is mood chemistry - eero castren

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PERSPECTIVES

searching for the genes that might be asso-ciated with these familial disorders, andresearchers hope to uncover a molecule that ismalfunctioning in people with depression8.These research strategies seem to be based onan extension of the monoamine hypothesis,the chemical hypothesis of depression (FIG. 2),which proposes that mood disorders arecaused by structural or functional changes inparticular molecules in the brain, and thatantidepressants function by counteractingthese molecular changes. Over the last fewdecades, the view that depression is producedby a chemical imbalance in the brain hasbecome widely accepted among scientists,clinicians and the public.

However, during the past decade, severalobservations indicated that there might bean alternative hypothesis to the chemicalview of depression. This network hypothesisproposes that mood disorders reflect pro-blems in information processing within par-ticular neural networks in the brain and thatantidepressant drugs and other treatmentsthat alleviate depression function by gradu-ally improving information processingwithin these networks (FIG. 3). This reviewdiscusses the evidence supporting and con-tradicting the network hypothesis and theimplications of the network view on drugdevelopment and the treatment of mooddisorders.

The chemical hypothesisWe will soon be celebrating the fiftiethanniversary of the discovery of antidepres-sants, although the exact date and place ofthe discovery is a matter of dispute (for thehistory of the discovery of antidepressants, see

REF. 9). Iproniazid, a drug registered for thetreatment of tuberculosis, was found to elevate the mood of patients that received it,and subsequent studies in patients who weredepressed but did not have tuberculosisshowed its effect as an antidepressant9. Sim-ultaneously and independently, imipramine,an experimental antihistamine with a tricyclicstructure, was found to have antidepressanteffects. These discoveries revolutionized therecognition and treatment of mood disorders.In retrospect, it seems unbelievable thatimipramine was introduced to the marketonly several years after its antidepressanteffects were discovered, mainly because thecompany producing it was unsure that thenumber of patients who would benefit fromantidepressant treatment was sufficientlyhigh9. This now sounds incredible given thecurrent estimate that major depression isthe single most expensive disorder faced by Western societies and that, overall, anti-depressants are among the best selling drugs.

Soon after this discovery, imipramine andiproniazid were found to increase the extra-cellular concentrations of two importantneurotransmitters — serotonin and nor-adrenaline — in the brain, by blocking theirre-uptake back to nerve endings or byinhibiting the main metabolizing enzyme,monoamine oxidase, respectively. As drugsthat alleviate depression increase extracellularmonoamine concentrations, it was proposedthat depression might be produced by aserotonin or noradrenaline deficiency atfunctionally important receptor sites in thebrain1–4 (FIG. 1), a proposal that is now knownas the monoamine hypothesis of depression.Initially, the idea that a complex psychiatricdisorder such as depression could be pro-duced by biochemical changes was met withwidespread scepticism among psychiatristsand laymen. Nevertheless, during the last fewdecades this hypothesis has strongly influ-enced views about the pathophysiology ofmood disorders, among not only pharma-cologists, but also clinicians, other scientistsand the public4.

Abstract | The chemical hypothesis ofdepression suggests that mood disordersare caused by a chemical imbalance in thebrain, which can be corrected byantidepressant drugs. However, recentevidence indicates that problems ininformation processing within neuralnetworks, rather than changes in chemicalbalance, might underlie depression, and thatantidepressant drugs induce plastic changesin neuronal connectivity, which gradually leadto improvements in neuronal informationprocessing and recovery of mood.

The first antidepressants were discovered bychance almost 50 years ago, when drugs thathad been developed for other disorders werefound to elevate the mood of psychiatricpatients. Soon after this, drugs with anti-depressant activity were shown to increase theextracellular concentrations of two importantmonoamine neurotransmitters in the brain —serotonin (5-hydroxytryptamine or 5-HT) andnoradrenaline — by inhibiting their cata-bolism or reuptake to nerve endings. Thesefindings were the basis for the monoaminehypothesis of depression, which proposes thatmood disorders are caused by a deficiency inserotonin or noradrenaline at functionallyimportant receptor sites in the brain1–4 (FIG. 1).

