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Sustained neurogenesis occurs in the olfactory epithelium of several species, including humans, to support olfactory function throughout life. We recently developed a modified lineage tracing method to identify adult neurogenesis in Drosophila. By applying this technique, here we report on the continuous generation of Olfactory Sensory Neurons (OSN) in the antennae of adult Drosophila. New neurons develop sensory dendrites and project axons targeting diverse glomeruli of the antennal lobes in the brain. Furthermore, we identified sustained apoptosis of OSN in the antennae of adult flies, revealing unexpected turnover in the adult olfactory system. Our results substantiate Drosophila as a compelling platform to expedite research about mechanisms and compounds promoting neuronal regeneration, circuit remodeling and its contribution to behavior in the adult.

Olfactory disorders have been regarded in the past with a sense of therapeutic nihilism. However, there have been remarkable advances in chemosensory research over the past several years. The clinical importance of olfactory disorders is well established, and entities such as presbyosmia have gained considerable broad attention. Powerful basic science experimental approaches have revealed aspects of olfactory neuron physiology, olfactory tissue maintenance, and regeneration that provide new potential therapeutic targets for certain forms of olfactory dysfunction. Although many recent advances remain in pre-clinical stages, there is considerable reason for optimism regarding future approaches for treatment of patients with olfactory loss.

The ability of insects to navigate toward odor sources is based on the activities of their first-order olfactory receptor neurons (ORNs). While a considerable amount of information has been generated regarding ORN responses to odorants, the role of specific ORNs in driving behavioral responses remains poorly understood. Complications in behavior analyses arise due to different volatilities of odorants that activate individual ORNs, multiple ORNs activated by single odorants, and the difficulty in replicating naturally observed temporal variations in olfactory stimuli using conventional odor-delivery methods in the laboratory. Here, we describe a protocol that analyzes Drosophila larval behavior in response to simultaneous optogenetic stimulation of its ORNs. The optogenetic technology used here allows for specificity of ORN activation and precise control of temporal patterns of ORN activation. Corresponding larval movement is tracked, digitally recorded, and analyzed using custom written software. By replacing odor stimuli with light stimuli, this method allows for a more precise control of individual ORN activation in order to study its impact on larval behavior. Our method could be further extended to study the impact of second-order projection neurons (PNs) as well as local neurons (LNs) on larval behavior. This method will thus enable a comprehensive dissection of olfactory circuit function and complement studies on how olfactory neuron activities translate in to behavior responses.

The mouse olfactory sensory neuron (OSN) repertoire is composed of 10 million cells and each expresses one olfactory receptor (OR) gene from a pool of over 1000. Thus, the nose is sub-stratified into more than a thousand OSN subtypes. Here, we employ and validate an RNA-sequencing-based method to quantify the abundance of all OSN subtypes in parallel, and investigate the genetic and environmental factors that contribute to neuronal diversity. We find that the OSN subtype distribution is stereotyped in genetically identical mice, but varies extensively between different strains. Further, we identify cis-acting genetic variation as the greatest component influencing OSN composition and demonstrate independence from OR function. However, we show that olfactory stimulation with particular odorants results in modulation of dozens of OSN subtypes in a subtle but reproducible, specific and time-dependent manner. Together, these mechanisms generate a highly individualized olfactory sensory system by promoting neuronal diversity. DOI: http://dx.doi.org/10.7554/eLife.21476.001, eLife digest Smells are simply chemicals in the air that are recognized by nerves in our nose. Each nerve has a receptor that can identify a limited number of chemicals, and the nerve then relays this information to the brain. Animals have hundreds to thousands of different types of these nerves meaning that they can detect a wide array of smells. Smell receptors are proteins, and the genes that encode these proteins can be very different in two unrelated people. This could partly explain, for example, why some people find certain odors intense and unpleasant while others do not. However, having different genes for smell receptors does not by itself completely explain why some people are more sensitive than others to particular smells. The amounts of each nerve type in the nose might also differ between people and have an effect, but to date it has not been possible to accurately count them all. Ibarra-Soria et al. have now devised a new method to essentially count the number of each nerve type in the noses of mice from different breeds. The method makes use of a technique called RNA-sequencing, which can reveal which genes are active at any one time, and thus show how many nerves are producing each type of smell receptor. Ibarra-Soria et al. learned that different breeds of mice had remarkably different compositions of nerves in their noses. Further analysis revealed that this was due to changes to the DNA code near to the genes that encode the smell receptor. Next, Ibarra-Soria et al. sought to find out how the amount of each nerve type is controlled by giving mice water with different smells for weeks and looking how this affected their noses. These experiments revealed that a small number of the nerve types became more or less common after exposure to a smell. The altered nerves were directly involved in recognizing the smells, proving that the very act of smelling can change the make-up of nerves in a mouse’s nose. These results confirm that the diversity in the nose of each individual is not only dictated by the types of receptors found in there, but also by the number of each nerve type. The next challenge is to understand better how these differences change the way people perceive smells. DOI: http://dx.doi.org/10.7554/eLife.21476.002

