
es ofodorsproc
ess edthroughonlyth
eolfa
cto
ryp a
thway,
incompar
isonwithre
trona
salo
lf
a c
tory
o
fthenosetoact
iva
tethesensoryce
ll
sintheol
fact
oryepi
the
lium(F
ig.2a
). percep
tionwhich invo
lvesonl
yfoodvola
ti
lesbutpro
cessed
incombinat
ionwithmanybra
inpathwa
ys.

3
17
©2006 Nat
urePubl
ishi
ngGr
oup
INS
IGHTREV
IEW NATURE|
Vo
l444|
16No
vemb
er2006

aO
rthona
salo
lfa
cto
ry b Re
trona
salo
lfa
cto
ry
pe
rcep
tua
lsy
stem f
lavou
rsy
stem
Mo
tor
co
rte
x SOM
D
I fa
ces
Insu
la SOM SOM
t
a s
te ta
ste tongue
AV
I PPC
ACC

MO
FC LH
MO
FC VPM VC
LO
FC AM LO
FC AM
OC OC
OB OB
OE OE

NST

V
II
Odou
rin Odourin
insp
ired e
xpired Tastebuds IX X
ai
r a
ir
Tongue mu
scle
s
Sa
liva
rygl
ands Sm el
l
M
ast
icat
ing mus
cle
s Ta
st e
Te
x tu
re
V
ision
Mo
to r

F
igure2|Thedua lo
lfa
ctorysy s
tem.a,B r
ainsys
temsinvo
lvedinsmellper
c ept
ionduringorthona
salol
fac
tion(sni
ff
ingin)
.b,Brainsy
stemsinvo
lved
insm e
llper
cept
ionduringret
ron a
salol
fac
tion(bre
ath
ingout)
,w i
thfoodinth eora
lcavi
ty
.A irf
lowsindi
catedbydashedanddo
ttedlin
es;dot
tedl
ines
indi
catea
ircarry
ingodou rmolecu
les.ACC,accumbens
;AM ,am ygda
la;AV I
,anter
iorvent
ralinsu
larcor
tex;DI
,do rs
alin
sula
rco
rt e
x;LH,lat
era
l
hypo
thalamus;LOFC,l
at e
ralorb
itof
ronta
lcortex
; MOFC,medialorb
itof
ront a
lcort
ex;NST,nu c
leu
softhesol
ita
r yt
ract
;OB,olfa
ctorybulb
;OC ,ol
fac
tor
y
cor
tex
;OE ,ol
fac
toryepithe
lium;PPC,poster
iorpar
iet
alco
rtex
;SOM ,som atosenso
rycorte
x;V,VII
,IX,X,cran
ialnerve
s;VC,pr
im aryvi
sualcor
tex
;
VPM,ventra
lposte
romed i
althal
amicnu c
leus
.