It soon became evident that themonoamine hypothesis in its original formcould not explain all of the effects of anti-depressants5. Therefore, the focus of researchwas directed towards the receptors and intra-cellular signal transduction molecules that areregulated by antidepressant treatment6,7.Furthermore, because mood disorders oftenrun in families, genetic studies have been

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Is mood chemistry?

Eero Castrén

O P I N I O N


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P E R S P E C T I V E S

principal role of the nervous system is not tohandle chemicals but to store and processinformation. Arvid Carlsson, one of the mainarchitects of the concept of chemical neuro-transmission in the brain, stated in his Nobellecture, ‘However, it must be recognized thatthe brain is not a chemical factory but anextremely complicated survival machine’18.Although chemical neurotransmitters arecrucial for the transfer of information bet-ween neurons, information in the brain is notstored in a chemical form but is thought to beprocessed by the complex interactions of neu-rons in neural networks19,20. These networksdevelop through interactions with the envi-ronment, and the neuronal structure of, andneurotransmission in these networks are con-stantly being refined through activity-depen-dent synaptic plasticity to optimally processand store relevant information21 (BOX 1). So,disorders of the nervous system, includingdepression, might represent disturbances inthe activity-dependent information process-ing of the brain, rather than in the chemicalbalance of signalling molecules.

It should be noted that the chemical andnetwork hypotheses are not mutually exclu-sive, but are complementary. As the synthesisand release of several important signallingmolecules are regulated by neuronal activity,changes in the activity of neural networksproduce changes in the concentration of thesesignalling molecules. Therefore, althoughthe initial effects of antidepressants are obvi-ously chemical and are, in most cases, directedtowards the metabolism of monoamines, theensuing adaptive changes in the concentra-tions of those signalling molecules are tightlylinked to the structure of the neural network,and might be a consequence of the alteredinformation processing rather than its cause.According to this view, antidepressants initiatea ‘self-repair’ process, whereby plasticity inneural networks and chemical neurotrans-mission indivisibly cooperate and graduallybring about mood elevation.

Evidence for the network hypothesisThe evidence that supports the networkhypothesis of depression and antidepressantaction is limited and mostly indirect. Part ofthe problem is the lack of appropriateexperimental models of depression. In par-ticular, there are no relevant and widelyaccepted in vitro models of what might begoing on in the brain during depression.Furthermore, methods for direct measure-ment of changes in neural networks in vivoare only now being developed and have notyet been applied to neuropharmacologicalresearch19,22.

growth factors and their receptors, andintracellular signalling molecules4,6,7,15 (FIG. 2).As a result of this development, the mono-amine hypothesis has evolved to what couldbe called a chemical or molecular hypothesisof depression. This hypothesis presumes thatmood disorders are produced by long-termchanges in the production or activity of mol-ecules in the brain and that antidepressantsfunction by counteracting these molecularchanges. Motivated by this hypothesis,researchers are using large-scale DNA micro-array searches to look for genes that are up- ordownregulated in depression or by anti-depressant treatments, in the hope that themolecules that are encoded by these genesmight be used as targets in the developmentof new antidepressant drugs4,16,17.

The network hypothesisBut is this view correct? Is mood chemistry?Observations that have been made during thelast few years indicate that there might be analternative to the chemical view of depressionand the action of antidepressants5. This newhypothesis, the network hypothesis, proposesthat problems in activity-dependent neuronalcommunication might underlie depression,and that antidepressants might work byimproving information processing in theaffected neural networks (FIG. 3). A key aspectof the network view is the recognition that the

The monoamine hypothesis focused theinterest of the pharmaceutical industry onmonoamine metabolism for decades.Imipramine, which inhibits the re-uptake ofboth serotonin and noradrenaline (and vari-ous other receptors and enzymes), has nowbeen largely replaced by a host of moleculesthat inhibit the uptake of either serotonin ornoradrenaline more selectively, and ipron-iazid, which inhibits monoamine oxidase,the main metabolizing enzyme for mono-amines, has given way to subtype-selectivemonoamine oxidase inhibitors. Althoughthis focused drug development effort hasclearly been successful from the point of viewof safety, it has been less successful in termsof efficacy. Modern antidepressants are nomore effective than the first generation ofdrugs that were discovered several decadesago, and electroconvulsive shock treatmentremains the most effective treatment fordepression5,10,11.

