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1.  A Large-Scale Analysis of Odor Coding in the Olfactory Epithelium 
The Journal of Neuroscience  2011;31(25):9179-9191.
Mammals can perceive and discriminate myriad volatile chemicals as having a distinct odor. Odorants are initially detected by odorant receptors (ORs) on olfactory sensory neurons (OSNs) in the nose. In the mouse, each OSN expresses one of ∼1000 different OR genes. Although OSNs and their expressed ORs constitute the fundamental units of sensory input to the brain, a comprehensive understanding of how they encode odor identities is still lacking. To gain a broader and more detailed understanding of odorant recognition and odor coding at this level, we tested the responses of 3000 mouse OSNs to 125 odorants with diverse structures and perceived odors. These studies revealed extraordinary diversity, but also bias, in odorant recognition by the OSN, and thus OR, repertoire. They indicate that most OSNs are narrowly tuned to detect a subset of odorants with related structures and often related odors, but that the repertoire also includes broadly tuned components. Strikingly, the vast majority of odorants activated a unique set of OSNs, usually two or more in combination. The resulting combinatorial codes varied in size among odorants and sometimes contained both narrowly and broadly tuned components. While many OSNs recognized multiple odorants, some appeared specific for a given pheromone or other animal-associated compound, or for one or more odorants with a particular odor quality, raising the possibility that signals derived from some OSNs and ORs might elicit an innate behavior or convey a specific odor quality.
PMCID: PMC3758579  PMID: 21697369
2.  A circuit supporting concentration-invariant odor perception in Drosophila 
Journal of Biology  2009;8(1):9.
Most odors are perceived to have the same quality over a large concentration range, but the neural mechanisms that permit concentration-invariant olfactory perception are unknown. In larvae of the vinegar fly Drosophila melanogaster, odors are sensed by an array of 25 odorant receptors expressed in 21 olfactory sensory neurons (OSNs). We investigated how subsets of larval OSNs with overlapping but distinct response properties cooperate to mediate perception of a given odorant across a range of concentrations.
Using calcium imaging, we found that ethyl butyrate, an ester perceived by humans as fruity, activated three OSNs with response thresholds that varied across three orders of magnitude. Whereas wild-type larvae were strongly attracted by this odor across a 500-fold range of concentration, individuals with only a single functional OSN showed attraction across a narrower concentration range corresponding to the sensitivity of each ethyl butyrate-tuned OSN. To clarify how the information carried by different OSNs is integrated by the olfactory system, we characterized the response properties of local inhibitory interneurons and projection neurons in the antennal lobe. Local interneurons only responded to high ethyl butyrate concentrations upon summed activation of at least two OSNs. Projection neurons showed a reduced response to odors when summed input from two OSNs impinged on the circuit compared to when there was only a single functional OSN.
Our results show that increasing odor concentrations induce progressive activation of concentration-tuned olfactory sensory neurons and concomitant recruitment of inhibitory local interneurons. We propose that the interplay of combinatorial OSN input and local interneuron activation allows animals to remain sensitive to odors across a large range of stimulus intensities.
PMCID: PMC2656214  PMID: 19171076
3.  Modeling Peripheral Olfactory Coding in Drosophila Larvae 
PLoS ONE  2011;6(8):e22996.
The Drosophila larva possesses just 21 unique and identifiable pairs of olfactory sensory neurons (OSNs), enabling investigation of the contribution of individual OSN classes to the peripheral olfactory code. We combined electrophysiological and computational modeling to explore the nature of the peripheral olfactory code in situ. We recorded firing responses of 19/21 OSNs to a panel of 19 odors. This was achieved by creating larvae expressing just one functioning class of odorant receptor, and hence OSN. Odor response profiles of each OSN class were highly specific and unique. However many OSN-odor pairs yielded variable responses, some of which were statistically indistinguishable from background activity. We used these electrophysiological data, incorporating both responses and spontaneous firing activity, to develop a Bayesian decoding model of olfactory processing. The model was able to accurately predict odor identity from raw OSN responses; prediction accuracy ranged from 12%–77% (mean for all odors 45.2%) but was always significantly above chance (5.6%). However, there was no correlation between prediction accuracy for a given odor and the strength of responses of wild-type larvae to the same odor in a behavioral assay. We also used the model to predict the ability of the code to discriminate between pairs of odors. Some of these predictions were supported in a behavioral discrimination (masking) assay but others were not. We conclude that our model of the peripheral code represents basic features of odor detection and discrimination, yielding insights into the information available to higher processing structures in the brain.
PMCID: PMC3153476  PMID: 21857978
4.  Rapid Encoding and Perception of Novel Odors in the Rat 
PLoS Biology  2008;6(4):e82.
To gain insight into which parameters of neural activity are important in shaping the perception of odors, we combined a behavioral measure of odor perception with optical imaging of odor representations at the level of receptor neuron input to the rat olfactory bulb. Instead of the typical test of an animal's ability to discriminate two familiar odorants by exhibiting an operant response, we used a spontaneously expressed response to a novel odorant—exploratory sniffing—as a measure of odor perception. This assay allowed us to measure the speed with which rats perform spontaneous odor discriminations. With this paradigm, rats discriminated and began responding to a novel odorant in as little as 140 ms. This time is comparable to that measured in earlier studies using operant behavioral readouts after extensive training. In a subset of these trials, we simultaneously imaged receptor neuron input to the dorsal olfactory bulb with near-millisecond temporal resolution as the animal sampled and then responded to the novel odorant. The imaging data revealed that the bulk of the discrimination time can be attributed to the peripheral events underlying odorant detection: receptor input arrives at the olfactory bulb 100–150 ms after inhalation begins, leaving only 50–100 ms for central processing and response initiation. In most trials, odor discrimination had occurred even before the initial barrage of receptor neuron firing had ceased and before spatial maps of activity across glomeruli had fully developed. These results suggest a coding strategy in which the earliest-activated glomeruli play a major role in the initial perception of odor quality, and place constraints on coding and processing schemes based on simple changes in spike rate.
