Vasopressin and social odor processing in the olfactory bulb and anterior olfactory nucleus

Ann. N.Y. Acad. Sci. ISSN 0077-8923

ANNALS OF THE NEW YORK ACADEMY OF SCIENCESIssue: Trends in Neuroendocrinology

Vasopressin and social odor processing in the olfactorybulb and anterior olfactory nucleus

Douglas W. Wacker,1,2 Mario Engelmann,3 Vicky A. Tobin,1 Simone L. Meddle,1,4

and Mike Ludwig1

1Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom. 2Department of Biology, ColgateUniversity, Hamilton, New York. 3Institute of Biochemistry and Cell Biology, Otto von Guericke University Magdeburg,Magdeburg, Germany. 4The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh,Edinburgh, United Kingdom

Address for correspondence: Mike Ludwig, Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Bldg.,George Square, Edinburgh EH8 9XD, United Kingdom. [email protected]

Central vasopressin facilitates social recognition and modulates numerous complex social behaviors in mammals,including parental behavior, aggression, affiliation, and pair-bonding. In rodents, social interactions are primarilymediated by the exchange of olfactory information, and there is evidence that vasopressin signaling is important inbrain areas where olfactory information is processed. We recently discovered populations of vasopressin neurons inthe main and accessory olfactory bulbs and anterior olfactory nucleus that are involved in the processing of socialodor cues. In this review, we propose a model of how vasopressin release in these regions, potentially from thedendrites, may act to filter social odor information to facilitate odor-based social recognition. Finally, we discussrecent human research linked to vasopressin signaling and suggest that our model of priming-facilitated vasopressinsignaling would be a rewarding target for further studies, as a failure of priming may underlie pathological changesin complex behaviors.

Keywords: olfaction; social memory; social recognition

Central vasopressin and social behavior

Vasopressin secreted from the posterior pituitarygland into the systemic circulation regulates pe-ripheral targets, notably the kidney and the bloodvessels. However, this nonapeptide also has impor-tant behavioral functions that are not linked toits classical neurohypophyseal release. For exam-ple, microinjection of vasopressin into the anteriorhypothalamus–medial preoptic area of subordinatemale hamsters induces flank marking, a dominance-related behavior,1 whereas microinjection of a vaso-pressin receptor antagonist reduces flank markingand biting in dominant hamsters when exposed tosubordinates.1,2

Further insight in the relevance of cen-tral vasopressin for social behavior has comefrom nontraditional laboratory model organisms.Highly affiliative, monogamous male prairie voles(Microtus ochrogaster) given a continual infusion

of vasopressin into the lateral ventricle not onlyshow increased aggression toward strangers, butalso increased partner preference.3 Interestingly,such effects on affiliative behavior are not inducibleby vasopressin in the promiscuous montane vole(M. montanus).4 This association between socialityand vasopressin signaling also extends into othervertebrate classes. Highly affiliative, colonial birdspecies show increased aggression when injectedwith vasotocin (the avian homolog of mammalianvasopressin) into the lateral septum, whereas terri-torial species show an attenuation in aggression.5–7

Vasopressin acts centrally on vasopressin 1a and1b receptors (V1a, V1b). Neural vasopressin bindingpatterns show differences that parallel differences inmating strategies in voles, with promiscuous speciesshowing higher levels of binding in the lateral sep-tum than monogamous species.8 Further studies re-vealed that a noncoding region upstream of the V1areceptor gene is crucial to the expression of social

doi: 10.1111/j.1749-6632.2010.05885.x106 Ann. N.Y. Acad. Sci. 1220 (2011) 106–116 c© 2011 New York Academy of Sciences.

