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Proc Natl Acad Sci U S A. Mar 16, 2010; 107(11): 5172–5177.
Published online Mar 16, 2010. doi:  10.1073/pnas.0915147107
PMCID: PMC2841925
Neuroscience

In vivo vomeronasal stimulation reveals sensory encoding of conspecific and allospecific cues by the mouse accessory olfactory bulb

Abstract

The rodent vomeronasal system plays a critical role in mediating pheromone-evoked social and sexual behaviors. Recent studies of the anatomical and molecular architecture of the vomeronasal organ (VNO) and of its synaptic target, the accessory olfactory bulb (AOB), have suggested that unique features underlie vomeronasal sensory processing. However, the neuronal representation of pheromonal information leading to specific behavioral and endocrine responses has remained largely unexplored due to the experimental difficulty of precise stimulus delivery to the VNO. To determine the basic rules of information processing in the vomeronasal system, we developed a unique preparation that allows controlled and repeated stimulus delivery to the VNO and combined this approach with multisite recordings of neuronal activity in the AOB. We found that urine, a well-characterized pheromone source in mammals, as well as saliva, activates AOB neurons in a manner that reliably encodes the donor animal’s sexual and genetic status. We also identified a significant fraction of AOB neurons that respond robustly and selectively to predator cues, suggesting an expanded role for the vomeronasal system in both conspecific and interspecific recognition. Further analysis reveals that mixed stimuli from distinct sources evoke synergistic responses in AOB neurons, thereby supporting the notion of integrative processing of chemosensory information.

Keywords: pheromones, sensory processing, vomeronasal, accessory olfactory bulb, mouse

In most animal species, the detection of pheromonal cues is essential to trigger and modulate sexual and social interactions between conspecifics. Genetic and surgical manipulations in the mouse have demonstrated the essential role of the vomeronasal system in this process (14). Moreover, tracing studies revealed dense projections from the vomeronasal system to hypothalamic nuclei involved in behavioral and endocrine control (5). The vomeronasal system thus offers a unique opportunity to explore principles of information processing underlying animal–animal communication and species-specific social and sexual interactions.

Although the rodent vomeronasal system is clearly involved in pheromone sensing, the range of stimuli it can detect is largely unknown (5). At one extreme, it may be exclusively dedicated to processing pheromonal (i.e., conspecific) information. Consistent with this view, several classes of conspecific cues were shown to directly activate isolated vomeronasal organ (VNO) preparations (see ref. 6 for a recent review). Moreover, genetic as well as surgical VNO silencing significantly impairs behavioral responses to conspecific cues (1, 2). Alternatively, the vomeronasal system may resemble the main olfactory system in which a wide variety of stimuli, including both pheromonal and nonpheromonal signals, are processed. This idea is supported by the finding that in vitro VNO preparations can be activated by large sets of diverse chemicals (7, 8).

The type and specificity of information extracted by the accessory olfactory bulb (AOB) represent another unresolved issue. AOB neurons can reliably detect conspecific sex from urinary cues (9) and strain information from as yet unidentified cues (10). One hint that the vomeronasal system can provide finer discrimination among individuals emerges from its role in the Bruce effect (4), in which a gestating female terminates pregnancy when exposed to an unfamiliar male. However, how sex, strain, and individual identity are encoded by AOB neurons remains poorly understood.

Exactly which stimulus features are encoded by the vomeronasal system depends ultimately on the nature and extent of information transmitted from the primary sensory neurons to the AOB. Unlike mitral cells in the main olfactory bulb (MOB), in which responses are shaped by input from one or a few receptor cell classes (11, 12), AOB output neurons receive convergent inputs from multiple glomeruli (13, 14). This architecture could provide a platform for integrative information processing that significantly differs from that observed in the main olfactory system. However, direct physiological evidence for integrative processing by AOB neurons is still lacking.