Author Summary
Olfactory stimuli elicit temporally complex patterns of activity across groups of receptor neurons as well as across central neurons. It remains unclear which parameters among these complex activity patterns are important in shaping odor perception. To address this issue, we imaged from the olfactory bulb of awake rats as they detected and responded to odorants. We used a spontaneously expressed response to novel odorants—exploratory sniffing—as a behavioral measure of odor perception. This assay allowed us to measure the speed with which rats perform simple odor discriminations by monitoring changes in respiration. Rats discriminated a novel odorant from a learned one in as little as 140 ms. Simultaneously imaging the sensory input to the olfactory bulb carried by receptor neurons revealed that the bulk of the response time is due to the peripheral events underlying odorant detection (inhalation and receptor neuron activation), leaving only 50–100 ms for central processing and response initiation. In most trials, responses to a novel odorant began before the initial barrage of input had ceased and before spatial patterns of input to the bulb had fully developed. These results suggest a coding strategy in which the earliest inputs play a major role in the initial perception of odor quality and place constraints on coding schemes based on simple changes in firing rate.
Imaging the olfactory bulb of awake rats reveals that odor discrimination occurs about 100 ms after sensory input reaches the brain, sharply limiting the role that spike rate and temporal integration can play in coding odor identity.
PMCID: PMC2288628  PMID: 18399719
5.  Perception of Odors Linked to Precise Timing in the Olfactory System 
PLoS Biology  2014;12(12):e1002021.
The temporal dynamics of glomeruli activity can be behaviorally discerned by mice down to 13 milliseconds.
While the timing of neuronal activity in the olfactory bulb (OB) relative to sniffing has been the object of many studies, the behavioral relevance of timing information generated by patterned activation within the bulbar response has not been explored. Here we show, using sniff-triggered, dynamic, 2-D, optogenetic stimulation of mitral/tufted cells, that virtual odors that differ by as little as 13 ms are distinguishable by mice. Further, mice are capable of discriminating a virtual odor movie based on an optically imaged OB odor response versus the same virtual odor devoid of temporal dynamics—independently of the sniff-phase. Together with studies showing the behavioral relevance of graded glomerular responses and the response timing relative to odor sampling, these results imply that the mammalian olfactory system is capable of very high transient information transmission rates.
Author Summary
Olfactory receptor neurons respond to odors in the olfactory epithelium located in the nasal cavity in mammals. Each olfactory receptor neuron expresses only one olfactory receptor, out of several hundred encoded in the mammalian genome. Olfactory receptor neurons expressing the same olfactory receptor are scattered throughout the olfactory epithelium; however, their axons converge in one of thousands of glomeruli in the olfactory bulb. The glomeruli are the first neural relay station in the olfactory system, where olfactory receptor neurons transmit olfactory information to mitral cells. It is well established that different odors evoke different spatial patterns across the glomeruli. It is believed that the more similar the patterns, the more similar the evoked odor perceptions. Glomeruli also are activated in odor-specific sequences in time. These dynamics could increase the amount of information about odors by immense amounts. We used transgenic mice, whose mitral cells were made responsive to light, and asked how well they could discriminate the temporal dynamics of simple spatial patterns of light presented to the olfactory bulb after each sniff. Mice could detect the presence of temporal dynamics down to 13 ms, which provides ample resolution for them to be able to detect the dynamics in response to actual odors. Mice could also discern whether virtual odors, based on actual olfactory bulb activity, were dynamic or static and did so without reference to exact sniff-time. We conclude that both the spatial glomerular activity patterns and the temporal dynamics thereof are used in the mammalian olfactory system to encode odors.
PMCID: PMC4267717  PMID: 25514030
6.  Plant odorants interfere with detection of sex pheromone signals by male Heliothis virescens 
In many insects, mate finding relies on female-released sex pheromones, which have to be deciphered by the male olfactory system within an odorous background of plant volatiles present in the environment of a calling female. With respect to pheromone-mediated mate localization, plant odorants may be neutral, favorable, or disturbing. Here we examined the impact of plant odorants on detection and coding of the major sex pheromone component, (Z)-11-hexadecenal (Z11-16:Ald) in the noctuid moth Heliothis virescens. By in vivo imaging the activity in the male antennal lobe (AL), we monitored the interference at the level of olfactory sensory neurons (OSN) to illuminate mixture interactions. The results show that stimulating the male antenna with Z11-16:Ald and distinct plant-related odorants simultaneously suppressed pheromone-evoked activity in the region of the macroglomerular complex (MGC), where Z11-16:Ald-specific OSNs terminate. Based on our previous findings that antennal detection of Z11-16:Ald involves an interplay of the pheromone binding protein (PBP) HvirPBP2 and the pheromone receptor (PR) HR13, we asked if the plant odorants may interfere with any of the elements involved in pheromone detection. Using a competitive fluorescence binding assay, we found that the plant odorants neither bind to HvirPBP2 nor affect the binding of Z11-16:Ald to the protein. However, imaging experiments analyzing a cell line that expressed the receptor HR13 revealed that plant odorants significantly inhibited the Z11-16:Ald-evoked calcium responses. Together the results indicate that plant odorants can interfere with the signaling process of the major sex pheromone component at the receptor level. Consequently, it can be assumed that plant odorants in the environment may reduce the firing activity of pheromone-specific OSNs in H. virescens and thus affect mate localization.
