Summary
Olfactory signals influence social interactions in a variety of species [1, 2]. In mammals, pheromones and other social cues can promote mating or aggression behaviors, can communicate information about social hierarchies, genetic identity and health status, and can contribute to associative learning [1–5]. However, the molecular, cellular and neural mechanisms underlying many olfactory-mediated social interactions remain poorly understood. Here, we report that a specialized olfactory subsystem that includes olfactory sensory neurons (OSNs) expressing the receptor guanylyl cyclase GC-D, the cyclic nucleotide-gated channel subunit CNGA3 and the carbonic anhydrase isoform CAII (GC-D+ OSNs) [6–11] is required for the acquisition of socially transmitted food preferences (STFPs) in mice. Using electrophysiological recordings from gene-targeted mice, we show that GC-D+ OSNs are highly sensitive to the volatile semiochemical carbon disulfide (CS2), a component of rodent breath and a known social signal mediating the acquisition of STFPs [12–14]. Responses to sub-micromolar concentrations of CS2 in the main olfactory epithelium or in identified GC-D+ OSNs are absent in mice lacking CNGA3 or CAII and drastically reduced in mice lacking GC-D. Mice in which GC-D+ OSN transduction mechanisms have been disrupted fail to acquire STFPs from either live or surrogate demonstrator mice and do not exhibit neuronal activation of the ventral subiculum of the hippocampus, a brain region implicated in STFP retrieval [15]. Our findings indicate that GC-D+ OSNs detect chemosignals that facilitate food-related social interactions.
Keywords: GC-D, semiochemical, CS2, CNGA3, carbonic anhydrase, social communication, odor, mouse
Results and Discussion
The olfactory system contains several subsystems, each of which can be distinguished by distinct sensory neuron subpopulations that express unique complements of chemosensory receptors, make discrete neural connections to the olfactory forebrain, and can respond to a plethora of diverse stimuli [16]. GC-D+ OSNs and their olfactory bulb targets, the necklace glomeruli (Figure 1A), comprise one subsystem of the main olfactory system [11, 16]. GC-D+ OSNs use a cGMP-mediated signaling cascade to transduce a small group of chemostimuli: urine [10], a rich source of social signals for mice; the natriuretic peptide hormones uroguanylin and guanylin [10]; and the gas carbon dioxide (CO2) [9]. We reasoned that the GC-D/necklace subsystem was an ideal candidate to mediate chemosignals related to the acquisition of socially transmitted food preferences (STFPs), which require the pairing of a food odor with a social stimulus such as CS2. First, GC-D+ OSNs respond to diverse stimuli implicated as semiochemicals [9, 10]. Second, carbonic anhydrases may play either a direct or indirect role in the metabolism of CS2 [17–19]. Third, the necklace glomeruli are innervated by more than one sensory neuron type and exhibit extensive connections with other main olfactory bulb glomeruli [20], suggesting that they could integrate diverse chemostimuli such as semiochemicals and food odors. Therefore, we sought to determine whether the GC-D/necklace subsystem plays an essential olfactory role in the detection of CS2 and the acquisition of STFPs.
GC-D+ OSNs respond to CS2 at sub-micromolar concentrations
We first used field potential recordings (electroolfactograms, or EOGs) to characterize CS2 responses in the main olfactory epithelium (MOE) of mice. EOG recordings from the MOE of C57BL/6 (B6) mice routinely showed responses to CS2 at concentrations as low as 0.13 µM (Figure 1B,C). Dose-response measurements confirmed that CS2 is a potent olfactory stimulus and that these responses are concentration-dependent (Figure 1C). CS2 concentrations of ~ 1 ppm (13 µM) are found in rat breath and can elicit the formation of an STFP when paired with a food odor [12]. Thus, the MOE can easily respond to CS2 at behaviorally relevant concentrations.