A major challenge to resolving these issues is that stimulus delivery to the VNO requires active pumping that is triggered only during exploratory behaviors (15). The relatively low throughput of chronic recording methods and, more fundamentally, the lack of control over stimulus uptake in freely behaving mice are not well suited for the systematic investigation of information processing in the AOB. Recently (9, 16), direct stimulus perfusion into the VNO of the anesthetized opossum and mouse has been used to show the importance of the AOB in distinguishing conspecific sex through urinary cues. However, delivery by perfusion requires relatively large samples, typically pooled from multiple individuals, hence limiting the ability to systematically address the processing of pheromonal stimuli with limited availability. Furthermore, stimulus delivery by perfusion effectively bypasses VNO pump dynamics, a physiological parameter that may play a significant role in the faithful transduction of stimulus information to downstream targets, much as sniffing does in the main olfactory system (17).

To overcome these limitations, we developed a unique experimental approach that enables repeatable and naturalistic delivery of small and physiologically relevant stimulus volumes to the intact VNO. By combining this approach with multisite electrophysiological recordings, we explored how AOB neurons respond to features in conspecific urine and saliva. These experiments revealed that AOB neurons respond to these complex stimuli in a manner that reliably encodes information about the strain and sex, as well as finer aspects that might represent the physiological state and the individual identity of conspecifics. This approach also led us to the surprising finding that cues present in a variety of predator urines can serve as potent and selective activators of AOB neurons. These results offer unique insights into how the vomeronasal system functions to enable individual recognition important to social and sexual behavior, while also suggesting an expanded role for this system in the recognition of other species.

Results

A Naturalistic Preparation for Recording Neural Activity in the Vomeronasal System.

To activate vomeronasal pumping in anesthetized animals, we implanted custom-built cuff electrodes over the cervical region of the sympathetic nerve trunk using the carotid artery as a scaffold (Fig. 1A). Initial experiments established that brief trains of biphasic current pulses applied to the sympathetic nerve (amplitude ±100 μA, frequency 33 Hz, duration 1.6 s) induced efficient uptake of fluorescent dye into the VNO (Fig. 1A). To flush the nasal cavity and VNO lumen and thus enable multiple cycles of stimulus presentation, we induced a flow of Ringer’s solution from the nostril through the nasopalatine duct and to the oral cavity (18) while repeatedly activating the VNO pump (Fig. 1A). A planar array of 32 electrodes (19) was inserted into the external cellular layer (ECL) of the AOB that contains the cell bodies of mitral and tufted cells (20). Subsequent confirmation of electrode placement in the ECL was performed by histological inspection of the fluorescent dye-painted (DiI) electrode tracks (Fig. 1A). Neuronal activity recorded in the AOB when a small volume of diluted urine (2 μL) was presented to the nasal cavity either alone or with sympathetic nerve stimulation is shown in Fig. 1B. These recordings reveal that both stimulus application and subsequent sympathetic stimulation are typically required to evoke a neuronal response in the AOB and show that repeated sympathetic stimulation during flushing can be used to efficiently “clean” the VNO (Fig. 1B).

Fig. 1.
Experimental setup. (A) Mouse nasal cavity and relevant structures. (Left Inset) Coronal section of the VNO showing uptake of DiI ipsilateral to nerve stimulation. BV, blood vessel; L, VNO lumen. (Right Inset) Sagittal AOB section showing a DiI-painted ...

Basic Characteristics of Vomeronasal Responses.

Using this approach, we analyzed responses of 711 single and 2,332 AOB multiunits to a variety of stimuli. Unless otherwise indicated, all analyses refer to single-unit data. Evoked responses of two single units recorded simultaneously following six trials of interleaved presentations of male and female urine are shown in Fig. 2A. In addition to demonstrating the repeatability and reliability of our experimental procedure, these data highlight the known (9) specificity of AOB units to male and female stimuli. The response specificity to sex-specific stimuli is further documented in SI Text.

Fig. 2.
Sex specificity of responses and temporal response profiles. (A) Sympathetic stimulation-induced spike times in interleaved presentations of dilute male or female mouse urine from two simultaneously recorded neurons (orange and green). (Lower) Averaged ...