from th eree xtend st oth eprim ary tasteco r

t ex(F ig.2 b)
.Ak eyf ac
ta bout wor
kingm em ory
.Asindicat
edinFig.2b
,itisa
lsop ar
ticu
larl
y impor-
31
tastes timu liisth at theye l
i c
itth emo stbasichum anemo t
ion so fple asu r
e tan
tin f
lavourper
ception
.An a
tom i
cals
tudies inm onke
yssh owth a
t
(sw eet )andd is gu st(bitter)
,wh icha renotl earn ed;th eya reh ard-w ir edin inaddit
iontotheprim aryneo
corti
calo
lfacto
rya r
eath e
rearev a
rious
28
,29
th eb rain s
t em fr omb irth .Inc on tras
tt ot a
st e,thea ffectiver espon ses sub
regionsdi
ffe
ren
tiat
ed t
orece
iveconnec
tions
fr omothersensor
yn eo-
tood ourim agess e em t ob em ost
lyl earned,wh ichp re
sum ablya cc oun t
s cor
ti
calareas
,inc
ludingtas
te
,hearing
,touchandv i
sion.Therearea
l so
for th een orm ou sd i ve
rsityo fflavou rsinth ew orld’scu is
in es.
Usin gb rainim agin g
,r es earchersh avestud i edh owsm e
lland ta s
t e Box1|Sme llimag es
, f
la vou r sand languag e
pathw a ysfun c
tion ,s ep aratelyand t og e
ther,inhum ans30.A t then eo cor-
ticall ev e
l,tastes tim ul
ia lon ea ct
i vatedth ep r
im ary t
a stec entres in the Itiscommon l ya ssum edth atth er eisar emo ter elation shipb e
tw e en
lan gu ageandsm e
ll
;fo re xamp le
, itisd i
fficultto findwo rd stod escribe
ton gu ea reaand in sula,wh ereasodou rst
imu lib y them selvesa ctivated the
thet a s
t eofaw ine.Ith asb eenpo stulat edth atodou r sa red i
fficultto
prim a ryo lfactoryr eceivinga reain th eorbitofron talr egiono fp refr ontal
nam eb ecau s eodou rand lan guag ep ro ce ss
in grel yonth es am en eu ral
corte x (Fig.2b )
,a se xpected .Th ein vest
igat orsth en tes
t edf orsimu lt ane- sub strates56
.O lfactoryp e
r cep t
ion sa r ealsoh eavilycond itionedb y
ousp r esen ta
tiono f theta steandodou rst
imu li
.Th isp rodu cedenh an ced verb a
lcu es
, inth esam ew ayth atth eya reinfluen c edb yo thers en s es5
7
.
activity inm an yof th ere g
ion sa c
tivat edby th e
ind ep end entstimu l ations How e ver
,th en am ingo fsm ellsre co gnizedth rou ghodou rim a gesm ay
asw ella sadd iti on ala c
ti v
it yinc on tiguou sa re asa round th ep rim ary benomo r edifficultth ann am in go fv isu alim age ssu cha s faces;bo th
recei vin gar ea
s(F ig.2 b).Th isind icatesth ataw iderr an geo finte gr at
ive invol veth einh erentd i
fficultyo fd escribin gcomp le xsp a t
i a
lp attern s
activit yund er
li esth em orec om ple xp e
rc eptiono ffla vour th anw ould inwo rds.W ea rev erygooda tre co gnizin ghum an f ace sbu th av eg reat
occu r th roughs im p
l eadd it
i ono fth etas
teandsm ellp athw a ys
. di
ff
i cultyd es cribingth em ,and itiss im ilarlydiff
icu ltfo ru stod e scrib e
B ycon trast
,n eo co rticalintegration inr odent sism inim al
.Th eimpo r- asm el
l.
tan tp rin c
iplei sth at inhum ansth ein cr
e aseinp ro cessinga tthish i gh e
r Th er elat
ion shipb etw e en f
la vou rand lan gua gei se venmo re
co gniti velevel isind epend entofth esm allersiz eo fth erec ept o
rr ep e
r- inter est
in gwh enr e
tron asalodou rim ag esar econ s
id er edtob eam ain
toire.Apo ss
ib lean alog yisw ithl an guag e
: thed evelopm en to fhum an compon ento f food flavou rs.Coo kin gh adac entr a
lro l einhum an
58
lan gu agew asno td ep end en tonmo reh airc ellso ramo rea cut es en s
e evolution ;th esh aredcommonm ealh aslon gb e enr eg ardeda sth e
ofh ea rin g
,bu ton th eela borationo fn eo cortic a
la re a
s for th ecom plex def
inin gso ci a
la ct
ivityo fe ar
l yhum ans27. W ithinth isso cialcon t ext,
pro cessin go flow -t om edium -
frequ encyaud it o rysign als
.S im ilarl y
,it lan gu agea ro seno ton ly inr e
l at
iontoth ea c
tivi
ti eso fhun tingand
canb ep ropo sed th atth ein creasedp rocessin gande l abo rationo f f
la- gath er
in g,bu ta lsoa san ec ess a
rym ean stocommun ic ateabou t
vou r th rou ghth e se largerco gnit
i ver eg
ion s i
sun iqu e tohum an s(Bo x thep r eparationo fth em ealand it sa ss essm en tint e
rm so fd es
i rabl e
1).P ro cessing in thi scas een comp assesodou rim age sto ge
th erw ith the flavou rs
. I
tc anb epropo sedth a
tth ead apt
i vead v ant ag eo flan gua ge
oth ers ens esth atcon tr
i bute toflav our.Bu thowdo esth iso ccur? al
low edhum an stoa tta chv erb a
ll ab elstoth eodou rim a gesa sso c
i ated
wi
thn ew flavou rsprodu cedb ycoo k
in g,f ac
ili
t at
in gth ep ro cesso f
extractin gmo r enu t
rit
iou sfood fromo th erwis eunp alat ablefood stuffs
Theo
rbi
tof
ron
talsen
sorypa
ckag
ingc
ent
re 58
sucha sroo ts,nu tso rto xicpl ants ,or forth ecu ltu ralad v antag eit
Th
epref
ron
talco
rte
xhas
longbe
enreco
gnizedasasp
eci
alco
rti
calare
a conf erredinth ecomp etit
ionb etw eenr ivalhum ang roup s.
inth
eh umanbra
inth
atisc
ruc
ialf
orplannin
g,abs
tra
ctthoughtand
3
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IGHTREV
IEW