Caenorhabditis elegans navigates thermal gradients by using a behavioral strategy that is regulated by a memory of its cultivation temperature ( T c ). At temperatures above or around the T c , animals respond to temperature changes by modulating the rate of stochastic reorientation events. The bilateral AFD neurons have been implicated as thermosensory neurons, but additional thermosensory neurons are also predicted to play a role in regulating thermotactic behaviors. Here, we show that the AWC olfactory neurons respond to temperature. Unlike AFD neurons, which respond to thermal stimuli with continuous, graded calcium signals, AWC neurons exhibit stochastic calcium events whose frequency is stimulus-correlated in a T c -dependent manner. Animals lacking the AWC neurons or with hyperactive AWC neurons exhibit defects in the regulation of reorientation rate in thermotactic behavior. Our observations suggest that the AFD and AWC neurons encode thermal stimuli via distinct strategies to regulate C. elegans thermotactic behavior.

The insect olfactory system plays an important role in detecting semiochemicals in the environment. In particular, the antennal sensilla which house single or multiple neurons inside, are considered to make the major contribution in responding to the chemical stimuli. By directly recording action potential in the olfactory sensillum after exposure to stimuli, single sensillum recording (SSR) technique provides a powerful approach for investigating the neural responses of insects to chemical stimuli. For the bed bug, which is a notorious human parasite, multiple types of olfactory sensillum have been characterized. In this study, we demonstrated neural responses of bed bug olfactory sensilla to two chemical stimuli and the dose-dependent responses to one of them using the SSR method. This approach enables researchers to conduct early screening for individual chemical stimuli on the bed bug olfactory sensilla, which would provide valuable information for the development of new bed bug attractants or repellents and benefits the bed bug control efforts.

International audience; Dogs have a great sense of olfaction, but unlike many other mammals, which also show superior olfactory performance, many dog breeds have been created for hunting purposes for which olfactory performance is particularly important. In this article, we review the dog genetic characteristics that could make dogs so gifted with respect to olfactory ability. We also present some preliminary results on RNA profiling analyses of dog olfactory epithelium and show that the level of olfactory receptor expression per olfactory neuron might be higher in dogs than in rats.

Through the sense of smell mammals can detect and discriminate between a large variety of odorants present in the surrounding environment. Odorants bind to a large repertoire of odorant receptors located in the cilia of olfactory sensory neurons of the nose. Each olfactory neuron expresses one single type of odorant receptor, and neurons expressing the same type of receptor project their axons to one or a few glomeruli in the olfactory bulb, creating a map of odorant receptor inputs. The information is then passed on to other regions of the brain, leading to odorant perception. To understand how the olfactory system discriminates between odorants, it is necessary to determine the odorant specificities of individual odorant receptors. These studies are complicated by the extremely large size of the odorant receptor family and by the poor functional expression of these receptors in heterologous cells. This article provides an overview of the methods that are currently being used to investigate odorant receptor-ligand interactions.

Neurodevelopment Neurons in the developing brain cooperate to build circuits. Mountoufaris et al. found that ∼50 variable protocadherin genes support a combinatorial identity code that allows millions of olfactory neuron axons to sort into ∼2000 glomeruli. Sharing olfactory receptors drives axons to one glomerulus, and protocadherin diversity allows the multiple axons to touch each other as they converge. On the other hand, Chen et al. found that a single C-type protocadherin underlies the tiled distribution of serotonergic neurons throughout the central nervous system. These neurons, which share protocadherin identity, enervate broad swaths evenly without touching neighboring neurons. Science , this issue p. [411][1], p. [406][2] [1]: /lookup/doi/10.1126/science.aai8801 [2]: /lookup/doi/10.1126/science.aal3231

