Current Biology Vol 19 No 21R988

Odor Memories: The First SniffCounts

A new study which combined associative memory tests with functionalmagnetic resonance imaging of the brain has identified a potential neuralcorrelate of the special association that is formed when an odor is first pairedwith a visual object.

Andreas Keller

Odor memories in humans are likely tobe processed by a separate memorysystem with distinctive features thatmake odor memories different fromvisual or auditory memories [1,2].Two peculiarities of odor memoryfascinate scientists and poets alike: thevividness of odor-evoked memories;and the difficulty of rememberinga smell. Odor-evoked memories aremore vivid and emotional thanmemories evoked by stimuli in othermodalities. Because the best knowndescription of this phenomenon isfound in Marcel Proust’s novel InSearch of Lost Time, this phenomenonis often called ‘Proust effect’. On theother hand, memories of odorsthemselves are elusive. Some haveargued that smells cannot beremembered at all — VladimirNabokov wrote in his debut novelMary ‘‘Memory can restore to lifeeverything except smells’’.

Early research into the curiousnature of smell memories relied onself-reported smell experiences andbehavioral measures of odormemories. Functional brain imagingoffers a new tool to objectively studyhow we remember odors by mappingactivity in the brain while we remember.In this issue of Current Biology,Yeshurun et al. [3] report a study inwhich functional magnetic resonanceimaging was used on subjectsperforming associative memory teststo study odor memories. Specificallythey address the psychologicalphenomenon called ‘resistance tointerference’ [4], or rather: whatmakes the first association of an odorwith an object stronger than laterassociations of the same odor witha different object? Their resultssuggest that the hippocampusis involved in the formation ofpersistent odor associations.

Resistance to interference of odormemories was first described byLawless and Engen [5], who showed

that over a two-week period the firstof two associations to an odor wereretained far better than the second.They concluded that ‘‘If the storagesystem offers only one permanent linkon a first-come first-served basis,subsequent learning will have littleeffect. The original associations willpersist as long as they are unaffectedby simple time-dependent decayprocesses’’. In another set ofexperiments, Zucco [1] showed thatthe persistence of first-learnedassociations is specific for odormemories in an experiment thatexposed subjects to olfactory, visual,or acoustic stimuli and then asked torate the pleasantness of differentstimuli. Afterwards, the subjects hadto recognize the original stimuli. Theirability to recognize odors was notimpaired by having to sniff a differentset of odors between learning andretrieval; however, their ability torecognize sounds or pictures wasimpaired by distracting soundsor pictures.

Psychophysical experiments thatdemonstrate the persistence offirst-learned odor associations agreewell with studies that suggest thatthe very first odor experiences in ahuman life in the womb and duringbreast-feeding persist throughout life.Positive associations with odors in theamniotic fluid and in breast milk thatreflect the mother’s diet have beenshown to persist for several decades[6,7]. This process — the resistance tointerference of a positive associationwith a food odor — may form thefoundation of cultural and ethnicalfood preferences that are difficultto change later in life.

In the experiments reported byYeshurun et al. [3], subjects had toassociate the same visual objects firstwith one set of stimuli and later on thesame day with a different set of stimuli.They used four groups of stimuli:pleasant odors (lemon or peach),unpleasant odors (manure or fish),pleasant sounds (guitar or waterfall),

and unpleasant sounds (chalk or drill).A week later, the subjects werepresented with the visual objectsagain and had to indicate whichsmell or sound was brought to mindfirst by the different visual objects.In addition to these behavioralmeasures, brain activity was imagedwhile subjects looked at the visualobjects and recalled the associatedodor or sound.

The brain imaging revealed thatthe hippocampus was more activewhen the subjects associated thevisual object with the odor that waspaired with it first than when theyassociated the visual object withthe odor that was paired with itlater. This activity in the hippocampuscould be due to the neuronalprocesses that make first-learnedodor associations persistent. Thishypothesis is strongly supported bythe finding that the effect is not foundwith sounds. The hippocampalactivation is not stronger when thefirst-learned sound is associatedwith the visual object than whenthe sound that was later learnedis used. It is therefore likelythat Yeshurun et al. [3] havediscovered the neuronal correlatesof the special character offirst-learned odor associations.

On the basis of previous research[1,5] and the new brain imaging data [3]one would expect that the first-learnedodor has formed a stronger associationthan the odor that was associated later.However, the situation is complicatedby the fact that the subjects in whomneuronal correlates of the specialcharacter of first odor associationswere identified did not show behavioralevidence that first odor associationsare indeed special — they showedno difference in the strength ofassociation. Instead, Yeshurun et al. [3]discovered that the pleasantness ofthe associated stimulus has a stronginfluence on its resistance tointerference. Associations of visualobjects with unpleasant odors orsounds are much more persistent thanassociations with pleasant odors orsounds. This very large effect may wellovershadow any effect of sensorymodality in the experimental design ofYeshurun et al. [3]. This finding alsoqualifies the previous research intoresistance to interference in whichthe stimuli were not balancedfor pleasantness.