su bre g
i onsw i
thr e cipr oc
alconn e c
ti on sw ithlim b
i csu b cortic a
lr e gions w
ithhum anlangu
ageare
as(Fig
.3)
.On theonehand,there
isthed
if-
su cha sth eam ygd alaand th eh ypo thalamu s.Ane xten sives erieso fph ys- ficu
ltyhumanshavedes
crib
inginwordsthesp
atio
tem pora
lpat
terns
32
iol ogicalstud ies inmon k
e ysw ithr e cord ings froms in glec el
l sin th es
e ofodourimage
saspar
toff
lavourpe
rcep
tion
.On theo
the rhand
,ther
e
are ash assh own th atr espons est otast eandbo tho rth on asalandr etro- isthest
rong
influ
enceofwordsonourf
lavourp
ercep
tionsandpre
fer-
nas a
ls t
imu liareh eavilyd epend en toncon te x
t,e spe c
i al
l yinconn ection ences(Box1
).
with learn in gandr ew ard.Sim i
l arr esult sh aveb eensh ownb yfMR I
stud iesinhum ans 3
3,34
.Th e
s esu g gestth att asteand , inp articul ar
,sm el
l F
rom
imag
eso
fsme
llto
imag
eso
fde
sir
e
per ception sa r
em oreh ea
vilyc ond it
i on edb ymu lt
i-s enso ry in puts than Thep erc eptiono ff l
a vourthu sin vol
vesm an ys en soryandmo t ors ys -
byp erception sino th ersystem ssu cha sth osef o
rv isi onandh e arin g. tem s
.Bu t ino rderf orafl avourt oplayap artinf oodp referen ceand
Int egralcom pon entsofou re xp erien ceo fe atin ga lsoa rise f roma l
l consump tion, itmu sta l
soconn ectwithoth ers yst ems thata rein volv ed
su bm od ali
tieso f th esom atos enso rys ystem : f
in e tou ch,c ream in e
s s
, inth ecom ple xcontr o
lo ffe ed
in g.R ecentr es earchh asb egunt oshow
de epp re ssure(f ore xam ple
,c run ch y)
, t em p
e ratur eandp ain( sucha s how flav ourp ercept
ionm ightd rivetheses yst em sa sw el
l.
th ebu rno fch i
llies )
.A s
tring en cy
,su cha sth a
to fad ryw in e,a lsog iv e
s Theo lfactor yco r
texand it
s in
t eract
ionsw itho th erlim bica reas forma
as en seo fbod y. centra
lhub in thi
sp ro ces
s(F igs2b ,3)
.In theo lfa ctoryco rtex,th eodou r
37–40
Th eses ys
t em sand thei
rsubmod alit
i esa rer epres ented inF ig.3 ,and im agesa rer e
fo rm at
ted intocon ten t
-addressab lem emo r yform .(Th e
th eirp athw ays from thesen so rst oth er e ceivin gco r
tic alre gion sa re o
lfactor yco rtexalsocon t
ain sas ensorforess entialam inoa cids41,wh ich
ind ic a
ted inF ig.2b .F lavouri salso influ en cedb yth esigh to fth e food to isindic atedb yth easteri
s kinF i g
.3 .
)Anum b ero fstud i
e sh av eid en ti
-
becon sum ed35.Ar ecentstud y36
t es
t edbo thn a
iv eande xp erien cedsub - fiedthesub -a reasthata reactivatedb yfood fl av ours.Th e seinc lud e the
je ctsonr edandwh it ewines.Bo thg r oup sc lassif
i ed th ew in esa c cord- OFC,p ar ahippo c
amp algyru s
,an te r
iorfusi
f ormg yrus,insul a
,st riatum
in gt oth econ tr astin gtasteso fredandwh itew in es.H ow ever, ther eds andcin gu late
.Th esea remo st
lyco r
tica
lare as,o rc entresclo selya sso ci-
in clud edwh i
tes th ath adb e enc o
l ou redr ed,sh ow in g th atth ec olour atedw ith th em .M o
r eover,th eOFCandam y gdal ah aveb een f ound to
hadano verridin ge ffecton th ep er ceiv ed flavou r
.Th evi su a
lco rte xis haveasso cia
tion sw i
th th ed esi
r abil
ityoffood s,w ithp leasur able f ood s
th erefor ein c
lud ed inF ig
.2ba sap arto f th egre aterfla vou rs ystem( see acti
v a
tin g them ed i
alOFCandun pleas
ant f ood sa ct
i vat
in g th el ateral
a
l soT able1 )
. OFC42.I tisth ereforepo ssiblet ob eg
in toid en t
if yth edifferent f eelin g
s
Insumm ary,th emu l
ti
s y
stemn atur eo fth eflav ourc en treo f theOFC andstat eso fmo t
i va
tiona boutfe edinginr e
l ation t olevelsofa c t
i vation
(Fi g
.2b )su ggests th atthiscanb er eg ard eda saso rto f‘sen sor yp ac kag- ofthee xt end edam ygd al
a rs ys
tem ,f
roma le velo flikin gord is l
i kin ga
in gc entre’in th eb rain,on eo fth eare as thatm a kesu ssu s ceptib let othe flavour to fee
lin gs t
r onglyattract edorrep e
ll edb yit(Fi g
.3 )
.
p
it cho fad vert
isers tobu yfood ind iffer entco lou redbo x eso rw ithmo re Th emo tivationt oe a
ti salso in vo
lved inc ravin gs,o v e
re at
in gand
crun chy texture.Th isc entreh asac r
iti calanda s ymm e
t r
i cr e
l at
ion ship condition ssu cha sob es
ity,inwh ichen ergyin ta kech r onical
l ye x ceed s

