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itive stimulation. However, a burst ofhigh-frequency stimulation can markedlyenhance the response to subsequent low-frequency pulses, a change known as long-term potentiation13 (LTP) that can last fora period of hours. LTP is widely consid-ered to be a cellular model of learning. Inthe striatum, LTP depends on activationof striatal dopamine synapses, as it isblocked by dopamine receptor blockadeand by lesions of the endogenousdopamine pathway6. Picconi et al.4 foundthat dopamine-dependent LTP wasrestored in lesioned animals by chronictreatment with low doses of L-DOPA (Fig. 1b), whether or not the animalsexhibited dyskinesia.

Although establishing new associa-tions is important, if learning is to beadaptive, the ability to ‘forget’ or ‘ignore’irrelevant associations is also key. Onemechanism for such regulation in LTP isdepotentiation, whereby several minutesof low-frequency stimulation can abol-ish the potentiation provided by thehigh-frequency burst in the initial estab-lishment of LTP (Fig. 1c). In the currentstudy, whereas L-DOPA restored LTP,including depotentiation, in the animalsthat did not develop dyskinesia, depo-tentiation was not induced in dyskineticanimals (Fig. 1d). Therefore, L-DOPA-induced dyskinesia is associated with(and perhaps results from) abnormalregulation of LTP in the striatum.

those that do not develop dyskinesias wouldfacilitate the identification of novel strate-gies to maintain or restore normal physio-logical plasticity in the striatum duringL-DOPA treatment and optimize the effica-cy of the drug as a dyskinesia-free therapyfor Parkinson’s disease.

1. Cotzias, G. C., van Woert, M.H. & Schiffere,L.M. New Engl. J. Med. 282, 31–33 (1967).

2. Poewe, W. & Granata, R. in MovementDisorders. Neurological Principles and Practice(eds. Watts, R.L. & Koller, W.C.) 201–219(McGraw-Hill, New York, 1997).

3. Obeso, J.A., Olanow, C.W. & Nutt, J.G. TrendsNeurosci. 23 (Suppl.), S2–S7 (2000).

4. Picconi, B. et al. Nat. Neurosci. 6, 501–506(2003).

5. Dunnett, S.B. & Robbins, T.W. Biol. Rev. 67,491–518 (1992).

6. Centonze, D. et al. J. Neurophysiol. 82,3575–3579 (1999).

7. Zigmond, M. J., Abercrombie, E. D., Berger,T.W., Grace, A.A. & Stricker, E. M. TrendsNeurosci. 13, 290–296 (1990).

8. Ungerstedt, U. Acta Physiol. Scand. 367(Suppl.), 69–93 (1971).

9. Bédard, P.J. et al. Mov. Disord. 14 (Suppl. 1),4–8 (1999).

10. Calabresi, P., Giacomini, P., Centonze, D. &Bernardi, G. Ann. Neurol. 47 (4 Suppl. 1),S60–S68, discussion S68–69 (2000).

11. Lundblad, M. et al. Eur. J. Neurosci. 15,120–132 (2002).

12. Cenci, M.A., Lee, C. S. & Björklund, A. Eur. J.Neurosci. 10, 2694–2706 (1998).

13. Bliss, T. V. P. & Lømo, T. J. Physiol. (Lond.)232, 331–356 (1973).

Because depotentiation elsewhere inthe brain involves protein phosphataseactivity, the authors4 confirmed that a sim-ilar mechanism applies in striatal LTP.Thus, inhibition of protein phospatase-1activity with okadaic acid blocked depo-tentiation of LTP in the normal striatum,an effect that depended on dopaminereceptor activation. Moreover, striatal neu-rons from dyskinetic rats had increasedphosphorylation of the striatal dopaminereceptor phosphoprotein DARPP-32.Phosphorylation of DARPP-32 promotesits conversion into a potent protein phosphatase-1 inhibitor, suggesting thatabnormal phosphorylation of DARPP-32in striatal neurons of rats with L-DOPA-induced dyskinesia causes the abnormalplasticity at corticostriatal synapses, whichin turn gives rise to the disrupted motorcontrol that underlies dyskinesia.