It was recognized early on that severalobservations conflict with a simple linkbetween monoamine concentrations in thebrain and depression11. For example, deple-tion of dietary tryptophan, which signifi-cantly decreases the concentration of sero-tonin in the brain, produces either no effectsor only a mild dysphoria in healthy volunteersand does not influence the mood of untreatedpatients with depression12,13. More impor-tantly, although the effects of antidepressantson monoamine metabolism can be seen soonafter administration, it typically takes severalweeks of continued treatment for the clinicalantidepressant response to appear11. The dis-covery that long-term antidepressant treat-ment produces adaptive changes inmonoamine receptors and in their couplingto intracellular signal transduction14 causedthe research focus to shift towards the effectsthat long-term antidepressant treatmentshave on the concentrations of neuropeptides,

a b cPresynaptic

Postsynaptic

Figure 1 | Monoamine hypothesis of mood disorders. a | In the normal brain, monoamineneurotransmitters (yellow) are released and bind to receptors on the postsynaptic neuron. Transmission isterminated by re-uptake of the transmitter. b | In depression, the decreased concentration of monoamine atsynaptic sites produces a mood disorder. c | Blockade of the re-uptake sites (grey) increases theconcentration of monoamine neurotransmitters available at receptor sites and restores mood.

It was recognized early onthat several observationsconflict with a simple linkbetween monoamineconcentrations in the brainand depression.



Imaging studies in patients with depres-sion have revealed reduced grey matter volume in the prefrontal cortex32–34 and thehippocampus35–39. Morphological changes inthe hippocampus are associated with, andmight be preceded by, functional deficits,such as memory impairment35. As the neu-ronal processes and synapses take up most ofthe space in the grey matter, reduced volumemight mean reduced neuronal complexityand connectivity. To at least some degree,these morphological alterations seem to bereversible by antidepressant therapies34,40.The results of a recent study show thatreduced hippocampal volume is particularlycommon in patients with depression whosuffered a childhood trauma41, which indi-cates that severe stress during a critical devel-opmental period might have lasting effectson the morphology of the brain. These datasupport the hypothesis that mood disordersare associated with compromised informa-tion processing in crucial neural networks,and that the action of antidepressants mightresult in morphological and physiologicalreorganization of specific neuronal connec-tions in the brain. Furthermore, imaging andgenetic studies are beginning to elucidatewhich neural structures are involved in differ-ent mental health disorders and which circuitsmight be important targets for successfulmedications6.

Perhaps the most important evidence forthe network hypothesis is the recent obser-vation that antidepressants increase the production of new neurons in the rodent hippocampus42. Importantly, the increasedneurogenesis that is brought about bychronic antidepressant treatment correlateswith the behavioural effects produced byantidepressants43. Newly generated neuronsdifferentiate over time, and are only matureenough to participate in information processing several weeks after their birth44.The fact that this time course correlates withthe delayed onset of the clinical effects ofantidepressants has created a lot of excite-ment among neuropharmacologists. In thehippocampi of rodents that have receivedantidepressant treatment, the elimination ofneurons through apoptotic cell deathincreases simultaneously with increasedneurogenesis, which indicates that antide-pressants might increase neuronal turnoverrather than neurogenesis per se45. This effectmight be functionally analogous to theoverproduction of neurons that occurs during the development of the peripheralnervous system (BOX 1), and indicates thatantidepressants might facilitate optimiza-tion of neuronal connectivity by increasing

Monoamines, particularly serotonin,have a significant role during brain develop-ment23. Genetic elimination of the 5-HT1Areceptor produces anxiety-type behaviour inadult mice, but only when the receptor wasabsent during early postnatal development— its absence in adulthood produces nobehavioural effects24. Furthermore, muta-tions in monoamine oxidase A producebehavioural alterations in both men andmice25,26, and disrupt the developmentalorganization of thalamocortical inputs andcortical modules in the brains of rodents23,27.A similar disruption in thalamocorticalorganization has also been produced withthe administration of antidepressants andmonoamine oxidase inhibitors during earlypostnatal development27,28. Furthermore,antidepressant treatment during early post-natal life can produce permanent behav-ioural disturbances in adult animals29,30.