Changes in metabolic state alter foraging behavior and food preference in animals. Here I show that normally attractive food becomes repulsive to C. elegans if animals are chronically under-nourished due to alimentary tract defects. This behavior plasticity is achieved in two ways: increased food leaving and induction of aversive behaviour towards food. A particularly strong food avoider is defective in the chitin synthase that makes the pharyngeal lining. Food avoidance induced by underfeeding is mediated by cGMP signaling in the olfactory neurons AWC and AWB, the gustatory neurons ASJ and ASK. Food avoidance is enhanced by increased population density and is reduced if the animals are unable to correctly interpret their nutritional state due to defects in the AMP kinase or TOR/S6kinase pathways. The TGF-β/DBL-1 suppresses food avoidance and the cellular basis for this is distinct from its role in aversive olfactory learning to harmful food. This study suggests that nutritional state feedback via nutrient sensors, population size, and olfactory neurons guide food preference in C. elegans.

Olfactory responses develop early in larval zebra fi sh and are important throughout life to direct physiological and behavioral responses. Responses are evoked by odorants, which act as ligands to the olfactory neuron receptors. A response of immediate relevance is the detection of food odors (i.e., amino acids) which fi sh have an excellent ability to detect. Characterizing responses of fi sh to distinct odorants, especially during developmental stages, allows for a robust endpoint to compare to genetically or chemically altered organisms. The following protocol describes the use of automated video analysis to detect changes in olfactory function apparent through a simple behavioral endpoint.

Insects have gustatory receptors with which they taste chemicals and make important choices about foods, mates, and egg deposition sites. Gustatory receptors are novel proteins, and understanding how they recognize diverse chemicals is an unmet challenge. We developed a method to examine taste receptor function using a Drosophila olfactory neuron as a host for expressing taste receptors. We individually tested all sweet receptors of the fly, which resulted in specific sugar responses in the olfactory neuron. We also successfully expressed a bitter receptor and a mosquito taste receptor. Our study describes a systematic view of how the fly’s taste receptors detect sweet substances and holds promise for uncovering functions of taste receptors from insects that transmit diseases or damage crops.

A new olfactory receptor model based on chaos is proposed in this paper. Simulating real olfactory receptor, the new olfactory receptor model is in a chaotic state as the basic state when there is no stimulus. It can be in active state when there is stimulus. Compared with K0 model, Gaussian noise is no need to the new model, which simplifies the olfactory nervous system model. Experimental results show that the proposed olfactory receptor model can change between chaotic and non-chaotic states according to the input, which is also consonant with the real olfactory neuron.

To investigate the interaction between the genes required for the functions of AWA olfactory neuron and insulin/IGF signaling in regulating the longevity of nematode Caenorhabditis elegans (C. elegans).The mutants that had loss-of-function mutation of the genes required for AWA, AWC, ASE, and AFD sensory neurons were employed. Lifespan, the speed of pharynx pumping, the intestinal autofluorescence, the dauer formation, and the brood size were examined. Rescue experiments were performed to confirm the role of the genes required for the functions of AWA neuron in regulating lifespan. Moreover, genetic interactions between genes required for the functions of AWA neuron and insulin/IGF signaling were investigated.Mutations of odr-7, odr-2, and odr-3 genes required for the functions of AWA neuron significantly increased the mean lifespan of nematodes and slowed the accumulation of intestinal autofluorescence. Besides, these mutations were closely associated with higher pumping rates during aging. However, mutation of odr-7, odr-2, or odr-3 did not obviously affect the brood size or the dauer formation, and the regulation of longevity by odr-7, odr-2, and odr-3 was temperature-independent. In contrast, mutations of genes required for the functions of ASE, AWC, and AFD sensory neurons did not influence the nematode lifespan. Moreover, expression of odr-7, odr-2 and odr-3 in AWA neuron could completely or largely restore the altered lifespan in odr-7, odr-2 and odr-3 mutants. Furthermore, genetic interaction assay demonstrated that the extended lifespan in odr-7 mutant could be suppressed by daf-16 mutation and enhanced by daf-2 or age-1 mutation, whereas mev-1 and pha-4 were not required for the long lifespan of odr-7 mutant.The genes required for the function of AWA sensory neuron could regulate the nematode longevity in an insulin/IGF signaling-dependent fashion in C. elegans.