PMCID: PMC3465774  PMID: 23060749
pheromone detection; antennal lobe; pheromone receptor; pheromone binding protein; olfaction
7.  Friends and Foes from an Ant Brain's Point of View – Neuronal Correlates of Colony Odors in a Social Insect 
PLoS ONE  2011;6(6):e21383.
Successful cooperation depends on reliable identification of friends and foes. Social insects discriminate colony members (nestmates/friends) from foreign workers (non-nestmates/foes) by colony-specific, multi-component colony odors. Traditionally, complex processing in the brain has been regarded as crucial for colony recognition. Odor information is represented as spatial patterns of activity and processed in the primary olfactory neuropile, the antennal lobe (AL) of insects, which is analogous to the vertebrate olfactory bulb. Correlative evidence indicates that the spatial activity patterns reflect odor-quality, i.e., how an odor is perceived. For colony odors, alternatively, a sensory filter in the peripheral nervous system was suggested, causing specific anosmia to nestmate colony odors. Here, we investigate neuronal correlates of colony odors in the brain of a social insect to directly test whether they are anosmic to nestmate colony odors and whether spatial activity patterns in the AL can predict how odor qualities like “friend” and “foe” are attributed to colony odors.
Methodology/Principal Findings
Using ant dummies that mimic natural conditions, we presented colony odors and investigated their neuronal representation in the ant Camponotus floridanus. Nestmate and non-nestmate colony odors elicited neuronal activity: In the periphery, we recorded sensory responses of olfactory receptor neurons (electroantennography), and in the brain, we measured colony odor specific spatial activity patterns in the AL (calcium imaging). Surprisingly, upon repeated stimulation with the same colony odor, spatial activity patterns were variable, and as variable as activity patterns elicited by different colony odors.
Ants are not anosmic to nestmate colony odors. However, spatial activity patterns in the AL alone do not provide sufficient information for colony odor discrimination and this finding challenges the current notion of how odor quality is coded. Our result illustrates the enormous challenge for the nervous system to classify multi-component odors and indicates that other neuronal parameters, e.g., precise timing of neuronal activity, are likely necessary for attribution of odor quality to multi-component odors.
PMCID: PMC3121771  PMID: 21731724
8.  Excitatory Local Interneurons Enhance Tuning of Sensory Information 
PLoS Computational Biology  2012;8(7):e1002563.
Neurons in the insect antennal lobe represent odors as spatiotemporal patterns of activity that unfold over multiple time scales. As these patterns unspool they decrease the overlap between odor representations and thereby increase the ability of the olfactory system to discriminate odors. Using a realistic model of the insect antennal lobe we examined two competing components of this process –lateral excitation from local excitatory interneurons, and slow inhibition from local inhibitory interneurons. We found that lateral excitation amplified differences between representations of similar odors by recruiting projection neurons that did not receive direct input from olfactory receptors. However, this increased sensitivity also amplified noisy variations in input and compromised the ability of the system to respond reliably to multiple presentations of the same odor. Slow inhibition curtailed the spread of projection neuron activity and increased response reliability. These competing influences must be finely balanced in order to decorrelate odor representations.
Author Summary
The antennal lobe of insects and the olfactory bulb of vertebrates represent the first centers of the olfactory system where information about odor properties can be reorganized and optimized for further processing. Complex excitatory and inhibitory synaptic interactions within the antennal lobe and the olfactory bulb alter the responses of the principal neurons throughout the duration of the odor stimulation. These dynamic changes progressively increase the difference between firing patterns evoked by structurally similar odors, potentially helping the animal distinguish one odor from another. However, this process, called odor decorrelation, appears to oppose another important goal of olfactory processing, to minimize the inevitable noisy variations in representations of the same odor encountered under different environmental conditions; such variations could potentially lead to misclassification. It remains an interesting mystery how olfactory circuitry can solve these two seemingly contradictory goals as they process olfactory stimuli: first, separating different but chemically similar odors (sensitivity, capacity); and second, identifying representations of the same odor in a noisy environment (reliability). Our results suggest a balance between inhibitory and excitatory connections mediated by local antennal lobe interneurons enhances the decorrelation of similar odors while keeping the representation robust in the presence of noise.
PMCID: PMC3395596  PMID: 22807661
9.  Single Sensillum Recordings in the Insects Drosophila melanogaster and Anopheles gambiae 
The sense of smell is essential for insects to find foods, mates, predators, and oviposition sites3. Insect olfactory sensory neurons (OSNs) are enclosed in sensory hairs called sensilla, which cover the surface of olfactory organs. The surface of each sensillum is covered with tiny pores, through which odorants pass and dissolve in a fluid called sensillum lymph, which bathes the sensory dendrites of the OSNs housed in a given sensillum. The OSN dendrites express odorant receptor (OR) proteins, which in insects function as odor-gated ion channels4, 5. The interaction of odorants with ORs either increases or decreases the basal firing rate of the OSN. This neuronal activity in the form of action potentials embodies the first representation of the quality, intensity, and temporal characteristics of the odorant6, 7.