DispatchR989

In our subjective every-dayexperience, it is apparent that odormemories are fundamentally differentfrom other memories; however, thephenomenon has proved to benotoriously difficult to study undercontrolled laboratory conditions.Yeshurun et al.’s [3] approach ofcombining associative memorytests with functional magneticresonance imaging allowed themto study how odor memories aredifferent at the neuronal level.The identification of brain regionsimplicated in the formation offirst-learned associations between

odors and objects opens the door forresearch that will explicate the role ofolfactory processing, emotion, andlong-term memory in this intriguingphenomenon.

References1. Zucco, G.M. (2003). Anomalies in cognition:

olfactory memory. Europ. Psychol. 8, 77–86.2. Herz, R. (2007). The Scent of

Desire - Discovering our EnigmaticSense of Smell (New York: William Morrow),61–89.

3. Yeshurun, Y., Lapid, H., Dudai, Y., and Sobel, N.(2009). The privileged brain representation offirst olfactory associations. Curr. Biol. 19,1869–1874.

4. Wilson, D.A., and Stevenson, R.J. (2006).Learning to Smell - Olfactory Perceptionfrom Neurobiology to Behavior

(Baltimore: The Johns Hopkins University Press),pp. 188–242.

5. Lawless, H., and Engen, T. (1977). Associationsto odors — interference, mnemonics, andverbal labeling. J. Exp. Psychol. Hum. Learn.Mem. 3, 52–59.

6. Mennella, J.A., Jagnow, C.P., andBeauchamp, G.K. (2001). Prenatal and postnatalflavor learning in human infants. Pediatrics107, e88.

7. Haller, R. (1999). The influence of earlyexperience with vanillin on food preferencelater in life. Chem. Senses 24, 465–467.

Rockefeller University, 1230 York Avenue,Box 63, New York NY 10065, USA.E-mail: kellera@rockefeller.edu

DOI: 10.1016/j.cub.2009.09.046

Phagocytosis: Invitation to a Feast

How does a macrophage find an apoptotic cell for ingestion? A recent studyshows that ATP and UTP released from the dying cell serve as importantchemoattractants for macrophages and are key contributors to the efficientclearance of apoptotic cells in vivo.

Peter M. Henson

The deletion of excess, previouslyused, unwanted or damaged cells isessential in metazoa for development,metamorphoses, tissue homeostasis,responses to injury and for thedevelopment and regulation of innateand adaptive immunity. It is achievedby the induction of various forms ofprogrammed cell death (PCD), of whichapoptosis is the best known. Criticalto the overall process, however, is thesubsequent recognition and removalof the dying cell in a manner that candistinguish between PCD and celldeath induced by external agents,toxins, physical damage or,particularly, infectious agents. For theformer, a quiet efficient removal is thenorm whereas, for the latter, the animalneeds to (and does) mount a protectiveresponse that can encompassengagement of the various innate andadaptive immune processes withwhich it is endowed. In mammals, thisis represented by the commonly notedbut also overly simplified distinctionbetween the non-inflammatoryand non-immunogenic responseto apoptotic cells versus the pro-inflammatory and pro-immunogeniceffects of cells dying by non-PCD(often loosely described as necrotic)pathways.

Dying cells are removed by uptakeinto phagocytic cells. In simplerinvertebrates, such as nematodes, thisis largely achieved by recognition by,and uptake into, neighboring tissuecells, and in fact this near-neighborremoval can also occur in mammals,as exemplified by post-lactationremodeling of the mammary gland or,for that matter, the constant dailyremoval of retinal outer rod segments,each achieved by epithelial cells. Butin animals with more professional andmobile phagocytes, these have takenon the major role in recognition,phagocytosis and digestion of thecells undergoing PCD. Many studieshave addressed these processes andshown them to involve uniquemechanisms of uptake (often involvingingestion of intact cells that can beas large as 20mm in diameter),unique sets of receptors and bridgemolecules (opsonins), and uniqueintracellular signaling pathways, withremarkable evolutionary conservationof the entire process [1–3]. However,the important question of how themobile phagocyte finds (is attractedto) the cells undergoing PCD hasreceived much less attention. Thisis the subject addressed in therecent paper by Elliot et al. [4]which reports identification of thenucleotides ATP and UTP as prime

candidates for what have beencolloquially called ‘find me’ signals,following the various use of ‘eat me’and ‘don’t eat me’ for apoptoticcell uptake or inhibitory signals,respectively.

The approach taken by Elliot et al. [4]was to show release of chemotacticfactors for macrophages fromapoptotic cells in vitro, confirm withmacrophage attraction into skinpouches in mice, identify candidatemolecules released from the apoptoticcells and finger the likely receptors onmacrophages that were responsible.To complete the story, they showedthat removal of the factors or blockadeof the candidate receptors reducedclearance of apoptotic cells in anin vivo model cell removal systemfollowing massive lymphocyteapoptosis in the thymus, which wasfirst described by Scott et al. [5]. Theirextensive series of experiments led tothe identification of ATP and UTP asresponsible molecules for apoptoticcell attraction of macrophages. Thesenucleotides are released from avariety of cells undergoing apoptosisin a caspase-dependent fashion,apparently before the cells undergoloss of plasma membrane permeability.They induce macrophage chemotaxisin vitro and in vivo, and apoptoticcell supernate induction of themacrophage attraction was shown tobe abrogated by introduction ofapyrase to hydrolyze the nucleotides.Overexpression of CD39 — amammalian ecto-enzyme involved innatural nucleotide inactivation — wasshown to have a similar blockingeffect.