The animal’s ability to maintain homeostasis in response to different environments can influence its survival. This chapter will discuss the mechanisms by which environmental cues act through sensory pathways to influence hormone secretion and homeostasis. Interestingly, recent studies also show that there is a sensory influence on lifespan that requires the modulation of hormonal signaling activities. Thus, this raises the possibility that the sensory influence on homeostasis underlies the sensory influence on lifespan.

■ The olfactory and gustatory systems rely on moleculereceptor-specific binding at specialized receptor sites to transduce afferent stimuli.

The nematode Caenorhabditis elegans can "remember" the temperature at which it was grown and will seek out that temperature if later exposed to a gradient of temperatures. In an effort to define the neuronal circuitry that allows this behavior, Kuhara et al . found that a neuron known as AWC has an important role in sensing temperature. This came as a surprise because the AWC cell is also known to function as an olfactory neuron. The cell could respond independently to odorants and temperature, even though when sensing temperature the neuron used a G protein-mediated intracellular signaling system similar to that used in olfactory responses. A. Kuhara, M. Okumura, T. Kimata, Y. Tanizawa, R. Takano, K. D. Kimura, H. Inada, K. Matsumoto, I. Mori, Temperature sensing by an olfactory neuron in a circuit controlling behavior of C. elegans. Science 320 , 803-807 (2008). [Abstract] [Full Text]

Studies of CNS processing of olfactory information have contributed significantly to understanding olfactory-guided behaviour in insects. Evidence in moths suggests that each glomerulus in the antennal lobes has a unique property: receptor-axon projections and dendritic arborizations of uniglomerular output neurons can relate to anatomically and functionally distinct glomeruli. Similar correlations are not typical of the concentrically organized locust antennal lobes. Insights about odour processing in the CNS of female mosquitoes should help us to understand how sensory information can lead to host-seeking behaviour. It will be interesting to learn how inputs from CO2 receptors on the maxillary palps and inputs from antennal olfactory receptors that respond to host odours are integrated centrally, so that pharmacological manipulation of olfactory neuron activity might provide a tool for the control of mosquitoes as important vector insects. The antennal lobe of male and female Aedes aegypti contains 20-25 glomeruli. Primary afferent projections from the antennae and maxillary palps target specific glomeruli of the ipsilateral antennal lobe. Maxillary palp projections are restricted to two posteromedial glomeruli, which do not receive antennal afferents. The latter arborize in the remaining glomeruli.

Drosophila olfactory receptor neurons are found within specialized sensory hairs on antenna and maxillary palps. The linking of odorant-induced responses to olfactory neuron activities is often accomplished via Single Sensillum Recordings (SSR), in which an electrode inserted into a single sensory hair records the neuronal activities of all the neurons housed in that sensillum. The identification of the recorded sensillum requires matching the neuronal responses with known odor-response profiles. To record from specific sensilla, or to systematically screen all sensillar types, requires repetitive and semi-random SSR experiments. Here, we validate an approach in which the GAL4/UAS binary expression system is used for targeting specific sensilla for recordings. We take advantage of available OrX-Gal4 lines, in combination with recently generated strong membrane targeted GFP reporters, to guide electrophysiological recordings to GFP-labeled sensilla. We validate a full set of reagents that can be used to rapidly screen the odor-response profiles of all basiconic, intermediate, and trichoid sensilla. Fluorescence-guided SSR further revealed that two antennal trichoid sensilla types should be re-classified as intermediate sensilla. This approach provides a simple and practical addition to a proven method for investigating olfactory neurons, and can be extended by the addition of UAS-geneX effectors for gain-of-function or loss-of-function studies.

Recent efforts to understand the contribution of neuronal activity in the creation of the olfactory sensory map have focused on odor-evoked events. In this issue of Neuron, Yu et al. discover a new role for neuronal activity in the organization and maintenance of the olfactory system. Their results highlight the role of spontaneous activity and synaptic transmission in axon outgrowth and olfactory neuron survival.

The last decade of the second millennium has witnessed an exceptionally increasing interest in the role that odours play in human life and in the understanding of the biochemical mechanisms undelying olfactory perception.