Sen
sorymoda
li
tie
s

V
is
ion P
rima
ten
eoco
rte
x
Co
lour Conscious Humanneo
cor
tex
Shap
e F
lavourp e
rcep
tion L
angu
agec
ircu
it
s
C
ircui
ts

Sound
Frequ
enc
y

Soma tosensory
Temp erature
Deeptou ch
As
tringen cy Amygda
la
L
ighttou ch s
ystems
Cr
e amine s
s
Pa
in Emot
ion
ci
rcu
its
Tas
te H
ippo
campus
,ol
fac
tory*and
Sweet limb
icsy
stems
)
Mo
tiv
ation
Umami
L
imbi
csubconsc
ious c
ircu
i t
s
Sa
lt
memor
ysyst
em s
Sou
r
B
itt
er C
raving
c
ircui
ts

Smel
l
Pa
tte
rn

Gut
Autonomicand Hypo
tha
lamu
s
metabo
lic* F
eed
ingc
ircu
its
proper
tie
s

F
igure3|Thehumanb rainflavours ys
tem sthateva
luateandr egu
latefoodin
tak .Th
e ediagr
amshow sth ea
reasinvol
v edintheperceptua
l,emotional
,
memory-
rela
ted,mo t
iva
tionaland linguis
ticaspec
tsoffoodev a
luat
ionm ediat
edb yfl
avourinpus32,41,54,55.L
t ef
t,di
fferentsensorymod al
it
iesand
submodali
tie
sth a
tcontr
ibut etoflavourpercep
tion
.M iddleandr i
ght,bra
inflavoursys
temthateva
lu at e sandregulat
esfood in
take
.R edregion
sm edi
ate
cons
cioussensoryper
ception;thickerout
linesindi
catethe
irgre a
terimport
an c
e inhum an
sando th
e rp r im a
tes
.G reenr eg
ionsm ed
iatesubconsc
iou s
feed
ingregul
a t
ion.Def
icienciesinessent
ialaminoa c
idsaresensedbytheanter
io ro
lfac
torycor
tex(a st e r
i sk
).
3
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urePubl
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IGHTREV
IEW NATURE|
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vemb
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energ ye xp end itu r e