Next, we sought to determine if proteins previously implicated in the transduction of chemosignals by GC-D+ OSNs are required for MOE responses to CS2. GC-D appears to serve as both receptor and effector enzyme for the peptide stimuli uroguanylin and guanylin [10, 21]. Alternatively, CAII promotes the hydration of CO2 [9], producing bicarbonate ion that may act to stimulate GC-D enzymatic activity [22, 23]. CAII may also play a role in the metabolism of CS2 or its oxidation product, carbonyl sulfide [18, 24] (carbonyl sulfide may also function as a social cue in STFP formation [12]). We measured EOG responses in the MOE of mice lacking GC-D (Gucy2d-Mapt-lacZ−/− mice [10], hereafter referred to as Gucy2d−/− mice) or CAII (B6.D2-Car2n [25] mice, hereafter referred to as Car2n mice; Figures 1B, 1C and 1D). Robust EOG responses to uroguanylin or guanylin (1 µM each) were present in Gucy2d+/− and Car2n mice but absent in Gucy2d−/− mice (Figures 1B and 1D and [10]). Drastically reduced CS2 responses were observed in Gucy2d−/− mice (Figures 1B and 1D), suggesting that while GC-D plays a role in CS2 transduction, it is not required to maintain minimal responses. In contrast, EOG responses to 0.4 µM CS2 were absent in Car2n mice (Figures 1B and 1D), suggesting that MOE responses to sub-micromolar concentrations of CS2 require CAII. The cGMP-gated channel subunit CNGA3 is thought to be the final common target of both branches of the chemotransduction cascade in GC-D+ OSNs [9, 10]. Cnga3−/− mice [26] show no EOG responses to either peptide (Figure 1E, and [10]) or to CS2 concentrations below 13.3 µM (Figures 1B and 1D). Higher CS2 concentrations have a perceptible odor that could activate canonical OSNs (Supplementary Figure S1), likely accounting for residual responses in Car2n and Cnga3−/− mice to 13.3 µM CS2. In contrast, even 1 mM CS2 failed to elicit responses in Grueneberg ganglion neurons (Figures 1E and 1F), a group of chemosensory neurons in the anterior nasal cavity that express CNGA3 but not GC-D [27, 28]. Together, these data indicate that CAII, CNGA3 and GC-D play critical roles in the MOE responses to CS2 and suggest that GC-D+ OSNs are the sole chemosensors for sub-micromolar concentrations of this semiochemical.
To directly demonstrate that GC-D+ OSNs are activated by CS2, we next performed cell-attached patch clamp recordings from β-galactosidase-expressing (β-gal+) dendritic knobs in Gucy2d+/− mice. These mice express a tau-β-gal fusion protein from the targeted allele under the control of the Gucy2d promoter [10]. Extracellular loose patch clamp recordings can be obtained from the dendritic knobs of identified GC-D+ OSNs in these mice as the cells can be visualized using a fluorescent β-gal substrate (Figure 2A; [10]). Both guanylin peptides (1 µM each) and CS2 (0.4 or 13.3 µM), but not saline, elicited a transient increase in action potential firing in β-gal+ OSNs from Gucy2d+/− mice (Figures 2B and 2D and data not shown; [10]). CS2-induced spike frequencies were concentration-dependent. Responses to CS2, but not guanylin, were significantly reduced in the presence of the CA inhibitor acetazolamide (AZ; 1 mM; Figures 2B, 2C). Consistent with the results of the EOG recordings, CS2 responses were strongly reduced but not fully abolished in β-gal+ OSNs from Gucy2d−/− mice (Figure 2D). Together with the EOG results (Figure 1) and our previous report [10], these data indicate that GC-D+ OSNs are exquisitely sensitive chemosensors, responding to sub-micromolar levels of CS2 and to picomolar concentrations of guanylin family peptides (EC50 = 60 - 770 pM [10]). In contrast, GC-D+ OSNs are at least 10,000-fold less sensitive to CO2 (spike threshold > 6.8 mM (Figures 2E and 2F); knob Ca2+ responses = 6.4 mM [22]; behavior threshold = ~ 15 mM [9]). The high degree of sensitivity to CS2 and guanylin peptides is strikingly reminiscent of that seen for other semiochemical-responsive OSNs and VSNs [16].