Baseline firing patterns of single units were low (0.94 ± 0.05 Hz, mean ± SEM), similar although slightly lower than values previously recorded in the anesthetized and behaving mouse (9, 10). These lower baseline values could reflect a more effective removal of residual stimuli with our cleaning procedure, our nonbiased approach to finding single units, or the anesthetic state. Rate increases started 4.34 ± 0.03 s following nerve stimulation and peaked at 10.9 ± 0.10 s, with a half time of 12.8 ± 0.06 s (Fig. 2B). Similar quantification of the temporal profiles of rate decreases was impractical due to the low baseline rates. The average response delay (4.34 s) was also similar to that measured in freely behaving mice (3.6 ± 0.7 s) (10). Because the vomeronasal signaling cascade has been estimated to require <0.5 s (21), the response latency observed here could reflect the combined delays of sympathetic stimulation, pump activation, and stimulus suction. Comparison of the temporal response profiles observed here with direct recordings of VNO pump activity in anesthetized (22) and awake animals (15) suggests that each sympathetic stimulation in our preparation triggers a single suction event. Thus, the basic vomeronasal response is significantly slower than the unitary sensory events in the main olfactory system, which occurs at a typical frequency of 4–12 Hz (23).

Stimulus-Induced Responses Require Functional TRPC2 Signaling.

In contrast to wild-type mice, recordings from TRPC2−/− mice failed to reveal any responses when stimulus application to the nasal cavity was paired with sympathetic nerve stimulation. Specifically, although baseline activity from AOB neurons of adult TRPC2−/− mice could be recorded (n = 221 units including multi-unit activity, eight recording sites from four males and two females), the distribution of stimulus-evoked response strengths was clearly different from that of WT mice (Fig. 3A) and, more importantly, the rate of significant responses (P < 0.01) was at chance levels (Fig. 3B). This finding indicates that the AOB responses evoked by pairing stimulus presentation with sympathetic nerve stimulation require an intact TRPC2 transduction pathway in the VNO. Thus, in contrast to recent reports that postulate residual TRPC2-independent vomeronasal activity (24), the present results employing direct measurement of electrical activity in the AOB reveal that the elimination of vomeronasal signaling is effectively complete following genetic ablation of TRPC2.

Fig. 3.
Dependence of AOB responses on functional TRPC2 signaling. (A) Percentages of stimulus-induced rate changes of individual units to the most effective stimulus (stimuli were male, female, and predator urine). (B) Percentage of significant responses (P ...

AOB Readout of Sex and Strain.

Prior studies involving chronic recordings from behaving mice revealed that AOB neurons can distinguish strain-specific cues (10), but the pheromonal source of this information was not identified. Interestingly, these recordings revealed strong and selective bursts of activity correlated with the animal’s investigation of both the anogenital and the facial region of conspecifics (10), suggesting that at least two bodily sources contain strain-specific information. Moreover, exocrine gland secreted peptides (ESPs) found in tears, mucosa, or saliva in a sex- and strain-specific manner have been shown to be effective vomeronasal stimuli (25, 26). We explored this issue by testing the responses of AOB neurons to urine and saliva samples from mice of different sex and strain combinations. Of 107 single units tested with urinary stimuli, 40 (37%) showed a significant response to one or more stimuli (P < 0.01, nonparametric ANOVA) with a prevalence of responses to only one stimulus (60%, 24 of 40; SI Text). Of 23 single units tested with salivary stimuli, 13 (57%) showed a significant response (P < 0.01) to one or more stimuli (Fig. 4 B and E). As seen with urinary stimuli (Fig. 4A), AOB neurons display responses triggered exclusively by saliva from one or a few strains, by all animals of a given sex, or in more complex patterns (Fig. 4B and SI Text). For both urine and saliva, units responding exclusively to urine of both sexes from the same strain were not observed. Thus, both urinary and salivary stimuli can elicit highly specific responses in single units in a manner that could be used by the mouse to unambiguously detect the strain and sex of the stimulus animal.

Fig. 4.
Responses to urine and saliva. (A) Responses of three different single units to urine from mice of distinct sex and strain. Significant responses (P < 0.01, either positive or negative) are shown on a gray background. (BC, BalbC; C57, C57/Black6). ...

Are the sex-specific responses observed here and elsewhere merely a by-product of the finer discrimination of strain and sex selectivity? To test this issue we analyzed the population responses to urinary and salivary stimuli using hierarchical clustering. This analysis revealed a perfect segregation of responses to male vs. female urine and an almost perfect segregation for salivary cues (Fig. 4 C and D). Thus, although individual AOB neurons are often tuned to specific strain/sex combinations, sex nevertheless emerges as a primary parameter distinguishing different classes of responses in the AOB.