Given the easy access to these sensory hairs, it is possible to perform extracellular recordings from single OSNs by introducing a recording electrode into the sensillum lymph, while the reference electrode is placed in the lymph of the eye or body of the insect. In Drosophila, sensilla house between one and four OSNs, but each OSN typically displays a characteristic spike amplitude. Spike sorting techniques make it possible to assign spiking responses to individual OSNs. This single sensillum recording (SSR) technique monitors the difference in potential between the sensillum lymph and the reference electrode as electrical spikes that are generated by the receptor activity on OSNs1, 2, 8. Changes in the number of spikes in response to the odorant represent the cellular basis of odor coding in insects. Here, we describe the preparation method currently used in our lab to perform SSR on Drosophila melanogaster and Anopheles gambiae, and show representative traces induced by the odorants in a sensillum-specific manner.
PMCID: PMC2830253  PMID: 20164822
10.  Heterogeneous Sensory Innervation and Extensive Intrabulbar Connections of Olfactory Necklace Glomeruli 
PLoS ONE  2009;4(2):e4657.
The mammalian nose employs several olfactory subsystems to recognize and transduce diverse chemosensory stimuli. These subsystems differ in their anatomical position within the nasal cavity, their targets in the olfactory forebrain, and the transduction mechanisms they employ. Here we report that they can also differ in the strategies they use for stimulus coding. Necklace glomeruli are the sole main olfactory bulb (MOB) targets of an olfactory sensory neuron (OSN) subpopulation distinguished by its expression of the receptor guanylyl cyclase GC-D and the phosphodiesterase PDE2, and by its chemosensitivity to the natriuretic peptides uroguanylin and guanylin and the gas CO2. In stark contrast to the homogeneous sensory innervation of canonical MOB glomeruli from OSNs expressing the same odorant receptor (OR), we find that each necklace glomerulus of the mouse receives heterogeneous innervation from at least two distinct sensory neuron populations: one expressing GC-D and PDE2, the other expressing olfactory marker protein. In the main olfactory system it is thought that odor identity is encoded by a combinatorial strategy and represented in the MOB by a pattern of glomerular activation. This combinatorial coding scheme requires functionally homogeneous sensory inputs to individual glomeruli by OSNs expressing the same OR and displaying uniform stimulus selectivity; thus, activity in each glomerulus reflects the stimulation of a single OSN type. The heterogeneous sensory innervation of individual necklace glomeruli by multiple, functionally distinct, OSN subtypes precludes a similar combinatorial coding strategy in this olfactory subsystem.
PMCID: PMC2645502  PMID: 19247478
11.  Complex and non-redundant signals from individual odor receptors that underlie chemotaxis behavior in Drosophila melanogaster larvae 
Biology Open  2014;3(10):947-957.
The rules by which odor receptors encode odors and allow behavior are still largely unexplored. Although large data sets of electrophysiological responses of receptors to odors have been generated, few hypotheses have been tested with behavioral assays. We use a data set on odor responses of Drosophila larval odor receptors coupled with chemotaxis behavioral assays to examine rules of odor coding. Using mutants of odor receptors, we have found that odor receptors with similar electrophysiological responses to odors across concentrations play non-redundant roles in odor coding at specific odor concentrations. We have also found that high affinity receptors for odors determine behavioral response thresholds, but the rules for determining peak behavioral responses are more complex. While receptor mutants typically show loss of attraction to odors, some receptor mutants result in increased attraction at specific odor concentrations. The odor receptor mutants were rescued using transgenic expression of odor receptors, validating assignment of phenotypes to the alleles. Vapor pressures alone cannot fully explain behavior in our assay. Finally, some odors that did not elicit strong electrophysiological responses are associated with behavioral phenotypes upon examination of odor receptor mutants. This result is consistent with the role of sensory neurons in lateral inhibition via local interneurons in the antennal lobe. Taken together, our results suggest a complexity of odor coding rules even in a simple olfactory sensory system.
PMCID: PMC4197443  PMID: 25238759
Odor receptors; Olfaction; Drosophila; Or42a; Or42b
12.  Intensity invariant dynamics and odor-specific latencies in olfactory receptor neuron response 
Odors elicit spatio-temporal patterns of activity in the brain. Spatial patterns arise from the specificity of the interaction between odorants and odorant receptors expressed in different olfactory receptor neurons (ORNs). But the origin of temporal patterns of activity and their role in odor coding remain unclear. We investigate how physiological aspects of ORN response and physical aspects of odor stimuli give rise to diverse responses in Drosophila ORNs. We show that odor stimuli have intrinsic dynamics that depend on odor type and strongly affect ORN response. Using linear-nonlinear modeling to remove the contribution of the stimulus dynamics from the ORN dynamics we study the physiological properties of the response to different odorants and concentrations. For several odorants and receptor types the ORN response dynamics normalized by the peak response are independent of stimulus intensity for a large portion of the neuron’s dynamic range. Adaptation to a background odor changes the gain and dynamic range of the response but does not affect normalized response dynamics. Stimulating ORNs with various odorants reveals significant odor-dependent delays in the ORN response functions. These differences however can be dominated by differences in stimulus dynamics. In one case the response of one ORN to two odorants is predicted solely from measurements of the odor signals. Within a large portion of their dynamic range ORNs can capture information about stimulus dynamics independently from intensity while introducing odor-dependent delays. How insects might use odor-specific stimulus dynamics and ORN dynamics in discrimination and navigation tasks remains an open question.
PMCID: PMC3678969  PMID: 23575828
13.  Segregation of Odor Identity and Intensity during Odor Discrimination in Drosophila Mushroom Body 
PLoS Biology  2007;5(10):e264.