It is well known that the plasticity of neuralconnectivity in the brain is greater and moreextensive during critical periods of postnataldevelopment than in adults, and that func-tional structures that are formed duringcritical periods remain relatively stable inadulthood31 (BOX 1). These data highlight theeffects that serotonin and antidepressanttreatments have on the plasticity of neuralnetworks, and link the effects of antidepres-sants with the environmental manipulationsthat are known to modulate neural networkformation during development31. Moreover,they indicate that the effects of the drugsmight be more robust in the brain duringearly postnatal development and qualita-tively different when compared with theeffects seen in the adult brain, which couldhave significant implications for the pre-scription of antidepressants to children andpregnant mothers.


BDNF

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Figure 2 | The chemical hypothesis of depression. The intracellular pathways that are affected bymood disorders and antidepressants. AKT, protein kinase B; BAD, BLC-associated death promoter;BCL2, B-cell leukaemia/lymphoma 2; BCL-X, BCL2-like protein 1; BDNF, brain-derived neurotrophicfactor; CREB, cyclic AMP responsive element binding protein; ERK, mitogen activated protein kinase 1; GR, glucocorticoid receptor; GSK3, glycogen synthase kinase 3; MEK, ERK kinase; VPA, valproate; NA, noradrenaline; P, phosphate; RAF, RAF proto-oncogene; ROS, reactive oxygenspecies; Ras GTP, Ras GTPase-activating protein; RSK2, ribosomal protien S6 kinase polypeptide 3;TRKB, neurotrophic tyrosine kinase receptor type B; 5-HT, 5-hydroxytryptamine (serotonin).Adapted, with permission, from REF. 6 © (2001) Macmillan Magazines Ltd.




of BDNF in the hippocampus and cortex52–54,and the injection of BDNF into the brain oroverexpression of its receptor in transgenicmice produces similar behavioural responsesto those typically observed after treatmentwith antidepressant drugs55,56. Consistentwith the importance of BDNF in the effectsof antidepressants, transgenic mice withreduced BDNF expression or signalling fail to show these characteristic behaviouralresponses after the administration of anti-depressants54, which indicates that normalBDNF signalling might be both necessary andsufficient for a normal antidepressant effect. Itshould be emphasized that the crucial point isnot the increased molecular concentrationsof BDNF as such, but the importance ofthis neurotrophin as a mediator of activity-dependent neuronal plasticity (BOX 1).

In conclusion, the data that are summa-rized above provide some evidence that anti-depressants, through their acute effects onmonoamine metabolism, activate processesof plasticity, which are thought to graduallylead to improved information processing inthe neural networks that are involved inmood regulation. These processes, whichinclude neurogenesis and selective neuralelimination, arborization and retraction ofaxons and dendrites, and synaptic formationand pruning, are expected to take time todevelop and mature, which is consistent withthe delayed appearance of the clinical effectsof antidepressants.

However, observations have also beenmade that seem to be incompatible with thenetwork hypothesis. Although depletion of tryptophan — the rate-limiting factor ofserotonin synthesis — does not influence themood of healthy volunteers and untreatedpatients with depression12,13,57, it does pro-duce a rapid relapse of depressive symptomsin about 50% of remitted patients who arebeing, or have recently been treated withserotonin selective antidepressants12,13.Furthermore, there is a circadian variation in mood, and sleep deprivation rapidlyimproves the mood of patients with depres-sion, albeit temporarily58. These relativelyrapid effects on mood are difficult to recon-cile with the view of their production by agradual change in the structure of mood-elevating neural networks. It is obvious thatmore experimental work will be necessary totest the new model, but the rapid develop-ment of neurophysiological methods andthe imaging of neural networks will help usto gain further insights into the relationshipbetween the effects of antidepressants andneural plasticity, which might become afruitful area of further research.

connectivity without any net change insynaptic number20. Unfortunately, it is difficultto quantify synaptic turnover in vivo.