Wacker et al. Vasopressin in the olfactory system

behavior across multiple vole species.4,9 Monoga-mous prairie voles possess a longer variant of anoncoding microsatellite in this region than promis-cuous montane voles.4 Transgenic mice geneticallyengineered to possess a prairie vole variant of thismicrosatellite not only show increased vasopressin-dependent affiliative behavior, but also display pat-terns of neural vasopressin receptors more typicalof the prairie vole, suggesting a link between thismicrosatellite and gene expression.4 Interestingly,variation in microsatellites upstream to the V1a re-ceptor gene have more recently been linked to char-acteristics of human social behavior.10–13

Both affiliative and aggressive behaviors requiresome level of social and potentially individual recog-nition, and research has revealed that vasopressinplays an important role in the formation of socialmemory. Microinjections of vasopressin into thelateral septum of adult male rats facilitates socialrecognition.14 Normal social recognition is ablatedin V1a receptor knockout mice,15 an effect that isrescued by selective viral-mediated V1a receptor re-placement in the lateral septum.16 These behavioraleffects of vasopressin were validated in wild-type an-imals, as viral-mediated overexpression of the V1areceptor gene into the lateral septum increased re-tention time in a social recognition paradigm inmice and rats.16,17

The V1b receptor also appears to play a role insocial recognition. Specifically, female V1b receptorknockout mice fail to show the Bruce effect, that is,there is no pregnancy block when paired with an un-familiar male after removal of their original mate.18

Interestingly, V1a receptor knockout mice do notshow this deficit in the Bruce effect, which suggeststhat vasopressin’s effects on social recognition arereceptor subtype dependent. Although male V1breceptor knockout mice do not show preference forfemale-soiled versus clean or male-soiled bedding,as is seen in wild-type mice, they can discriminatebetween male and female urine, suggesting that V1breceptor effects on social recognition may be relatedto changes in motivation rather than specific mem-ory deficits.19 Although these studies clearly indicatea role for vasopressin in processing social memories,how this translates to changes in complex social be-havior still requires more attention.

Recently, we discovered new populations of va-sopressin neurons in the main and accessory ol-factory bulbs (MOB and AOB, respectively), and

anterior olfactory nucleus (AON) of the rat, whichappear to be involved in the modulation of socialrecognition.20,21

Olfactory bulb and AON functionThe powerful behavioral effects of olfactory sig-nals, including those of social odor cues, have beenwell documented in many species, including hu-mans.22–26 The processing of olfactory cues in mam-mals is handled by two anatomically distinct path-ways, the main and accessory olfactory systems.27

In the accessory olfactory system, odors are receivedat the vomeronasal organ, then processed at theAOB and then higher brain regions, most notablythe medial amygdala. In the main olfactory system,odors are received at the main olfactory epithelium,then processed at the MOB, and subsequently by theAON, piriform cortex, and the cortical nucleus ofthe amygdala.28

Although recognized as a distinct brain regionsince the early 1900s,29 the AON has attracted farless attention than the piriform cortex. The AON isa first-order olfactory cortex located just caudal tothe olfactory bulbs, which acts not simply as a relaybetween the MOB and higher brain regions,30–32 butis also involved in the integration of olfactory infor-mation.33 Histologically, the AON has two majorregions, the pars principalis and pars externa, andthe pars principalis is further subdivided into foursubdivisions: the pars lateralis, pars dorsalis, parsmedialis, and pars ventroposterioralis.34,35 Being acomponent of the main olfactory system, the AONhas subdivision-specific connections to and fromthe MOBs and piriform cortex, as well as betweenthe left and right AONs.30,31,36

Classically, it was thought that the main olfac-tory system processed primarily volatile odors viaclassical odorant receptors, whereas the accessorysystem processed nonvolatile, social odor cues (i.e.,pheromones), but it is now known that these sys-tems interact and that pheromonal cues can beprocessed by both systems.37–39 This point is ex-tremely important when considering the effects ofpheromones on human behavior, as adult humansdo not possess a functional vomeronasal organ orAOB.40 Humans do, however, possess a fully func-tional main olfactory system, including MOB, AON,and vasopressin-sensitive regions that are involvedin the processing of social odor cues in other mam-malian taxa.20,21,41–43

Ann. N.Y. Acad. Sci. 1220 (2011) 106–116 c© 2011 New York Academy of Sciences. 107

Vasopressin in the olfactory system Wacker et al.