Mice lacking CNGA3, GC-D or CAII function fail to acquire socially transmitted food preferences
The acquisition of STFPs requires both a social cue (e.g., breath of a conspecific, or the semiochemical CS2) and a food odor [12–14, 29]. We modified a bioassay used for assaying STFPs in rodents (Figure 3A; [13, 14, 30, 31]) to test whether GC-D+ OSNs are required for the formation of an STFP. First, group housed “observer” mice (B6, Cnga3+/−, Cnga3−/−, Gucy2d+/− or Gucy2d−/−) were introduced to a food odor by a live “demonstrator” mouse that had eaten that food (standard mouse chow with either 1% cinnamon or 2% cocoa added) for the previous hour. Following a 1 hr interaction with the demonstrator, observers were separated and provided with a choice of cinnamon- or cocoa-odorized food. The amount of each food consumed was measured after 60 min. B6 and Cnga3+/− (Figure 3B) observers show a preference for the demonstrated food (see figure legend for preference ratios and statistics). In parallel experiments, both B6 and Gucy2d+/− (Figure 3C) observers also showed a preference for the demonstrated food. In contrast, neither Cnga3−/− nor Gucy2d−/− mice showed a preference for the demonstrated food (Figures 3B and 3C). The most robust effect of the genotype was seen in Cnga3−/− mice, which showed significantly lower PRs than either B6 (p = 0.03) or Cnga3+/− (p = 0.002) mice (one-way ANOVA of ranks with Mann-Whitney U test). Together, these results indicate that CNGA3 and GC-D, both of which are required for normal sensitivity to sub-micromolar CS2-sensitivity of GC-D+ OSNs, are necessary for the acquisition of STFPs.
Rodents are able to form food preferences to odorized food in the absence of a live demonstrator when CS2 is presented as the sole social stimulus [12]. Furthermore, CS2 enhances preference for, and ingestion of, food by mice [32]. We next asked if mice with disruptions in GC-D+ transduction mechanisms would fail to display a preference for odorized food demonstrated with CS2. First, Cnga3−/− observer mice were presented with a cotton surrogate instead of a live demonstrator (Figure 3D). Surrogates were first treated with powdered food odorized with the demonstrated odor (1% cinnamon or 2% cocoa) along with 13.3 µM CS2. Observer mice were then given a choice to consume cinnamon- or cocoa-odorized food. B6 mice preferred to consume food odorized with the demonstrated odor, while Cnga3−/− mice showed no preference (Figure 3E). Observers did not form a preference from surrogate demonstrators treated with a food odor alone (data not shown; PR = 0.45 ± 0.08; z = −0.63, p = 0.25), consistent with the observation that activation of the GC-D/necklace subsystem requires external stimuli, not components of the observer’s breath [33]. Next, we used the same behavioral paradigm to test the role of CA activity in the acquisition of CS2-mediated food preferences. B6 mice pretreated with an intranasal application of the CA inhibitor methazolamide (MZ; 10 mM) failed to form a preference (Figure 3F). In contrast, saline treated mice preferred the demonstrated food (Figure 3F). The ability of mice to acquire olfactory-mediated STFPs is impaired after pharmacological or genetic disruption of each of three transduction proteins (CAII, GC-D and CNGA3) expressed in GC-D+ OSNs and required for electrophysiological responses to sub-micromolar concentrations of CS2. Although we cannot fully exclude the possibility that all three proteins act somewhere in the central nervous system to influence this specific behavior, we conclude that the acquisition of STFPs requires functional GC-D+ OSNs.
The acquisition of an STFP is not a purely sensory phenomenon, but is a learned association that requires memory formation. To control for deficits in short-term memory that might prevent the acquisition of an STFP, B6 and Cnga3−/− mice were tested in a standard habituation/dishabituation assay (Figure 3G). Mice were presented with cotton swabs odorized with cinnamon for three 1 min trials, each trial separated by a 2 min interval. During the fourth trial, the swab was changed to a cocoa odor. Both B6 and Cnga3−/− mice showed decreasing investigation time with each presentation of the cinnamon odor (habituation) followed by increased investigation time of the novel cocoa odor (dishabituation), indicating that the failure of Cnga3−/− mice to acquire an STFP does not result either from a deficit in short term memory or the inability to detect food odors such as cocoa or cinnamon. However, in a similar experiment using three habituation trials of water and a final trial with 13.3 µM CS2 (Figure 3H), only B6 mice exhibited dishabituation upon presentation of 13 µM CS2 (SNK, p = 0.02); exploration time of Cnga3−/− mice was not significantly different than the last water presentation (SNK, p = 0.31). Thus, Cnga3−/−, but not B6 mice, fail to differentiate CS2 from water in an olfactory task.
