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Dense Representation of Natural Odorants in the Mouse Olfactory Bulb

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Dense Representation of Natural Odorants in the Mouse Olfactory Bulb BRIEF COMMUNICATIONS Dense representation of Online Methods), leading to a reduced number of activated glomeruli (n = 6 odorant-mouse pairs, paired t test, P < 0.005; Fig. 1e). natural odorants in the mouse We then applied 40 different natural odorants using the olfactom- eter to minimize the animal’s stress and to have a better temporal olfactory bulb control of the odorant application. In all of the mice that we tested (n = 8), every odorant evoked a specific dense pattern of glomerular Roberto Vincis1,2, Olivier Gschwend1–3, Khaleel Bhaukaurally1–3, activity (Fig. 2a and Supplementary Fig. 1). For each odorant, we Jonathan Beroud1,2 & Alan Carleton1,2 analyzed the image sequence (Online Methods and Supplementary Fig. 2) and quantified the number of activated glomeruli (Fig. 2b In mammals, odorant molecules are thought to activate and Supplementary Fig. 3). We found that the number of activated only a few glomeruli, leading to the hypothesis that odor glomeruli for each stimulus ranged between 10 and 40 glomeruli representation in the olfactory bulb is sparse. However, the (Fig. 2b). For the same set of 30 natural stimuli, the total number of studies supporting this model used anesthetized animals or activated glomeruli per olfactory bulb was 443 ± 15 glomeruli (n = 5 monomolecular odorants at limited concentration ranges. mice; Fig. 2c,d). By merging the glomeruli activated by several odor- Using optical imaging and two-photon microscopy, we found ants (Online Methods), we obtained a map composed of glomeruli that natural odorants at their native concentrations could elicit with a unique identity showing that the natural odorants that we dense representations in the olfactory bulb. Both anesthesia used activated a large portion of the dorsal olfactory bulb (127 ± 3 and odorant concentration were found to modulate the glomeruli; Fig. 2c,d). representation density of natural odorants. We then addressed the issue of the fraction of the total number of glomeruli activated by the odorants. Using two-photon imaging In the olfactory bulb, odorant molecules evoke complex spatio- temporal patterns of activated glomeruli1–10 that substantially vary in density with stimulus concentration1,6,7,10,11. To better under- a Olfactometer application b stand how odorants are normally coded in the glomeruli array, it Direct application Imaging device is important to use concentrations that are behaviorally relevant. Head fixation system Odor delivery Mixed odorants from natural products come, by definition, in system Light fibers behaviorally relevant concentrations and ratios. Such complex odorants activate only a few glomeruli12, providing evidence for a © 2012 Nature America, Inc. All rights reserved. America, Inc. © 2012 Nature 12,13 Aspiration general theory of sparse glomerular coding . However, the studies c supporting the model of sparse coding were performed on anesthe- P tized animals or used monomolecular odorants in a limited range Olfactometer Direct 1.5 1.5 ML npg of concentrations. Using intrinsic optical signal imaging, we investigated how natural A –4 –4 odorants are represented in awake mice (Fig. 1a,b). We presented the ∆R/R stimuli either directly to the mouse snout (Fig. 1b) or using an olfacto- (‰) meter (Fig. 1a). In the latter case, the concentrations were reduced at least twofold compared with the concentrations that a mouse would experience when being close to the odor source (Fig. 1c,d and Cloves Cloves 250 µm d e Olfactometer Direct * Figure 1 Intrinsic optical signal imaging of glomerular-evoked activity 2.5 1.5 150 in awake mice. (a,b) Schema showing natural odorants delivered by an olfactometer in a and natural products drawn up to the mouse snout in a –3.5 –3.5 spoon in b. (c,d) Glomeruli maps evoked by two natural odorants presented 100 either by an olfactometer or directly. The blood vessel pattern is shown in c (right image). P, posterior; A, anterior; L, lateral; M, medial. (e) Comparison 50 of the number of glomeruli activated in the two mode of applications. The number of glomeruli activated by the olfactometer application served as a Glomeruli (% of control) control (control, 100%) for each natural odorant-mouse pair (n = 6; 0 Rosemary Rosemary Olfacto. Direct *P < 0.005, paired t test). Data are presented as mean ± s.e.m. 1Department of Basic Neurosciences, School of Medicine, University of Geneva, Geneva, Switzerland. 2Geneva Neuroscience Center, University of Geneva, Geneva, Switzerland. 3These authors contributed equally to this work. Correspondence should be addressed to A.C. ([email protected]). Received 28 November 2011; accepted 24 January 2012; published online 11 March 2012; doi:10.1038/nn.3057 NATURE NEUROSCIENCE VOLUME 15 | NUMBER 4 | APRIL 2012 537 B RIEF COMMUNICATIONS Figure 2 Dense representation of natural 2.5 2 2 2 2 a P stimuli in the olfactory bulb of awake mice. ML –5.5 –2.5 –2.5 (a) Glomerular activity patterns evoked by a A –3.5 –2 ∆R/R variety of natural odorants in a single mouse. (‰) The images represent the average of all frames during odor application. (b) Number of glomeruli activated by each natural odorant 500 µm Banana Chocolate Cloves Coffee Ginger tested (number of mice tested in white). 