후각은 단순히 냄새를 맡는 일에서부터 미각과 함께 맛을 느끼는 중요한 감각으로 영양, 성생활, 감정과 관련된 역할을 수행하는 등 일상 생활을 영위하는 데 중요한 역할을 수행하 고 있다. 또한 삼차 신경과 함께 화재나 가스 누출 등 위험한 상황을 가장 먼저 감지하는 감시 시스템의 역할을 수행한다. 하지만 청각, 시각 등 다른 감각 기관에 비해 주목을 덜 받 아왔고 그에 대한 연구가 미진하였다. 2004년 Buck과 Axel이 “odorant receptors and the organization of the olfactory system”의 발견에 대한 공로로 노벨 생의학상을 수상하였고, 그 이후 후각에 대한 관심들이 증가하면서 연구는 활기를 띠 게 되었다. 후각에 대한 연구는 후각 자극을 인지하는 후각 수용 세포 부터 후각 피질로 가는 통로인 후각 신경로, 중심 신경계인 대뇌 피질까지 각 부분에 대하여 다양하게 진행되고 있다. 그러나 아직까지 국내에서는 후각에 대한 임상 연구나 기초 연구가 다른 연구에 비해 활발하지 못하다. 특히 이비인후과 에서 후각에 대한 기초 연구는 이제 시작 단계이고, 활발한 연 구를 위한 노력들이 적극적으로 요구되는 상황이다. 이에 저자는 최근에 연구되고 있는 후각 관련 기초 연구 중 일부를 간략히 소개하고자 한다.

Innate chemosensory preferences are often encoded by sensory neurons that are specialized for attractive or avoidance behaviors. Here we show that one olfactory neuron in Caenorhabditis elegans, AWCON, has the potential to direct both attraction and repulsion. Attraction, the typical AWCON behavior, requires a receptor-like guanylate cyclase GCY-28 that acts in adults and localizes to AWCON axons. gcy-28 mutants avoid AWCON–sensed odors; they have normal odor-evoked calcium responses in AWCON, but reversed turning biases in odor gradients. In addition to gcy-28, a diacylglycerol/protein kinase C pathway that regulates neurotransmission switches AWCON odor preferences. A behavioral switch in AWCON may be part of normal olfactory plasticity, as odor conditioning can induce odor avoidance in wild-type animals. Genetic interactions, acute rescue, and calcium imaging suggest that the behavioral reversal results from presynaptic changes in AWCON. These results suggest that alternative modes of neurotransmission can couple one sensory neuron to opposite behavioral outputs.

It is well established that each olfactory neuron of the mammalian olfactory system expresses only one olfactory receptor (OR) out of the 1000 OR proteins encoded by the mammalian genome. In their Perspective, [Lewcock and Reed][1] discuss new findings ([ Serizawa et al .][2]) that show how the OR protein itself participates in a negative feedback mechanism, which ensures that only one OR is expressed in each olfactory neuron. [1]: http://www.sciencemag.org/cgi/content/full/302/5653/2078 [2]: http://www.sciencemag.org/cgi/content/short/302/5653/2088

Response selectivity of neocortical neurons to specific odors has been observed in adult mammals [1,2]. We wondered if neurons of this type were already present in newborn animals or if olfactory experience or learning is required. For technical reasons it is difficult to obtain data from naive animals, i.e., those without olfactory experience. In this study, neocortical neuron responses of very young pups to specific odor patterns were recorded and compared with results from adults.

The olfactory system detects and processes chemicals in the environment providing long-range information that is necessary for survival. Many vertebrates rely chiefly on olfactory input for social interactions, food locating, migration, reproduction, and alerting to the presence of predators.

Olfaction, the ability to recognize and discriminate with great accuracy and sensitivity myriads of airborne molecules either by themselves or as complex mixtures, is one of the most remarkable and least understood senses of virtually all vertebrates. The sense of smell, like the immune system, specializes in molecular recognition and is crucial for the survival of most animal species. This chapter will discuss biochemical aspects of odorant recognition and chemosensory transduction.

Vertebrate olfactory neurons are unique among neurons in that they are continually replaced throughout the life of the animal. The rate of neurogenesis can be regulated by manipulating the system to abbreviate or prolong the average life of a sensory neuron. Moreover, the neuron may die before or after reaching full maturity. When compared with other neurons, the fully mature olfactory neuron retains juvenile characteristics; it is probable that genetic controls operate to maintain this relatively immature state.