Molecular and cellular studies have begun to unravel a neurobiological basis of olfactory processing, which appears conserved among vertebrate and invertebrate species. Studies have shown clearly that experience-dependent coding of odor identity occurs in “associative” olfactory centers (the piriform cortex in mammals and the mushroom body [MB] in insects). What remains unclear, however, is whether associative centers also mediate innate (spontaneous) odor discrimination and how ongoing experience modifies odor discrimination. Here we show in naïve flies that Gαq-mediated signaling in MB modulates spontaneous discrimination of odor identity but not odor intensity (concentration). In contrast, experience-dependent modification (conditioning) of both odor identity and intensity occurs in MB exclusively via Gαs-mediated signaling. Our data suggest that spontaneous responses to odor identity and odor intensity discrimination are segregated at the MB level, and neural activity from MB further modulates olfactory processing by experience-independent Gαq-dependent encoding of odor identity and by experience-induced Gαs-dependent encoding of odor intensity and identity.
Author Summary
Considerable progress has been made in understanding how olfaction works as the receptor proteins, sensory neurons, and brain circuitry responsible have become increasingly well-characterized. However, olfactory processing in higher brain centers, where neuronal activity is assembled into the perception of odor quality, is poorly understood. Here, we have addressed how the mushroom body (MB)—a secondary olfactory center—is involved in olfactory discrimination. We manipulated the MB by ablation, disruption of synaptic transmission, and interruption of key cellular signaling molecules in naïve flies and in flies trained to discriminate odors. We first show that although both odor identity and intensity are encoded in the MB, only the former requires Gαq-dependent signaling and is necessary for naïve flies to spontaneously discriminate different odors. We then show that training flies to alter their olfactory response requires Gαs-mediated signaling in MB for both odor intensity and odor identity. We have thus identified (i) segregation of odor identity and odor intensity at the MB level in naïve flies and (ii) different G-protein-dependent signaling pathways for spontaneous versus experience-dependent olfactory discrimination.
Experience-dependent modification of odor identity and intensity occurs in the mushroom body (MB) of flies exclusively via Gαs-mediated signaling. In contrast, Gαq-mediated signaling in MB modulates spontaneous discrimination of odor identity but not odor intensity.
PMCID: PMC1994992  PMID: 17914903
14.  Spatiotemporal Alterations in Primary Odorant Representations in Olfactory Marker Protein Knockout Mice 
PLoS ONE  2013;8(4):e61431.
Olfactory marker protein (OMP) is highly and selectively expressed in primary olfactory sensory neurons (OSNs) across species, but its physiological function remains unclear. Previous studies in the olfactory epithelium suggest that it accelerates the neural response to odorants and may modulate the odorant-selectivity of OSNs. Here we used a line of gene-targeted mice that express the fluorescent exocytosis indicator synaptopHluorin in place of OMP to compare spatiotemporal patterns of odorant-evoked neurotransmitter release from OSNs in adult mice that were heterozygous for OMP or OMP-null. We found that these patterns, which constitute the primary neural representation of each odorant, developed more slowly during the odorant presentation in OMP knockout mice but eventually reached the same magnitude as in heterozygous mice. In the olfactory bulb, each glomerulus receives synaptic input from a subpopulation of OSNs that all express the same odor receptor and thus typically respond to a specific subset of odorants. We observed that in OMP knockout mice, OSNs innervating a given glomerulus typically responded to a broader range of odorants than in OMP heterozygous mice and thus each odorant evoked synaptic input to a larger number of glomeruli. In an olfactory habituation task, OMP knockout mice behaved differently than wild-type mice, exhibiting a delay in their onset to investigate an odor stimulus during its first presentation and less habituation to that stimulus over repeated presentations. These results suggest that the actions of OMP in olfactory transduction carry through to the primary sensory representations of olfactory stimuli in adult mice in vivo.
PMCID: PMC3632605  PMID: 23630588
15.  Imaging a Population Code for Odor Identity in the Drosophila Mushroom Body 
The Journal of Neuroscience  2013;33(25):10568-10581.
The brain represents sensory information in the coordinated activity of neuronal ensembles. Although the microcircuits underlying olfactory processing are well characterized in Drosophila, no studies to date have examined the encoding of odor identity by populations of neurons and related it to the odor specificity of olfactory behavior. Here we used two-photon Ca2+ imaging to record odor-evoked responses from >100 neurons simultaneously in the Drosophila mushroom body (MB). For the first time, we demonstrate quantitatively that MB population responses contain substantial information on odor identity. Using a series of increasingly similar odor blends, we identified conditions in which odor discrimination is difficult behaviorally. We found that MB ensemble responses accounted well for olfactory acuity in this task. Kenyon cell ensembles with as few as 25 cells were sufficient to match behavioral discrimination accuracy. Using a generalization task, we demonstrated that the MB population code could predict the flies' responses to novel odors. The degree to which flies generalized a learned aversive association to unfamiliar test odors depended upon the relative similarity between the odors' evoked MB activity patterns. Discrimination and generalization place different demands on the animal, yet the flies' choices in these tasks were reliably predicted based on the amount of overlap between MB activity patterns. Therefore, these different behaviors can be understood in the context of a single physiological framework.