The authors provide a plausible inter-pretation of the cellular changes underlyingthe development of dyskinesias in rats;although, inevitably, further experimentswill be required to determine the generali-ty of the mechanism for humans. More crit-ically, the fundamental question of whysome rats develop dyskinesias whereas oth-ers do not may simply have been shiftedfrom a behavioral to a cellular level of uncer-tainty, although possibly one that is nowmore tractable to molecular analysis. Nev-ertheless, a cellular handle on the processesthat distinguish susceptible animals from

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Nosing into pheromonedetectorsIvan Rodriguez

Mice lacking a functional main olfactory system are shown tobe able to detect some odorants via their vomeronasal organ,suggesting this system is not restricted to sensing pheromones.

To make sense of the chemical world inwhich they live, most vertebrates use twoolfactory subsystems, the main olfactoryand the vomeronasal systems. These senseodorants and pheromones, respectively,and their sensitivity is impressive. Forexample, a squirrel monkey can detectspecific compounds at concentrationsbelow one part per billion1. In the main

olfactory system, information is processedin cortical areas involved in odor discrim-ination, which may give rise to the conscious representation of odorous mol-ecules. In contrast, the vomeronasal sys-tem projects to the hypothalamus andamygdala, two structures that controlinstinctive behaviors and hormonal levels(Fig. 1). The vomeronasal system is com-monly thought to be restricted to pro-cessing pheromones—originally describedas chemicals exchanged between insects2,but now a term used more generally todescribe molecules produced by an

individual and detected by another mem-ber of its own species. Pheromones inducean innate endocrine or behavioral modi-fication in the recipient.

In this issue, Trinh and Storm3 showthat in mice with genetically disrupted sig-naling in the main olfactory system, thevomeronasal system is able to detect reg-ular odors. This result confirms recentobservations in vitro4 and suggests that thetraditional view of vertebrate olfactorysubsystems—that the main olfactory sys-tem detects odors and the vomeronasalsystem detects pheromones—may have tobe re-examined.

Odorant perception starts at the den-dritic ends of sensory neurons located in themain olfactory neuroepithelium. The firststep involves the recognition of a volatilechemical by a seven-transmembrane recep-tor, part of the superfamily of odorant recep-tors5, which is followed by a transductioncascade that reaches a critical step with theactivation of a type-III adenylyl cyclase (Fig. 1). In mice, genetic disruption of the

The author is in the Department of Zoology andAnimal Biology, University of Geneva, QuaiErnest Ansermet, Geneva 1211, Switzerland.e-mail: ivan.rodriguez@zoo.unige.ch

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nature neuroscience • volume 6 no 5 • may 2003 439

electro-olfactograms. Odorants identifiedin the habituation experiments as beingdetected by the cyclase-deficient miceelicited electrical activity in thevomeronasal neuroepithelium of bothwild-type and mutant mice, as well as inthe main olfactory epithelium of wild-type mice. No activity was detected in themain olfactory system of the mutant ani-mals, arguing against involvement of thissystem in the detection of these molecules(although activity from a limited subsetof sensory neurons might be difficult tomeasure with this technique).

In a parallel approach, confirming andcomplementing the results obtained withthe genetically engineered mice, theauthors physically rendered non-functional the entire olfactory system(including the vomeronasal system) orspecifically eliminated the main olfactoryepithelium in wild-type animals. Thedestruction of the main olfactory systemwas based on intranasal administration ofZnSO4. Although this old-fashionedlesion approach is not as precise and ele-gant as the genetic approach, it is of greatinterest because it probably kills most ofthe sensory neurons in the main olfactorysystem, without regard to adenylyl cyclaseexpression. The authors found that odor-ants identified as having been perceivedby the vomeronasal system were notdetected by the bulbectomized mice; thiswas an important control because manyof these odorants (or oxidized forms ofthem) are irritants, and could thus poten-tially activate the trigeminal system. How-ever, the odorants were still detected inthe chemically treated animals, support-ing the suggestion that the vomeronasalsystem can sense these molecules.

Thus, we are left with a puzzling obser-vation that contradicts the prevailing ideathat the vomeronasal system is specializedfor the perception of pheromones. Howmight this be explained? At a chemicallevel, although some pheromones arelarge and non-volatile, they are not nec-essarily different from odorants; they canbe volatile and strongly odorous, and theycan be perceived as single compounds ormixtures. What distinguishes them is theirspecific effect on other members of thesame species. Pheromones are part of alarger family of ‘semiochemicals’—adiverse set of molecules that areexchanged between living organisms andshare the property of being advantageousto the emitter or to the receiver. Thus,among terrestrial vertebrates, manyspecies instinctively use their olfactory sys-tem not only to recognize specific

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gene coding for this cyclase prevents animalsfrom detecting odors via their main olfactory system6. However, because thetransduction of sensory signals in thevomeronasal organ uses other olfactoryreceptor types7 (Fig. 1), mice deficient inthis cyclase still possess a functionalvomeronasal system. Trinh and Storm tookadvantage of this situation—which dissoci-ates the olfactory subsystems—to ask whichvolatile chemicals are perceived by mice withonly a vomeronasal system.