One possible mechanism through whichantidepressants might enhance the plasticityof neuronal connections in the hippocampusand cerebral cortex is the activation of neuro-trophin signalling48,49. Brain-derived neuro-trophic factor (BDNF), which is producedand released by neurons in an activity-dependent manner50, has been proposed tobe a crucial factor in the selection and stabi-lization of active synaptic contacts51 (BOX 1).Both antidepressants and electroconvulsiveshocks increase the expression and signalling

the choice of neurons available for selectionthrough activity-dependent mechanisms. Ata more subtle level, antidepressant drugscan enhance the sprouting of axons46 anddendrites47, and support the morphologicalmaturation of the newborn neurons47.These data indicate that, in addition to theirestablished function in elevating neuronalturnover in the dentate gyrus, antidepres-sants might also stimulate the turnover ofaxonal branches and synaptic contacts,thereby providing more material for activ-ity-dependent selection. It should be notedthat increased synaptic turnover might leadto significant reorganization of neuronal

a Healthy b Depressed

c During treatment d Recovered

Figure 3 | The network hypothesis of depression. a | In the healthy brain, information is processedin partially overlapping neural networks. b | In depression, information processing in some networksdoes not function properly. c | Antidepressant treatment enhances connectivity in neural networks. d | Activity-dependent pruning of synapses selects out and stabilizes the active synapses and networks.



be expected to be more beneficial than eithertreatment alone, and there is evidence thatthis might be the case59. As the networkhypothesis emphasizes the importance ofenvironmental information in the process ofactivity-dependent selection of neurons andsynapses (BOX 1), it predicts that full recoverywould not even be possible with drug treat-ment alone, but that external stimuli, such associal communication, would be required toprovide environmental input for the selec-tion of the appropriate network connections(FIG. 3). The role of environmental stimula-tion might also be related to the fact thatmajor depression is typically cyclical andoften self-limiting, and many patientsimprove with time even in the absence ofactive treatment.

Finally, the effects of antidepressant drugson network plasticity in the brain mightexplain why they are effective for manyneuropsychiatric disorders, including anxiety,obsessive-compulsive disorder, eating dis-orders, chronic pain and tinnitus. It has beenproposed that some of these disorders, par-ticularly chronic pain, might be produced byaberrant neuronal connectivity60.

The hypothesis that mood represents afunctional state of neural networks mightsound incompatible with the efforts of ratio-nal drug development. However, the datareviewed above indicate that the antidepres-sant drugs that have been used successfullyfor several decades might function by initi-ating such plastic processes, apparentlyindirectly, by influencing monoaminemetabolism. It is possible that a similarprocess could also be initiated throughother pharmacological mechanisms, whichmight become the targets of new anti-depressants that could help patients who areresistant to current drugs and only respondto electroconvulsive shock treatment.

Future perspectivesThe view of mood disorders as problems ofinformation processing in the brain has several important implications. As devel-opmental neurobiologists have been investi-gating activity-dependent plastic processesfor decades, collaboration between neuro-pharmacologists, developmental neuro-scientists and behavioural geneticists shouldbe encouraged. Recent studies clearly showthat genetic manipulation of neural circuitsand assessment of the consequences throughin vivo recording techniques and behav-ioural assays might provide an incrediblepotential for begining to define the relation-ship between circuit properties, behaviouraldeficits and potential therapeutics23,24.

During development and in adults, train-ing and rehabilitation produce functional andanatomical changes in neural networks,which are reflected in the gradual improve-ment of the rehearsed action. Analogously,psychotherapy, cognitive behavioural therapyand other forms of psychological rehabilitationcould also have therapeutic effects on mooddisorders through use-dependent neuronal

plasticity. Therefore, psychological andpharmacological therapies, electroconvulsiveshock treatment and placebo effects might alllead to improved information processing andmood recovery through mechanisms that ini-tiate similar processes of plasticity (FIG. 4). Inthis scenario, a combination of drug treat-ment and psychological rehabilitation would