PMCID: PMC3685844  PMID: 23785169
16.  Octopamine modulates activity of neural networks in the honey bee antennal lobe 
Neuronal plasticity allows an animal to respond to environmental changes by modulating its response to stimuli. In the honey bee (Apis mellifera), the biogenic amine octopamine plays a crucial role in appetitive odor learning, but little is known about how octopamine affects the brain. We investigated its effect in the antennal lobe, the first olfactory center in the brain, using calcium imaging to record background activity and odor responses before and after octopamine application. We show that octopamine increases background activity in olfactory output neurons, while reducing average calcium levels. Odor responses were modulated both upwards and downwards, with more odor response increases in glomeruli with negative or weak odor responses. Importantly, the octopamine effect was variable across glomeruli, odorants, odorant concentrations and animals, suggesting that the octopaminergic network is shaped by plasticity depending on an individual animal’s history and possibly other factors. Using RNA interference, we show that the octopamine receptor AmOA1 (homolog of the Drosophila OAMB receptor) is involved in the octopamine effect. We propose a network model in which octopamine receptors are plastic in their density and located on a subpopulation of inhibitory neurons in a disinhibitory pathway. This would improve odor-coding of behaviorally relevant, previously experienced odors.
Electronic supplementary material
The online version of this article (doi:10.1007/s00359-013-0805-y) contains supplementary material, which is available to authorized users.
PMCID: PMC3825135  PMID: 23681219
Olfaction; Insects; Octopamine; Plasticity; Calcium imaging
17.  Associative Conditioning Tunes Transient Dynamics of Early Olfactory Processing 
Odors evoke complex spatiotemporal responses in the insect antennal lobe (AL) and mammalian olfactory bulb. However, the behavioral relevance of spatiotemporal coding remains unclear. In the present work we combined behavioral analyses with calcium imaging of odor induced activity in the honey bee AL to evaluate the relevance of this temporal dimension in the olfactory code. We used a new way for evaluation of odor similarity of binary mixtures in behavioral studies, which involved testing if a match of odor sampling time is necessary between training and testing conditions for odor recognition during associative learning. Using graded changes in the similarity of the mixture ratios, we found high correlations between the behavioral generalization across those mixtures and a gradient of activation in AL output. Furthermore, short odor stimuli of 500 ms or less affected how well odors were matched with a memory template, and this time corresponded to a shift from a sampling-time-dependent to a sampling-time-independent memory. Accordingly, 375 ms corresponded to the time required for spatiotemporal AL activity patterns to reach maximal separation according to imaging studies. Finally, we compared spatiotemporal representations of binary mixtures in trained and untrained animals. AL activity was modified by conditioning to improve separation of odor representations. These data suggest that one role of reinforcement is to “tune” the AL such that relevant odors become more discriminable.
PMCID: PMC2756734  PMID: 19692594
olfaction; synchrony; transients; spatiotemporal coding; plasticity; calcium imaging; discrimination
18.  Functional recovery of odor representations in regenerated sensory inputs to the olfactory bulb 
The olfactory system has a unique capacity for recovery from peripheral damage. After injury to the olfactory epithelium (OE), olfactory sensory neurons (OSNs) regenerate and re-converge on target glomeruli of the olfactory bulb (OB). Thus far, this process has been described anatomically for only a few defined populations of OSNs. Here we characterize this regeneration at a functional level by assessing how odor representations carried by OSN inputs to the OB recover after massive loss and regeneration of the sensory neuron population. We used chronic imaging of mice expressing synaptopHluorin in OSNs to monitor odor representations in the dorsal OB before lesion by the olfactotoxin methyl bromide and after a 12 week recovery period. Methyl bromide eliminated functional inputs to the OB, and these inputs recovered to near-normal levels of response magnitude within 12 weeks. We also found that the functional topography of odor representations recovered after lesion, with odorants evoking OSN input to glomerular foci within the same functional domains as before lesion. At a finer spatial scale, however, we found evidence for mistargeting of regenerated OSN axons onto OB targets, with odorants evoking synaptopHluorin signals in small foci that did not conform to a typical glomerular structure but whose distribution was nonetheless odorant-specific. These results indicate that OSNs have a robust ability to reestablish functional inputs to the OB and that the mechanisms underlying the topography of bulbar reinnervation during development persist in the adult and allow primary sensory representations to be largely restored after massive sensory neuron loss.
PMCID: PMC3882662  PMID: 24431990
olfactory bulb; regeneration; sensory neurons; synaptopHluorin; axon targeting
19.  Long term functional plasticity of sensory inputs mediated by olfactory learning 
eLife  2014;3:e02109.
Sensory inputs are remarkably organized along all sensory pathways. While sensory representations are known to undergo plasticity at the higher levels of sensory pathways following peripheral lesions or sensory experience, less is known about the functional plasticity of peripheral inputs induced by learning. We addressed this question in the adult mouse olfactory system by combining odor discrimination studies with functional imaging of sensory input activity in awake mice. Here we show that associative learning, but not passive odor exposure, potentiates the strength of sensory inputs up to several weeks after the end of training. We conclude that experience-dependent plasticity can occur in the periphery of adult mouse olfactory system, which should improve odor detection and contribute towards accurate and fast odor discriminations.
eLife digest
The mammalian brain is not static, but instead retains a significant degree of plasticity throughout an animal’s life. It is this plasticity that enables adults to learn new things, adjust to new environments and, to some degree, regain functions they have lost as a result of brain damage.
However, information about the environment must first be detected and encoded by the senses. Odors, for example, activate specific receptors in the nose, and these in turn project to structures called glomeruli in a region of the brain known as the olfactory bulb. Each odor activates a unique combination of glomeruli, and the information contained within this ‘odor fingerprint’ is relayed via olfactory bulb neurons to the olfactory cortex.
Now, Abraham et al. have revealed that the earliest stages of odor processing also show plasticity in adult animals. Two groups of mice were exposed to the same two odors: however, the first group was trained to discriminate between the odors to obtain a reward, whereas the second group was passively exposed to them. When both groups of mice were subsequently re-exposed to the odors, the trained group activated more glomeruli, more strongly, than a control group that had never encountered the odors before. By contrast, the responses of mice in the passively exposed group did not differ from those of a control group.