A remarkable result was observed:despite their apparently non-functionalmain olfactory system, the mutant micewere able to detect several odors. Two dif-ferent tests were used to evaluate the olfac-tory capacities of the gene-targetedanimals. The first was an olfactory habitu-ation assay. Here, an odor-laced cottonswab was introduced into the cages, andthe number of odor sniffs was determinedand compared with the number of sniffsof a water-laced cotton swab; a high num-ber of sniffs upon initial exposure indicat-ed the detection of a novel odorant. Thesecond assay was a buried-food test, inwhich mice were trained to associate an

odor with a food reward, and the latencyto retrieve food pellets was recorded. Notsurprisingly (because they still had intactvomeronasal organs), mutant mice wereable to detect a variety of different mousepheromones. The mice were then exposedto volatile odorants such as ethyl vanillin,ethyl acetate, citralva, butanone or lilial, allcompounds not thought to be pheromonesin mice (as they are not produced in bodi-ly fluids). Interestingly, both assays showedthat the mutant animals were able to detectsome of these odorants.

Could it be that a neuronal populationin the main olfactory system of themutant animals that does not depend onadenylyl cyclase III signaling was recog-nizing these odorants? Indeed, the senso-ry population in the main olfactorysystem is not homogenous: some groupsof cells have unique gene expression pro-files, including, for example, a small neu-ronal population expressing a receptorguanylyl cyclase8 and no adenylyl cyclaseIII. Trinh and Storm explored this possi-bility by measuring electrophysiologicalresponses to odorants in the main olfactory and vomeronasal systems with

Vomeronasalorgan

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Fig. 1. Dorsal view of rodent brain, showing the differential organization of the vomeronasal andmain olfactory organs. The tip of the nose is on the left. The inserts show how the vomeronasaland main olfactory systems use distinct signaling cascades. Transduction cascade in vomeronasalsensory neurons is still unclear; see ref. 13 for details on this proposed cascade.

Bob Crimi

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effects of genotype and those of mater-nal behavior on the behavior of the adultoffspring. In this issue, Francis et al.3 usean elegant combination of prenatal andpostnatal cross-fostering (of embryosand infants, respectively) to show thatthe combination of both environmentalmanipulations is critical in determininglater adult behaviors of an inbred mousestrain (C57BL/6J; abbreviated here asB6) (Fig. 1). B6 mice that were bothborn of and reared by a BALB/cJ (BALB)mother showed BALB-like behavioralcharacteristics.

Francis et al.3 obtained embryos fromB6 mice, which were then inserted intothe uterus of either a B6 dam or a BALB dam. After birth, the result-ing offspring were then cross-fostered,again to either B6 or BALB mothers,where they experienced strain-specificmaternal rearing until weaning threeweeks later (Fig. 1). When they reachedadulthood, mice were tested for four

Genes do not specify behaviors absolute-ly. Comparisons between even geneticallyidentical individuals, such as identicaltwins or inbred strains of rodents, showthat environment can have marked effectson behavioral, disease-related and evenmorphological traits1. Environmentalmanipulations such as increased com-plexity (‘enrichment’) during rearing,daily handling of infants and maternalinteractions all affect subsequent patternsof adult rodent strain differences inbehavior. In other words, genes and envi-ronments interact2.

Postnatal cross-fostering has longbeen used to discriminate between the

440 nature neuroscience • volume 6 no 5 • may 2003

members of their own group (a femalemouse will form a specific olfactory mem-ory of a male after mating with him9), butalso to trace prey (a garter snake follow-ing an earthworm10) or to respond todanger (a rat’s defensive response onexposure to cat odor11). Some of thesebehaviors are mediated, at least in part, bythe vomeronasal organ, as removing thisstructure affects them. Therefore, inmammals it may be that the vomeronasalsystem processes scents that belong to thewider class of semiochemicals. It is notknown, however, whether the odorantsdetected by mice lacking the main olfac-tory system3 (and others in in vitro exper-iments) are semiochemicals in rodents.