Box 1 | Activity-dependent refinement of neural networks

During the development of the peripheral nervous system, neurons are produced in excessand compete to innervate the target tissues61. Neurotrophic factors, which are secreted bythe target tissues (for example, muscles) in limited quantities, and which are required byinnervating neurons for their survival, select from the competing neurons those that bestinnervate the target, and the defeated neurons are eliminated by apoptosis. This competitiveprocess matches the number of neurons and targets and ensures optimal innervation of thetarget cells61–63. In the CNS, neurons target other neurons and competitive selection takesplace at several levels: among neurons (as in the peripheral nervous system), among axonbranches and among synaptic contacts64. In the brain, the release of target-derived trophicfactors is activity dependent: the innervating neuron must sufficiently stimulate the targetneuron in order to induce the production and release of the trophic factor50,51. Neurons canalso cooperate to increase the release of trophic factors: simultaneously active neurons thatinnervate the same target neuron can induce the release of trophic factors through a muchlower level of activity than is required for a single innervating neuron51. This activity-dependent cooperative selection of simultaneously active neurons and the elimination ofinactive and incoherent contacts is considered to be crucial in the development of large,coherently active neural networks: ‘the neurons that fire together, wire together’21. Throughthese mechanisms, neuronal structure and neurotransmission are optimized to best storeand process relevant information. During critical periods in early postnatal development,much larger changes in the connectivity and organization of neural networks take placethan is possible in the adult brain31. Nevertheless, even the adult brain still shows significantplasticity. The crucial event in activity-dependent plasticity is not the formation of neuronalcontacts (which might occur stochastically and in excess) but the activity-dependentselection and stabilization of those synapses that mediate useful signals, together with theselective pruning and elimination of those that produce random noise20. Therefore,neurogenesis and synaptogenesis cannot simply be considered beneficial, and neuronaldeath and synapse elimination harmful; what matters is the optimization of thesignal–to–noise ratio in the network. Neurotrophins are important in this process throughtheir selective release from active connections; indiscriminate increases in the levels ofneurotrophic factors or their signalling (as, for example, would be produced by aneurotrophic factor receptor agonist) is not expected to be beneficial to the network, as bothactive and inactive connections would be similarly supported.

Pharmacotherapy

Psychotherapy

Aci

tivity

-dep

ende

nt p

last

icity

Electroconvulsive therapy

Figure 4 | A combinatorial approach for treating depression based on the network hypothesis.Depression might reflect disturbed information processing in neural networks (left panel). Antidepressantdrugs, electroconvulsive shock and psychotherapy can all induce activity-dependent plasticity, whichgradually leads to the recovery of connectivity in the affected neural networks (right panel).




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Acknowledgments I would like to thank H. Rauvala, M. Saarma, M. Castrén and R. Galuske for their comments to the manuscript, and the SigridJusélius Foundation, Sohlberg Foundation and the Academy ofFinland and for support.

Competing interests statementThe author declares no competing financial interests.

Online links

DATABASESThe following terms in this article are linked online to:Mouse Genome Informatics: http://www.informatics.jax.org/ BDNF | 5-HT1A

FURTHER INFORMATIONCastrén’s homepage:http://www.helsinki.fi/neurosci/castren.htmAccess to this interactive links box is free online.

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41. Vythilingam, M. et al. Childhood trauma associated withsmaller hippocampal volume in women with majordepression. Am. J. Psychiatry 159, 2072–2080 (2002).

42. Malberg, J. E., Eisch, A. J., Nestler, E. J. & Duman, R. S.Chronic antidepressant treatment increasesneurogenesis in adult rat hippocampus. J. Neurosci. 20,9104–9110 (2000).

43. Santarelli, L. et al. Requirement of hippocampalneurogenesis for the behavioral effects ofantidepressants. Science 301, 805–809 (2003).

44. van Praag, H. et al. Functional neurogenesis in the adulthippocampus. Nature 415, 1030–1034 (2002).

Our view of mood disorders and theaction of antidepressants is beginning tochange from a chemical view towards a net-work hypothesis, in which problems in infor-mation processing and neuronal connectivityin the brain are the central questions.However, several important issues have yet tobe addressed. How are neural networksformed and sustained during developmentand in adults? Which neuronal connectionsare involved, and are the same networksaffected in all patients? How do antidepres-sants initiate and support the process of plas-ticity? Does the delayed appearance of clini-cal antidepressant effects reflect slowmaturation of neuronal connections, andcould these processes be accelerated? In anycase, it is increasingly evident that the activ-ity-dependent plasticity and connectivity ofneural networks must be considered whendesigning future strategies of antidepressanttreatment, whether they are pharmacologi-cal, psychological or combinatorial.

Eero Castrén is at the Neuroscience Center,University of Helsinki, Finland.e-mail: [email protected]

doi:1038/nrn1629

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