Given that the response of glomeruli correlates with the ability of mice to discriminate between odors, these results suggest that trained animals would now be able to discriminate between the odors more easily than other mice. In other words, sensory plasticity ensures that stimuli that have been associatively learned with or without reward will be easier to detect should they be encountered again in the future.
PMCID: PMC3953949  PMID: 24642413
sensory perception; imaging; behavior; mouse
20.  Odorant-Evoked Nitric Oxide Signals in the Antennal Lobe of Manduca sexta 
The gaseous signaling molecule nitric oxide (NO) can affect the activities of neurons and neural networks in many different systems. The strong expression of NO synthase (NOS) in the primary synaptic neuropil (the antennal lobe in insects and the olfactory bulb in vertebrates) of the olfactory system of most organisms, and the unique spheroidal geometry of olfactory glomeruli in those neuropils, have led to suggestions that NO signaling is important for processing olfactory information. No direct evidence exists, however, that NO signals are produced in olfactory glomeruli. We investigated the production of NO in the antennal lobe of the moth, Manduca sexta, by using immunocytochemistry and real-time optical imaging with a NO-sensitive fluorescent marker, diaminofluorescein diacetate. We confirmed that NOS was expressed in the axons of olfactory receptor neurons projecting to all glomeruli. Soluble guanylyl cyclase, the best characterized target of NO, was found in a subset of postsynaptic antennal lobe neurons that included projection neurons, a small number of GABA-immunoreactive neurons, and a serotonin-immunoreactive neuron. We found that odorant stimulation evoked NO signals that were reproducible and spatially focused. Different odorants evoked spatially distinct patterns of NO production. Increased concentrations of pheromone and plant odorants caused increases in peak signal intensity. Increased concentrations of plant odorants also evoked a dramatic increase in signal area. The results of these experiments show clearly that odorant stimulation can evoke NO production in the olfactory system. The NO signals produced are likely to play an important role in processing olfactory information.
PMCID: PMC1794326  PMID: 15240798
diaminofluorescein; nitric oxide synthase; moth; olfactory; optical imaging; soluble guanylyl cyclase
21.  Temporal response dynamics of Drosophila olfactory sensory neurons depends on receptor type and response polarity 
Insect olfactory sensory neurons (OSN) express a diverse array of receptors from different protein families, i.e. ionotropic receptors (IR), gustatory receptors (GR) and odorant receptors (OR). It is well known that insects are exposed to a plethora of odor molecules that vary widely in both space and time under turbulent natural conditions. In addition to divergent ligand specificities, these different receptors might also provide an increased range of temporal dynamics and sensitivities for the olfactory system. To test this, we challenged different Drosophila OSNs with both varying stimulus durations (10–2000 ms), and repeated stimulus pulses of key ligands at various frequencies (1–10 Hz). Our results show that OR-expressing OSNs responded faster and with higher sensitivity to short stimulations as compared to IR- and Gr21a-expressing OSNs. In addition, OR-expressing OSNs could respond to repeated stimulations of excitatory ligands up to 5 Hz, while IR-expressing OSNs required ~5x longer stimulations and/or higher concentrations to respond to similar stimulus durations and frequencies. Nevertheless, IR-expressing OSNs did not exhibit adaptation to longer stimulations, unlike OR- and Gr21a-OSNs. Both OR- and IR-expressing OSNs were also unable to resolve repeated pulses of inhibitory ligands as fast as excitatory ligands. These differences were independent of the peri-receptor environment in which the receptors were expressed and suggest that the receptor expressed by a given OSN affects both its sensitivity and its response to transient, intermittent chemical stimuli. OR-expressing OSNs are better at resolving low dose, intermittent stimuli, while IR-expressing OSNs respond more accurately to long-lasting odor pulses. This diversity increases the capacity of the insect olfactory system to respond to the diverse spatiotemporal signals in the natural environment.
PMCID: PMC3499765  PMID: 23162431
odorant receptors; ionotropic receptors; pulse resolution; single sensillum recording
22.  An RNA-Seq Screen of the Drosophila Antenna Identifies a Transporter Necessary for Ammonia Detection 
PLoS Genetics  2014;10(11):e1004810.
Many insect vectors of disease detect their hosts through olfactory cues, and thus it is of great interest to understand better how odors are encoded. However, little is known about the molecular underpinnings that support the unique function of coeloconic sensilla, an ancient and conserved class of sensilla that detect amines and acids, including components of human odor that are cues for many insect vectors. Here, we generate antennal transcriptome databases both for wild type Drosophila and for a mutant that lacks coeloconic sensilla. We use these resources to identify genes whose expression is highly enriched in coeloconic sensilla, including many genes not previously implicated in olfaction. Among them, we identify an ammonium transporter gene that is essential for ammonia responses in a class of coeloconic olfactory receptor neurons (ORNs), but is not required for responses to other odorants. Surprisingly, the transporter is not expressed in ORNs, but rather in neighboring auxiliary cells. Thus, our data reveal an unexpected non-cell autonomous role for a component that is essential to the olfactory response to ammonia. The defective response observed in a Drosophila mutant of this gene is rescued by its Anopheles ortholog, and orthologs are found in virtually all insect species examined, suggesting that its role is conserved. Taken together, our results provide a quantitative analysis of gene expression in the primary olfactory organ of Drosophila, identify molecular components of an ancient class of olfactory sensilla, and reveal that auxiliary cells, and not simply ORNs, play an essential role in the coding of an odor that is a critical host cue for many insect vectors of human disease.