.V ariou sanim alstud iesh a veshownth atth e Ex
t end ing thes estud ie
s tor e
t ron asa
lo lfact
ionand theb as
iso fflavou r
reg
ion sin volv ed inc raving sin c
lud eth eam ygdala,an ter
iorcin gulate, wi
llrequ i remo recon certedeff ortsb yn eur o
scien t
iststo in tegrateo l
f ac -
OFC,insu la
,h ippo c ampu s
,c audateanddo rso la
teralp refront
alco rte x
. tionw ith tasteand th eoth ers enso rys ystem s
,andw ithp sychoph ysi ca
l
Function al
im a g
in gstud ies inhum an sh ave tes
ted fora ct
i v
ityinth ese and in gestiveb eh aviou rstud ies.In thismu l
tidisciplin aryapp ro ach,th e
43
area
s b ym a
in tain ingsub j ectsonamono tonou sdi e
tanda skingth em exp er
tis eof foods cientis
tsandnu trit
ion istswil
la lsob en eeded.Inadd i-
toim agin eth etast e
,sm e
lland texture( inoth erw ords,flavour)of th e
ir tion,an th ropo lo gistsn e
ed t op rovid eab etterund erstand ingo f ther o
le
favouritefood s.C r avin g-relatedin c
r easesin thefMR Iblood -oxyg en- ofsm e
ll inth ed e velopm ento fcu isinesdu r
in ghum ane v o
lution .
leve
ld ep end en t(BOLD )s ign alw er
es eenin theh ippo c
am pu s
,in sula Th
i sin tegr a
teda pproachshou ldm a keitpo ssiblef orr esear ch e
rs t o
andc aud atenu cleu s.Th eau th or
sch a racterizedth esea ct
ivi
t ysitesa s attack th edifficultqu est
ion sa bou thum anflav ourp er ception . Wh atis
‘imag esofd esire’
. th erelation shipb etw een flavou randnu tri
tion ?Th i sw ouldh aveb een
Ther egionsa cti vated inhum ansb yf oodc ravingsa resimila
r totho se criti
c a
l f orhum ane volut
ion ,and i
sa tth ecor eo fth ecu rren tcon cern
act
ivateddu rin gd ru ganda l coholadd ic t
ion.Th er esultsarecon s
ist ent a bouth ealth yd iets. Wh ydof a
s tfood sandc e r
t a
inf l avou rsa ttr act
wi
thth ecommonsub s
tr a
t esh ypoth e
sis— th eidea,a r
isin gf
romm an y hum an st oth epo in tofc ravin g?If thesm el
lo fth efla vou risan im a ge,
convergin glin eso fw ork,th attheb raina reasund e r
l y
in gfoodc ravin gs th ew o rkr eview edh eresu g geststh atth esm el
l im a gepl aysa l argep ar
t
sharec e
llularands ystem sm echanism sw ith thosein volvedina lcoho l in thata ttra ct
ion .I sa fast-
f ood fl avou rana ttractive‘c aricatu re
’o f the
44
,45
andd ru gabu se . odou r im a geo fth en aturalfood ,in th es am ew ay thatM ic keyM ouse is
Thu s
,th eim age so fsm e
llsin theo l
f actoryp athw ayl eadtoim age sof ana t
t ractivec a
ric atureo far ealmou se?
des
irefora cqu irin gand in gestingtheob j ec
tsupp lying thatsm ell
im age
, Thetr adit
ion alv iew isth a
tw ea reattractedto food sb y theirb ioch em -
andso ,i
tc anb ep r opo sed, th ecyclerep eatsitsel
f.Th ek eypo intisth at ic a
lcompo sition,e sp eci
allyb y tho secon sti
tuen tsth atm aketh emsw ee
t
understandin go ver eat
in gandob esi
ty in vo
l vesnoton lyund e
rstand ing or fa
t;r ecentl y
,att entionh a
ssh if
t edt oth ebioch em ic a
la c
tion so ff ood
theh ypoth alam i cfe edin gc entresandhow theyrespond tofats,carbo - con s
titu entsonadd ictionc ent resin th eb ra
in.H erew eh a ver eview ed
hydra
t esandp rotein s(F ig.3 ),buthow thos ecentresa red r
ivenb y the eviden ceth atfla vou risam a
jo rf actor.Ifw er eco gnize th epow erth at
bra
inm ech anism sund erlyin gthe f
lav ou r
so fthosef ood sandth ed esir
e con sciou sim agesh aveonou rd a
il yl
i ves,thepow ero fth eun con sciou s
tocon sum e th em . odou r im a gesth atdom in at
e fla vourss eem sw orthin vestig a
tin g. ■