Rodents that acquire an STFP show increased immunoreactivity for the immediate early gene product c-Fos in the ventral subiculum of the hippocampus, but not in dorsal subiculum or entorhinal cortex [15] (Figure 4A). Using random subsets of mice tested in Figure 3B, we found that B6 but not Cnga3−/− observer mice showed increased c-Fos immunoreactivity in the ventral subiculum after acquiring an STFP (Figures 4B and 4C; demonstrated odor: cinnamon; presented foods flavored with cocoa or cinnamon). Both B6 and Cnga3−/− mice demonstrated an irrelevant odor (ginger; presented foods odored with cocoa or cinnamon) failed to show an increase in c-Fos immunoreactivity in the ventral subiculum (Figures 4B and 4C). No significant differences were seen between genotypes or demonstrated odor in either dorsal subiculum or entorhinal cortex (Figures 4D and 4E; and see Figure S2 in Supplementary Materials). Thus, Cnga3−/− mice do not exhibit central nervous system correlates of STFP retrieval, a result consistent with their failure to acquire an STFP.
Conclusions
We conclude that GC-D+ OSNs and the GC-D/necklace olfactory subsystem mediate the detection of social chemostimuli necessary for the formation of STFPs. Rodents and other animals make use of a diverse repertoire of chemical cues to communicate with conspecifics [34]. While some of these chemostimuli may elicit innate behaviors, it is likely that most only have their full meaning in the context of additional sensory cues or previously learned associations. By linking a specific olfactory subsystem to both the expression of an established social learning behavior and to the detection of a chemostimulus that can elicit that behavior (Figure 4F), we highlight the possibility that the subsystem structure of the mammalian main olfactory system may help mammals associate chemostimuli with other sensory cues in a meaningful and organized way. The GC-D/necklace subsystem may be particularly well suited for putting olfactory cues in context. Each necklace glomerulus is innervated by more than one OSN population: GC-D+ OSNs and GC-D-negative OSNs [20]. The heterogeneous sensory innervation of necklace glomeruli is strikingly different from the homogeneous sensory innervation of other MOB glomeruli [35, 36], and suggests that necklace glomeruli could be capable of integrating multiple sensory inputs. Furthermore, extensive connections with other MOB glomeruli via interneurons [20] provide the opportunity to further integrate social stimuli such as CS2 with more general odor stimuli. In this way, the olfactory system could facilitate the initial association of social and food cues that is necessary for STFP formation (Figure 4F). Indeed, the olfactory bulb (or its equivalent in invertebrates) has been implicated as an important site of plasticity with odor-dependent associative learning in several species [37–39]. STFPs are likely critical to survival in the wild, allowing conspecifics to make rapid decisions about whether a particular food is safe to eat and if a food source is nearby. We have speculated that guanylin peptides, which can also activate GC-D+ OSNs, may similarly serve as social signals to communicate information about food [10, 11]. Levels of uroguanylin secreted in urine rise postprandially [40], providing an opportunity for this chemostimulus to convey information that food has been safely eaten and digested. In this light, the GC-D/necklace olfactory subsystem is ideally suited to integrate information about the presence and safety of food.
Highlights
A mammalian olfactory subsystem is essential for a type of social learning.
A food-related social stimulus, CS2, activates specialized olfactory neurons.
Mice with impaired CS2 responses don’t acquire socially transmitted food preferences.
Supplementary Material
Acknowledgements
We thank G. Schoenbaum for helpful comments on the manuscript. These studies were supported by the NIDCD (DC005633 to SDM; DC006603 to K.R.K.) and the DFG (SFB 530/A7 to FZ). T.L.-Z. is a Lichtenberg Professor of the Volkswagen Foundation.
Footnotes
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Supplemental Data
Supplemental Data include supplemental experimental procedures, one supplemental table and two supplemental figures and are available with this article online at
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