To explore whether AOB neuron responses to individual samples reflect the genetic background of the donor animals, we presented three distinct urine samples from males of each of three distinct strains (CBA, BalbC, or C57Bl6). For each strain, two samples were collected from one individual and one was collected from a different mouse. Of 51 single units tested, 16 showed a significant response to at least one stimulus. Population analysis of these responses showed that urinary cues from the same strain and, for two of three strains, even from the same individual within a strain clustered together (Fig. 4F). However, in addition to neurons that responded to all samples of a given strain, we observed specific responses to samples from an individual mouse and even to individual samples from a given mouse (Fig. 4C). The subset of neurons that differentiated samples from different mice and even different samples of the same mouse could provide the basis for detection of more subtle features, which might reflect the individual’s physiological state and identity. One should stress that these responses are not likely to reflect random fluctuations in the neuronal responses, as they are consistent across multiple presentations of the same stimuli.

Responses to Allospecific Stimuli.

To investigate the potential role of the mouse vomeronasal system in detecting allospecific stimuli, we measured the responses of AOB single units to a mix of urinary cues from three mouse predators: bobcat, fox, and rat. We found that the mix of predator urines could evoke remarkably robust responses from AOB neurons. Of 186 single units tested with both mouse and predator stimuli, an equal fraction (19%) showed a significant (P < 0.01) response to mouse (male or female) or to predator urine. Importantly, most neurons (60%, 31 of the 51 single units that showed any response) responded specifically only to predator or mouse urine (Fig. 5 A and C). This specificity and the similar distribution of response magnitudes to mouse and to predator stimuli (Fig. 5B) suggest that mouse AOB neurons respond to predator urine because it contains specific predator-related cues and not simply because it contains cues also common to mouse urine.

Fig. 5.
Responses to predator urine. (A) Percentages of units with significant responses (P < 0.01) to each of the stimulus combinations (n = 51 single units responding to at least one stimulus). Stimulus categories are male mouse urine, female mouse ...

To further explore the specificity of these responses, we tested the responsiveness of individual AOB units to the urine of individual predators. Of 35 units tested, 12 showed a response to at least one of these stimuli (P < 0.01). Of these 12, 5 responded to only one predator stimulus in addition to the mixed predator cues (Fig. 5D), 2 responded to all stimuli, and the rest responded to only one of the stimuli (Fig. 5B and SI Text). The robustness of predator responses and the specificity of discrimination between mouse and predator cues show that the vomeronasal system could participate in the detection and discrimination of allospecifics.

Responses to Conflicting Stimuli.

The detection of conspecific female, male, or predator cues triggers dramatically different behavioral responses. It is therefore intriguing that although ~60% of the single units (31 of the 51 responding units) are specifically activated by only one stimulus class (P < 0.01) and thus can convey unambiguous information to downstream targets, a substantial fraction (the remaining 40%) respond to multiple stimulus classes with conflicting significance (Fig. 5 A and E).

To explore how conflicting cues are processed by the AOB, we measured responses to male and female mouse urinary cues, to predator urine, and to their mixtures [n = 61 single units, of which 36 (59%) showed significant response (P < 0.05) to at least one stimulus]. The mixtures were prepared as averages of the elemental stimuli (SI Methods). Specifically, we asked whether a mix of conflicting cues generates an intermediate or a novel response and whether the response to one cue can override others. At the population level, similarity relationships (given as correlation distances; SI Text) reveal that female and male mice stimuli are considerably closer to each other than each is to predator urine (0.46 vs. 0.78 and 0.82, normalized distances). This result indicates that AOB activity readily allows differentiation of conspecific from nonconspecific urine stimuli. Moreover, mixes of predator with female or with male urine yielded intermediate representations between mouse and predator stimuli. Thus, the predator stimulus does not override or inhibit the response to conspecific cues. These relationships are depicted in Fig. 6A using multidimensional scaling (MDS) to approximate these distances in two-dimensional space (Methods). For comparison, also shown are distance relationships for simulated cases in which the predator response entirely inhibits or, alternatively, combines linearly with the mouse urine response. Comparison of the actual data with the two simulated cases supports the idea that responses to mixed stimuli resemble intermediate responses to the elemental stimuli.