So far, we know of three differentchemosensory receptor superfamiliesexpressed in the olfactory system: theodorant4, V1r and V2r12 receptor fami-lies, expressed respectively in the mainolfactory and in the vomeronasal sys-tems. A better understanding of the

semiochemical world of simpler lifeforms, such as insects, or even yeasts.

1. Laska, M. & Seibt, A. Behav. Brain Res. 134,165–174 (2002).

2. Karlson, P. & Luscher, M. Nature 183, 55–56(1959).

3. Trinh, K. & Storm, D.R. Nat. Neurosci. 6,519–525 (2003).

4. Sam, M. et al. Nature 412, 142 (2001).

5. Buck, L. & Axel, R. Cell 65, 175–187 (1991).

6. Wong, S.T. et al. Neuron 27, 487–497 (2000).

7. Berghard, A., Buck, L.B. & Liman, E.R. Proc.Natl. Acad. Sci. USA 93, 2365–2369 (1996).

8. Fulle, H.J. et al. Proc. Natl. Acad. Sci. USA 92,3571–3575 (1995).

9. Bruce, H.M. Nature 184, 105 (1959).

10. Kirschenbaum, D.M., Schulman, N. &Halpern, M. Proc. Natl. Acad. Sci. USA 83,1213–1216 (1986).

11. Dielenberg, R.A. & McGregor, I.S. Neurosci.Biobehav. Rev. 25, 597–609 (2001).

12. Dulac, C. Curr. Opin. Neurobiol. 10, 511–518(2000).

13. Spehr, M., Hatt, H. & Wetzel, C.H. J. Neurosci.22, 8429–8437 (2002).

physiological relevance of the volatileodorants activating the vomeronasal sys-tem (in both olfactory systems), willprobably require the identification of thereceptors responsible for their detection,and more importantly, of the centralstructures receiving inputs from the sen-sory neurons expressing these receptors.Anatomical tracing techniques usinggenetic markers will enable researchersto address this latter question. Thesetechniques may also help us to under-stand how several animals, such as pigs,ferrets and rabbits, can perceive somepheromones using their main olfactorysystems—a finding that mirrors the find-ings of Trinh and Storm3.

The simple concept of separate olfac-tory subsystems for odorants versuspheromones will need to be reassessed.This may be a surprise to some of us, butperhaps it should not, as our currentknowledge of vertebrate semiochemistrylies well behind what we know of the

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Mother nature meets mothernurtureJohn C. Crabbe and Tamara J. Phillips

Using prenatal and postnatal cross-fostering methods in mice, anew experiment shows that the intrauterine environment andpostnatal care cooperate to influence behavior in adulthood.

The authors are at the Portland AlcoholResearch Center, Department of BehavioralNeuroscience, Oregon Health & ScienceUniversity, VA Medical Center (R&D 12), 3710 SW US Veterans Hospital Road, Portland,Oregon 27239, USA.e-mail: crabbe@ohsu.edu

behavioral responses. Two were indica-tive of anxiety-like behavior (center timein a novel open arena and ratio of timespent in open versus closed arms of anelevated plus maze). A third reflectedlearning (latency to find a hidden plat-form on the last trial of a water escapetest), and the fourth measured sensorygating (percent prepulse inhibition ofstartle behavior to a loud noise). Untreat-ed B6 and BALB mice differ on all fourof these measures. The behavior of B6mice fostered twice (prenatally and post-natally) to B6 mothers did not differ fromthat of non-fostered B6 mice. Similarly,the behavior of B6 mice was not affectedby fostering to a BALB mother only post-natally or only prenatally. However, afterboth prenatal and postnatal BALB fos-tering, B6 mice behaved in adulthood likeBALB mice for all behaviors except pre-pulse inhibition. Thus, there was evidenceof an interaction between prenatal andpostnatal influences.

An interesting feature of the new studyis that the specific combination of bothpre- and postnatal environments wasinfluential—no surprise, but an importantresult. Part of the importance derives fromthe recent rediscovery4 of older findings5,6

that some effects of postnatal rearing canbe faithfully transmitted by their recipi-ents to future generations (‘epigenetical-ly’). Furthermore, the behaviors that canbe transmitted epigenetically importantlyinclude maternal behavior. The mediating

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