Table 1. Comparison of vasopressin neurons in the MOB, AOB, and pars principalis and pars externa of the AON

AON, pars AON, pars

MOB AOB principalis externa

Cell number 5,000–7,000 ∼1,000 3,800 2,250

V1a receptor − − √ √V1b receptor

√ √ √ √Glutamate

√ √ − −GABA − − √ √Calretinin − − − −Calbindin − − √ √

Vasopressin neurons in the olfactorybulb and AON

As revealed by studying transgenic rats engineeredwith an enhanced green fluorescent protein (eGFP)reporter for vasopressin synthesis,44 there are 5,000–7,000 vasopressin neurons in each MOB androughly 1,000 vasopressin neurons in each AOB20

(Table 1). There are also vasopressin neurons inthe AON,21 with approximately 2,250 vasopressinneurons in the pars externa and 3,800 vasopressinneurons in the pars principalis of each hemisphere(Table 1). Unlike in other regions of the brain,such as the bed nucleus of the stria terminalis, thenumbers of vasopressin neurons in the olfactorybulbs and AON are not sexually dimorphic in adultrats.20,21,45

In the MOB, vasopressin neuron somata are∼15 �m in diameter, ovoid, and the majority isfound in the outer third of the external plexiformlayer. The primary dendrite ramifies in a glomeru-lus. This ramification, unlike those of periglomeru-lar cells does not necessarily contact the closestglomerulus to its somata. Secondary dendrites ex-tend into the rostral–caudal aspect of the outerhalf of the external plexiform layer (Fig. 1).20 Vaso-pressin neurons in the pars principalis of the AONare roughly of the same size (∼15 �m in diame-ter) and shape as those in the olfactory bulbs, butare morphologically more heterogeneous, with den-drites typically extending outward into the plex-iform area. They are also more densely packed,especially in more lateral aspects of the pars lat-eralis and pars dorsalis (Fig. 1). These vasopressinneurons are found throughout the inner cell zone

(layer II) of the pars principalis, but are more abun-dant along its superficial edge, and there do notappear to be differences in the size or morphologyof vasopressin neurons between its different subdi-visions. Some of these neurons are also found later-ally into what is normally considered the piriformcortex. Vasopressin neurons in the pars externa arealso oval, but smaller (∼10 �m in diameter) andeven more closely packed than those in the parsprincipalis.

Despite some morphological similarities, vaso-pressin neurons in the olfactory bulbs and AONare neurochemically different (Table 1). In theMOB and AOB, these neurons are glutamater-gic and do not coexpress GABA or the calcium-binding proteins calbindin or calretinin.20 By con-trast, vasopressin neurons in the AON coexpresscalbindin-D-28K, and are GABAergic, not gluta-matergic (Fig. 1).21

Based on their electrical and neurochemical prop-erties, vasopressin neurons in the MOB and AOBappear to be a subpopulation of external tuftedcells. Cell types are not well defined in the AON.Based on functional differences between the olfac-tory bulbs and AON and the aforementioned dif-ferences in the coexpressed neurochemicals in va-sopressin neurons in these regions, it is likely thatAON neurons synthesizing vasopressin represent acompletely different population of cells from thosein the olfactory bulbs. As the adult neurogenesisof olfactory interneurons is well documented,46,47

and the main route of migration for these neuronsis via the rostral migratory stream,46 which runsthrough the AON, it would be conceivable that vaso-pressin neurons in the AON are newly born neurons

108 Ann. N.Y. Acad. Sci. 1220 (2011) 106–116 c© 2011 New York Academy of Sciences.


Figure 1. (A) Low resolution sagittal section through the anterior part of the rat brain, indicating the areas in which vasopressinsynthesizing cells were found, namely the MOB, AOB, and the AON. (B) Most vasopressin cells (green) in eGFP transgenic ratsare in the periglomerular region throughout the MOB. An apical dendrite ramifies into a glomerulus (red staining, periglumerularcell marker calbindin-D28k; blue staining DAPI). (C) Vasopressin neurons in the pars principalis of the AON are morphologicallymore heterogeneous, with dendrites typically extending outward into the plexiform area (blue staining, periglumerular cell markercalbindin-D28k; red staining marker for V1b receptors).