Fig. 6.
Responses to conflicting stimuli. (A) Relationship of population responses to the elemental stimuli and to their combinations using multidimensional scaling (MDS). Each circle represents the population response to one stimulus (see color legend).The “predator ...

At the single-unit level, a substantial proportion of responses to the combined predator and mouse stimuli (38%, 20 of 53 cases) display intermediate magnitudes to that of the individual stimuli, consistent with the population data shown in Fig. 6A. Surprisingly, the data also reveal a prevalence of synergistic interactions between predator and mouse stimuli (42%) (Fig. 6B). In comparison, mixes of urine from distinct samples of mouse urine elicited fewer and weaker synergistic interactions (SI Text). Because mouse and predator stimuli are likely to contain a large number of nonoverlapping components, as compared to two conspecific stimuli, this result suggests that a specific combination of components is sometimes required to elicit a robust response, thus providing direct support to the notion that AOB units integrate information from distinct components.

Discussion

The importance of the mouse vomeronasal system in processing chemical cues required for sex- and species-specific social and reproductive behaviors has been documented in various studies (1, 2, 4, 27). However, many fundamental aspects of vomeronasal function have not been addressed yet: Is the vomeronasal system dedicated to pheromone detection? How are the representation and computation of social parameters achieved? The challenges posed by the unique mode of stimulus delivery to the vomeronasal organ, primarily the sympathetic activation of a vascular pump, have so far hampered in vivo physiological investigation of vomeronasal function, leaving the range of chemical stimuli detected by the vomeronasal system and the basic rules of vomeronasal information processing largely unknown.

Here we describe a unique experimental preparation for studying vomeronasal function that is noninvasive, engages the natural pumping mechanism, requires small volumes of test stimuli, and allows many cycles of stimulus presentation. By combining this method with multielectrode recording in the AOB of the anesthetized mouse, we confirmed the high selectivity of vomeronasal activation by male and female mouse urinary and salivary cues and showed that when challenged with increasingly more subtle discriminations, AOB neurons can achieve multilevel distinctions, namely, among animals from different strains, among individuals from the same strain, and even among distinct samples from an individual mouse.

The wiring diagram of the AOB identified by anatomical and genetic tools has suggested that, in contrast to the MOB, integration of information by output neurons may involve multiple chemosensory receptors (20, 28). Whereas the VNO appears to reliably convey information about sex (21, 29), an earlier study suggested that a population code is required to derive information about strain (30). In our AOB recordings we identified mostly units with selectivity to sex/strain combinations, a few single units with generalized sex responses, and no units with specific responses to strain regardless of sex (Fig. 4). In contrast to VNO recordings, we also observed single units that generalized across all male samples of the same strain or across distinct samples from the same individual (Fig. 4).

We found here that many AOB units could respond to cues present in predator urine. These findings suggest that in addition to serving an important role in individual recognition of conspecifics, the vomeronasal system of the mouse is also likely to serve an important role in recognizing animals of other species, perhaps especially predators. Responses of AOB neurons to predator urines were robust in magnitude and frequency and appear highly specific, even among distinct predator species. Intriguingly, reproductive processes can be affected by the presence of predator stimuli (31). Because the behavioral (1) and physiological (4, 32) involvement of the vomeronasal system in reproductive processes is well established, predator odors may act via the VNO to affect such functions. However, predator-related responses have been recently detected in the main olfactory system (33), raising the question about the respective role of each chemosensory system in this process. The slow timing of AOB activation after stimulus detection, in the order of several seconds compared to a fraction of seconds in the main olfactory system, together with the need for contact for VNO stimulus detection, suggests that the vomeronasal system may provide a means to survey the presence of predators within the ecological niche. This, in turn, could provide long-term modulation of the mouse’s reproductive physiology, whereas olfactory detection may provide immediate avoidance of predators. Previous work showed the importance of the vomeronasal system for predator and prey detection in reptiles (34, 35), and more recent studies implicated the rodent vomeronasal system in detecting predator cues as well (3537). However, our findings reveal that such odorants elicit robust, frequent, and specific electrical activity in the mouse AOB.