Each sensory system has a code for the information it receives. The olfactory system, for example, encodes odors by chemical composition. Now, a team of neurobiologists has devised a powerful new way to read the brain9s smell code. Each of the thousands of little clusters of neurons in the brain9s olfactory bulb called glomeruli receives input from a specific type of olfactory neuron in the nose. That means each smell should activate a unique pattern of glomeruli--the code for that smell. In the July issue of Neuron , neuroscientists now report that they have used an optical imaging technique to see those patterns--the first time that9s been done in living mammals. The technique should offer neurobiologists a rare opportunity to examine and manipulate the ways the brain processes specific sensory information.

SummaryIn the mouse olfactory system, the anatomical locations of olfactory sensory neurons (OSNs) roughly correlate with their axonal projection sites along the dorsal-ventral (D-V) axis of the olfactory bulb (OB). Here we report that an axon guidance receptor, Neuropilin-2 (Nrp2), and its repulsive ligand, Semaphorin-3F (Sema3F), are expressed by OSNs in a complementary manner that is important for establishing olfactory map topography. Sema3F is secreted by early-arriving axons of OSNs and is deposited at the anterodorsal OB to repel Nrp2-positive axons that arrive later. Sequential arrival of OSN axons as well as the graded and complementary expression of Nrp2 and Sema3F by OSNs help to form the topographic order along the D-V axis.

Using the peroxidase-antiperoxidase immunohistochemical technique, carnosine-like immunoreactivity was demonstrated to localize specifically within the primary olfactory neuron.

Perhaps because the sense of smell involves the discrimination of molecules by neural tissue, most neurophysiological studies of vertebrate olfaction have used purified compounds as stimuli and have been directed at relating neural response parameters to the structural and/or physicochemical properties of molecules. In studies of odor responses by individual neurons (single units), a commonly employed paradigm has been one in which individual members from a preselected battery of “odors” (volatile molecules in otherwise highly purified air) are puffed sequentially onto the nasal mucosa and an attempt is made to derive the relevant structural and/or physicochemical parameters of odor from the relative response spectra of the units recorded. When employed in studies of peripheral olfactory neurons (cf. Gesteland, Lettvin and Pitts, 1965), this paradigm is consistent with the assumption that these neurons contain receptor sites for odoriferous molecules and in effect is aimed at a preliminary answer to the two interrelated questions of how specific are the receptor sites and do the peripheral neurons have more than one type of receptor site. This general paradigm also has been used in studies of central olfactory neurons to test hypotheses about the physical dimensions of odors. For example, Higashino, Takeuchi and Amoore (1969) attempted to verify a stereochemical theory of odor quality by using a battery of pure chemical stimuli and comparing the response spectra of single units recorded in the olfactory bulbs with generalization gradients derived from psychophysical studies.

Sex pheromones are intraspecific olfactory signals emitted by one sex to attract a potential mating partner. Behavioural responses to sex pheromones are generally highly stereotyped. However, they can be modulated by experience, as male moths previously exposed to female sex pheromone respond with a lower threshold upon further detection, even after long delays. Here, we address the question of the neural mechanisms underlying such long-term modulation. As previous work has shown increased responses to pheromone in central olfactory neurons, we asked whether brief exposure to the pheromone increases input activity from olfactory receptor neurons. Males pre-exposed to sex pheromone exhibited increased peripheral sensitivity to the main pheromone component. Among nine antennal genes targeted as putatively involved in pheromone reception, one encoding a pheromone-binding protein showed significant upregulation upon exposure. In the primary olfactory centre (antennal lobe), the neural compartment processing the main pheromone component was enlarged after a brief pheromone exposure, thus suggesting enduring structural changes. We hypothesise that higher peripheral sensitivity following pre-exposure leads to increased input to the antennal lobe, thus contributing to the structural and functional reorganization underlying a stable change in behaviour. F.J.G. is a former scientific collaborator of Max-Planck-Gesellschaft (MPG; Germany), funded by the European Research Group in Neurosciences between the National Centre for Scientific Research (CNRS; France) and the MPG. C.G. was funded by the 'Programa de movilidad' Ministerio de Ciencia e Innovacion (MICINN), Spain. This work was supported by French National Funding Agency Grants ANR-07-NEURO-037-01 and ANR-09-BLAN-0239-01.