bound for the olfactory bulb. However, we showedthat vasopressin neurons are not replaced in theolfactory bulbs or AON in the mature rat, dispellingthis possibility.21

The discovery of an endogenous vasopressin sys-tem within the olfactory bulb and a distinct sec-ond population of vasopressin neurons in the AONhighlight the importance of vasopressin signalingin these areas. Vasopressin receptor mRNAs are ex-pressed in the rat olfactory bulb, with V1a receptormRNA in the granular cell layer and V1b receptormRNA in the mitral cell layer, and to a lesser extentwithin the external plexiform layer.48–50 Immuno-histochemical analyses have revealed V1a receptorson mitral cells and many cells in the periglomerulararea, but not on vasopressin neurons themselves.20

However, some vasopressin neurons in the olfactorybulbs coexpress V1b receptors, opening up the pos-sibility of autocrine or paracrine feedback.20 BothV1a and V1b receptor mRNA are also found in therat AON, and vasopressin binding has been reportedin multiple AON subdivisions.48,49,51 A subset of va-sopressin neurons in the AON coexpress V1a recep-tors, and all express V1b receptors (Fig. 1), poten-tially allowing for short loop feedback on their ownsecretion.

Behavioral relevance of olfactoryvasopressin signaling

Vasopressin signaling in olfactory regions is involvedin the processing of social odor cues.20,21,52 Malerats can remember juvenile conspecifics after a 30-min retention interval in a social discriminationtest, but not at 120 min,14,53 and evidence suggeststhat vasopressin is important for this short-termsocial recognition.14,15,52,54 Vasopressin infused bi-laterally into the MOB facilitates the memory ofa conspecific juvenile at 120 min,52 but interpre-tation of these results is difficult, as a peptide V1receptor antagonist failed to disrupt normal mem-ory retention at 30 minutes. Recently, a more readilydiffusible, nonpeptide V1 receptor antagonist, withproven ability to inhibit dendritically released vaso-pressin,55 was bilaterally infused into the MOB andled to a decrease in the retention of social memoriesover this shorter interval.20 Infusion of a virus con-taining a V1a receptor siRNA into the MOBs alsoinhibited retention of social memories at 30 min-utes. Moreover, application of this siRNA only dis-rupted the remembrance of a conspecific juvenile,but not a nonsocial food-based odor cocktail in a ha-bituation/dishabituation test. We hypothesize thatvasopressin facilitates the creation of a short-term



social odor memory. This memory does not appearto be consolidated for long-term storage, but ratherserves as an ephemeral representation for retrievalwhen animals reencounter each other after shortintervals (less than 120 minutes).

The above studies show that vasopressin signalingin the olfactory bulbs is involved in social recogni-tion. To test whether endogenous vasopressin pro-duced locally in the olfactory bulbs mediated thesebehavioral effects, transgenic rats were developed inwhich the gene for the human diphtheria toxin re-ceptor was inserted and placed under the transcrip-tional control of the vasopressin gene promoter.20

Thus, this gene and the resulting human diphtheriareceptor protein are only produced in vasopressincells. When diphtheria toxin is selectively infusedinto the MOBs of these transgenic rats, the sub-sequent specific ablation of only local vasopressinneurons impairs social discrimination after a 30-minute retention interval.20 The behavioral effectsof vasopressin administration into the AON haveyet to be examined.