2.5 2 2 1.5 2 (c) Total number (middle image; glomeruli activated by multiple odorants and plotted –2.5 –5 –2.5 –2 –2.5 several times) and individual number (right 40 image; Unique I.D.: that is, each activated b glomerulus is only plotted once) of glomeruli activated by 30 natural odorants presented to 30 Honey Kiwi Mint Oregano Vinegard one mouse and overlaid on the blood vessel pattern (left image) after realignment with the blood vessels. (d) Quantification of the total 20 and unique I.D. numbers of activated glomeruli (n = 5 mice that shared the same 30 natural 10 odorants). Data are presented as mean ± s.e.m. Number of activated glomeruli 8 8 5 5 5 5 5 5 53 5 5 5 5 3 3 58 3 53 55555533 5 3 55553 5 3 55 0 14 Kiwi Mint Basil Pear Milk Lime GarlicOnion Apple of Omp-GFP mice, we estimated the HoneyCoffee ThymeCloves Ginger TomatoOrange Cumin Lemon Banana Oregano Nutmeg Tobacco Olive oil Wine rosé RosemaryPineapple Black tea Strawberry CardamomMouse food Sesame oil dorsal olfactory bulb accessible to imaging Cinnammon Mouse feces Lemon grass MouseBlack urine pepper Italian Cheese Vinegar (white) Sesame seeds contains ~200 glomeruli (Supplementary Swiss chocolate Fig. 4). Thus, natural odorants activated c d 260 10–30% of the total glomeruli number 400 (including the correction factor of 1.5 calcu- lated in Fig. 1e), although this value may have been underestimated (Online Methods). 200 Our observations differ considerably from Glomeruli number a previous report in isoflurane anesthetized 500 µm animals12. We tested the hypothesis that 0 All activated glom. Unique glom. I.D. Total Unique I.D. isoflurane may alter odorant-evoked pat- terns. Used as a regular smell, isoflurane specifically and stereotypically activated glomeruli in the posterior- natural odorant–evoked patterns could represent the summation of lateral portion of the olfactory bulb in awake mice (Fig. 3a,b and multiple monomolecular odorant–evoked patterns12. We compared Supplementary Fig. 5a,b). We then assessed the potential effect of natural odorants with monomolecular odorants at concentrations constant isoflurane application on odorant maps. All the odorants that are perceived by humans to smell the same and as strong as © 2012 Nature America, Inc. All rights reserved. America, Inc. © 2012 Nature tested consistently activated more glomeruli in the awake condition the natural odorants (Supplementary Fig. 8a–c). The number of than during isoflurane anesthesia (Fig. 3c–h and Supplementary activated glomeruli was comparable between natural and mono- Fig. 5c–f). The effect was independent of odorant concentration molecular odorants (Supplementary Fig. 8d). Thus, even a mono- npg (Fig. 3i,j), reversible after ending gas anesthesia (Fig. 3i,j) and not molecular odorant can activate a large number of glomeruli in the homogenous across the olfactory bulb surface (Supplementary olfactory bulb at some concentrations. This result differs from the Fig. 5d,f). Thus, gas anesthesia led to previous underestimations12 sparse patterns that have been reported in studies that used weaker of the number of glomeruli normally that are activated by natural concentrations of monomolecular odorants13. However, decreas- odorants (Supplementary Fig. 6). ing the concentrations of odorants (up to similar concentrations We identified two mechanisms that could explain the isoflurane- as those used previously) led to a sparsening of activated glomeru- mediated glomeruli suppression. First, long-term exposure to the lar patterns and a decrease in the glomerular response amplitude anesthetic may alter normal neuronal function (pharmacological (Supplementary Fig. 9). effect). Second, constant application of isoflurane may induce adap- We conclude that the odorant representation can vary in density tation and/or desensitization of a large number of olfactory receptor with concentration and anesthesia. Natural odorants at their native neurons, as could result from constant application of a non-anesthetic concentrations evoke dense patterns of activated glomeruli in awake odorant (odorant effect; Supplementary Fig. 7). Further work will be mice. Given that coactivation of multiple glomeruli is required to fire necessary to identify the exact mechanisms underlying the isoflurane- a pyramidal neuron in the piriform cortex in vivo15, a dense repre- mediated glomeruli suppression. sentation should improve processing of odorants from the olfactory Natural odorants evoked denser patterns than were previously bulb to the olfactory cortex. reported for monomolecular odorants13. In this regard, one impor- tant parameter is the odorant concentration that is used6,7,9–11. METHODS Natural odorants are complex mixtures of monomolecular com- Methods and any associated references are available in the online ponents, each of which can bind different olfactory receptors. version of the paper at http://www.nature.com/natureneuroscience/.
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