Author Summary
Olfaction underlies the attraction of insect pests and vectors of disease to their plant and human hosts. In the genetic model insect Drosophila, the neuronal basis of odor coding has been extensively analyzed in the antenna, its major olfactory organ, but the molecular basis of odor coding has not. Additionally, there has been little analysis of any olfactory cells other than neurons. We have undertaken a comprehensive and quantitative analysis of gene expression in the Drosophila antenna. This analysis revealed a surprisingly broad dynamic range of odor receptor and odor binding protein expression, and unexpected expression of taste receptor genes. Further analysis identified 250 genes that are expressed at reduced levels in a mutant lacking an evolutionarily ancient class of sensilla, antennal hairs housing neurons that respond to human odors. One of these genes, a transporter, is expressed in non-neuronal cells but is essential to the response of a neuron to ammonia, a key cue for insect vectors of disease. A mutation in this transporter can be rescued by its mosquito homolog. While many studies of sensory coding consider the neural circuit in isolation, our analysis reveals an essential role for an auxiliary cell.
PMCID: PMC4238959  PMID: 25412082
23.  Decorrelation of Odor Representations via Spike Timing-Dependent Plasticity 
The non-topographical representation of odor quality space differentiates early olfactory representations from those in other sensory systems. Decorrelation among olfactory representations with respect to physical odorant similarities has been proposed to rely upon local feed-forward inhibitory circuits in the glomerular layer that decorrelate odor representations with respect to the intrinsically high-dimensional space of ligand–receptor potency relationships. A second stage of decorrelation is likely to be mediated by the circuitry of the olfactory bulb external plexiform layer. Computations in this layer, or in the analogous interneuronal network of the insect antennal lobe, are dependent on fast network oscillations that regulate the timing of mitral cell and projection neuron (MC/PN) action potentials; this suggests a largely spike timing-dependent metric for representing odor information, here proposed to be a precedence code. We first illustrate how the rate coding metric of the glomerular layer can be transformed into a spike precedence code in MC/PNs. We then show how this mechanism of representation, combined with spike timing-dependent plasticity at MC/PN output synapses, can progressively decorrelate high-dimensional, non-topographical odor representations in third-layer olfactory neurons. Reducing MC/PN oscillations abolishes the spike precedence code and blocks this progressive decorrelation, demonstrating the learning network's selectivity for these sparsely synchronized MC/PN spikes even in the presence of temporally disorganized background activity. Finally, we apply this model to odor representations derived from calcium imaging in the honeybee antennal lobe, and show how odor learning progressively decorrelates odor representations, and how the abolition of PN oscillations impairs odor discrimination.
PMCID: PMC3016707  PMID: 21228906
olfaction; gamma oscillations; sparse synchronization; STDP; olfactory bulb; antennal lobe; odor learning; conditioning
24.  Mice with a “Monoclonal” Nose: Perturbations in an Olfactory Map Impair Odor Discrimination 
Neuron  2008;60(6):1068-1081.
The recognition of odors is accomplished in the sensory epithelium where individual olfactory neurons express only one of 1,300 odorant receptor genes. Neurons expressing a given receptor project to two spatially invariant glomeruli in the olfactory bulb such that each odor elicits a distinct and sparse pattern of glomerular activity. We have altered the neural representation of odors in the brain by generating a mouse with a “monoclonal nose” in which greater than 95% of the sensory neurons express a single odorant receptor, M71. As a consequence, the frequency of sensory neurons expressing endogenous receptor genes is reduced twenty-fold. We observe that these mice can smell but odor discrimination and performance in associative olfactory learning tasks are impaired. However, these mice cannot detect the M71 ligand acetophenone despite the observation that virtually all sensory neurons and glomeruli are activated by this odor. The M71 transgenic mice readily detect other odors in the presence of acetophenone. These observations have implications for how receptor activation in the periphery is represented in the brain and how these representations encode odors.
PMCID: PMC2732586  PMID: 19109912
25.  Axon fasciculation in the developing olfactory nerve 
Neural Development  2010;5:20.
Olfactory sensory neuron (OSN) axons exit the olfactory epithelium (OE) and extend toward the olfactory bulb (OB) where they coalesce into glomeruli. Each OSN expresses only 1 of approximately 1,200 odor receptors (ORs). OSNs expressing the same OR are distributed in restricted zones of the OE. However, within a zone, the OSNs expressing a specific OR are not contiguous - distribution appears stochastic. Upon reaching the OB the OSN axons expressing the same OR reproducibly coalesce into two to three glomeruli. While ORs appear necessary for appropriate convergence of axons, a variety of adhesion associated molecules and activity-dependent mechanisms are also implicated. Recent data suggest pre-target OSN axon sorting may influence glomerular convergence. Here, using regional and OR-specific markers, we addressed the spatio-temporal properties associated with the onset of homotypic fasciculation in embryonic mice and assessed the degree to which subpopulations of axons remain segregated as they extend toward the nascent OB. We show that immediately upon crossing the basal lamina, axons uniformly turn sharply, usually at an approximately 90° angle toward the OB. Molecularly defined subpopulations of axons show evidence of spatial segregation within the nascent nerve by embryonic day 12, within 48 hours of the first OSN axons crossing the basal lamina, but at least 72 hours before synapse formation in the developing OB. Homotypic fasciculation of OSN axons expressing the same OR appears to be a hierarchical process. While regional segregation occurs in the mesenchyme, the final convergence of OR-specific subpopulations does not occur until the axons reach the inner nerve layer of the OB.
PMCID: PMC2936880  PMID: 20723208

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