F
oods
cien
ceandbe
yond 1
. Bu c k
,L .&A xel
,R .Ano velmu ltig ene familyma yen codeodo ran tr e cep tor s
:amo le cular
basis forodo rr ecogn it
ion .C ell65 ,175 –187( 199 1).
Beh aviour a
lt es
tingo fth eeff ectso ff oodf l avou rsandcon sum erp ref- 2
. Zhang ,X .&F ir estein,S .Theo lf acto ryrec ep torg enesupe rfam ilyo fthemou se.Na ture
eren cef orth em isc arriedou t in foods cien ce,a fielda lm osten tirely Neur osci. 5,124 –133(2002 ).
un knownt on eurosci entist
sonth eon eh andandnu trition i
stsonth e 3
. C ra sto,C ., Ma ren co,L .
,M iller,P .&Shephe rd,G .O lfa c
to ryr e cepto rda taba se:ame tada ta-
other.U singcom b
in ation so fg asch rom atog raph icm ethod slin k
edt o dri
v enau toma tedpopu la tion fromsou rce so fg eneandp ro teinsequen c es
.Nu cle
i cA cids
Res
.30 , 354 –360(2002 ).
odou rt es
tin g,theses tud iesa r ep r ovid in ge ssenti a
l l
in ksb etw eenth e 4
. Qu ignon ,P .e ta l.Thedogandr a
to lfactor yr e cepto rr eperto ires.G en om eBi o
l. 6, R83
phy s
ic a
landch emic alp rop ertieso ff ood sandth e flav ou rp erception s (2005 )
.
the yp rodu ce.Th e lev e
lo fd etailc anb ee x quisi
t e;on esu chs tud y,f o
r 5
. La sk a,M .
,Se ibt,A .& W ebe r
,A .‘M icrosma t
i c’p rima te sre visi
ted :o lf acto rysen sit
i v
ity in
thesqu ir relmon k ey.Ch em .S en s es25 , 47 –53(2000 )
.
exam ple
,an a
l ys
edth et yp eo fg r asscon sum edb ycow sh ourlydu rin g 6
. Shephe rd ,G .M .Thehumansen seo fsme l
l:a r ew ebe tterthanw eth in k?P L oSB iol
.2 ,e 146
thed ayand ind i
ffer ents eason s,andhowth isr elatedt oth ech em i ca
l (2004 ).
com posit
ionandf l av ourqu alitieso fch eesep rodu cedf romth ecow s
’ 7
. S tew art
,W .B.,Kaue r
,J.S .&Shephe rd,G.M .Fun ctiona lorgan izationo fr ato l
f actor ybu lb
anal ysedb ythe2 -deo x yglu co seme thod .J.C omp .N eu ro
l.185 ,7 15 –734( 1979 )
.
mi
l k46.An otherstud yin ve st
i gat edth ech an ge inr etr on asalv olatiles 8
. Ad rian ,E .D .Sen so r yme ssag e sandsen sation ;ther espon seo ftheo lfa ctor yo rganto
releaseddu rin gsucc essivest ageso fin g es
tion ,m asticat
ionandsw a
llow - d
iffer en tsme lls.A ctaPh ysiol.S cand .29 ,5 –14( 1953 )
47
in g .Su chr esearch iscon tribu tin g to th eeff or
t toenh anc etrad i
tion al 9
. John son ,B .A .,F ar ahbod ,H .
,Sabe r
,S .&L eon ,M .E f
fe ctso ffun c
tiona lg rouppo s
itionon
spatia lr epr esen ta t
ion so falipha ti codo rant sinther ato l
f acto rybu lb.J .C omp .N eur o
l.483,
method so fpr oducin gf ood sw ithn atur al
l yrich flav ours48,a sw el
la s to 192 –204(2005 ).
thee ffortt om a
int a
ino rs imu lateth es equ al
ities inp r odu cef o
rm as
s 10
. Xu,F .Q .e ta l
. Odo rmap so faldeh ydesande ster sre vealedb y fMR I intheg lome rular laye
r
market s
.R e
c entstud iesh avea lsoa s sess edth ed eclin eth ato c curs in ofthemou seo lfa ctor ybu lb.P ro c
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