Cues from conspecifics and predators provide ecologically conflicting information that could lead to strikingly different behavioral/physiological outputs, the former by enticing social and reproductive interactions, the latter by arousing fear and delaying reproduction. How would animals resolve the simultaneous detection of conflicting stimuli? In one scenario, information about conflicting classes of stimuli is already processed at early stages by largely independent units that in turn convey the prospect for friendly or harmful encounters to distinct effector nuclei in the amygdala and hypothalamus. In addition, some cross-inhibition in the response to both stimuli presented simultaneously may exist, such that the anticipation of a mating partner, for example, can be dampened by the detection of a possible threat. We indeed identified AOB neurons that displayed specific responses to either female or male mice or to predators. However, we also detected surprisingly large cohorts of neurons that responded to both mouse and predator urine, which is hard to reconcile with a highly segregated opponent mechanism. What is the functional significance of this dual specificity? One possibility is that features used to distinguish between two classes of conspecific stimuli may also be present in predator urine. Alternatively, the feature space defined by AOB neurons may not be explicitly related to the ecological significance of the stimuli. Instead, AOB processing might maximize the efficiency of information transfer to downstream targets regardless of their ethological value. Under this scenario, the significance of the various response patterns is relegated to subsequent processing stages in the amygdala and hypothalamus. Finally, the synergistic responses to mouse/predator odors uncovered in our study may provide a sensory alert for the presence of conflicting cues. According to this hypothesis, AOB processing would not only encode chemical features, but also attribute salience to a specific combination of cues. Regardless of their significance, the observation of these synergistic responses provides direct physiological support to the notion that some AOB mitral cells effectively integrate information from multiple glomeruli.

Summing the frequencies of responses to each of the stimuli tested indicates that, on average, single units respond to more than one type of stimulus. Indeed, some units display responses across distinct stimulus classes (i.e., conspecific and predator urine; Fig. 5). This result suggests that single units cannot unambiguously encode the identity of the stimulus. Instead, it seems that activity across a population is required to extract information about stimuli and the relationships between them. This is supported by our population level analyses, which show that small ensembles can reliably encode the relationships between stimuli (e.g., Fig. 4 D–F).

Finally, we have described a powerful experimental platform that, in addition to providing insights about AOB function, should be further instrumental in exploring the processing of vomeronasal as well as olfactory chemosensory information in amygdala and hypothalamic behavioral control centers to generate physiologically relevant responses.

Methods

Surgical Procedures.

Experiments were performed under National Institutes of Health, Duke University, and Harvard University guidelines. See SI Text for details on surgery, stimulus delivery, and electrophysiology.

Data Analysis.

Responses were quantified as the rate change following stimulation (30 s) relative to the preceding 10 s. Response significance for a given stimulus was determined with a one-way nonparametric ANOVA with the set of poststimulation rates (over a 30-s period) compared to the set of all prestimulation rates. All data analyses were performed with custom written or built-in MATLAB code. See SI Text for further details.

Stimuli.

Fresh urine samples were frozen at −80 °C. For stimulation, urine was diluted in water or in Ringer’s solution (1/100). Saliva was collected from the oral cavity using a micropipette. Salivation rate was increased by pilocarpine–HCL injections (10 mg/kg, i.p.). Bobcat and fox urine was kindly provided by PredatorPee. Rat urine was collected similarly to mouse urine. Artificial urine and Ringer’s solution were prepared as described in ref. 21. See SI Text for further details.

Supplementary Material

Supporting Information:

Acknowledgments

We thank G. Buzsaki for help with the recording setup; D. Purves and G. Feng for assistance with the surgical procedure; R. Irving and D. Kloetzer for technical support; A. Adani, A. Reinhart, L. Pont-Lezica, and D. Lin for stimuli; R. Hellmiss for artwork; and B. Arenkiel, I. Davison, S. Shea, the Dulac laboratory, and two anonymous reviewers for helpful comments and suggestions.

Footnotes

The authors declare no conflict of interest.

This article contains supporting information online at www.pnas.org/cgi/content/full/0915147107/DCSupplemental.

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