In addition to microinjection and antagoniststudies, research analyzing the selective expressionof immediate early gene products in vasopressinneurons has shed light on vasopressin’s potentialrole in the processing and integration of social odorcues. Exposing a rat to a conspecific juvenile leadsto overall increases in the expression of the tran-scription factors, early growth response element 1(Egr-1) and c-Fos in both the MOB and AOB inadult rats (Fig. 2). Egr-1 is a relatively ubiquitoustranscription factor that is essential for the con-solidation of recognition memory.56 Interestingly,exposure to a conspecific juvenile does not lead toincreases in Egr-1 or c-Fos in vasopressin neuronsin the MOB and AOB. Colocalization of Egr-1 inolfactory bulb vasopressin neurons was quite rarein this study, with less than 1% of vasopressin cellsshowing Egr-1 colocalization across all treatmentsin the MOB and AOB. Comparable examination ofc-Fos and vasopressin immunoreactivity in the ol-factory bulb neurons also yielded extremely low lev-els of colocalization in the MOB and AOB (data notshown). Exposure to a predator odor also failed toyield significant colabeling of Egr-1 and vasopressinin the MOB and AOB. Colocalization of Egr-1 in ol-factory bulb vasopressin neurons was also very rarein this study with only approximately 1% of vaso-pressin cells showing Egr-1 colocalization across all

Figure 2. Exposing adult male rats to a conspecific juvenileleads to overall increases in the synthesis of the transcriptionfactors c-Fos (A) and early Egr-1 (B) in both the MOB and AOBin adult rats. However, exposure to a conspecific juvenile doesnot lead to increases in Egr-1 or c-Fos in vasopressin neuronsin the MOB and AOB (not shown). ∗P < 0.05, compared tocontrol. Error bars represent Mean±SEM.

treatments in the MOB and even less in the AOB.This general paucity of immediate early gene (Egr-1and c-Fos) synthesis in olfactory bulb vasopressinneurons, regardless of stimulus, might simply meanthat these cells do not typically express these tran-scription factors.

In the AON, both heterospecific predator andconspecific odor stimuli stimulate Egr-1 expressionin the pars principalis of the AON, with preda-tor odors activating neurons in the pars lateralisand pars dorsalis, and conspecific odors activatingneurons in the pars lateralis only.21 This is consis-tent with studies showing that both heterospecificpredator42,43,57 and conspecific41 odors increase thesynthesis of the immediate early gene product,c-Fos protein in the AON of the rat and ewe,respectively.

We have shown that exposure to a conspecificjuvenile leads to increases in the ratio of activatedto inactivated vasopressin neurons in the pars lat-eralis and pars dorsalis, but not the pars medialis(Fig. 3).21 Although exposure to trimethylthiazoline(a volatile component of fox feces) increased overallEgr-1 protein expression in AON neurons, neitherthat odor nor exposure to cat odors significantlyincreased Egr-1 expression in vasopressin neurons



Figure 3. (A) Exposure to a conspecific juvenile, but not non-social or predator odors, increased the ratio of vasopressin cellssynthesizing Egr-1 over the total number of vasopressin cells(i.e., activated: total) in the AON pars lateralis and pars dorsalis.(B) Example of an eGFP-vasopressin cell (brown) colabeled forEgr-1 (black nuclear labeling). ∗P < 0.05, compared to controland nonsocial odor group. Error bars represent Mean ± SEM.Modified from Ref. 21.

in any region of the AON (Fig. 3). This suggests thatvasopressin in the AON is involved in the modula-tion of responses to same, but not different speciesodor stimuli. These findings further oppose the clas-sical notion that the AON, being part of the mainolfactory system, does not process pheromone or so-cial odor information. Again, recent studies suggestthat social odors can be processed by both the mainand accessory system,37,38 and the AON may specif-ically be involved in processing both conspecific andheterospecific social odor cues.41–43,57

Potential mechanisms of action

The mechanisms by which olfactory vasopressinmodulates early olfactory processing of social odorsare far from clear. As vasopressin neurons in theolfactory bulb do not project outside the bulb, theactions of these neurons must be focused on thatintrinsic neuronal network.20 In vivo electrophysio-logical studies have shown that vasopressin has aninhibitory effect on the firing of mitral cells,20 theprimary output neurons of the olfactory bulb.27,58

The pathway by which vasopressin acts to inhibitmitral cell activation is not known. As V1a and V1breceptors are found on mitral cells,20 this inhibi-tion could be mediated directly. However, in malerats where noradrenaline was depleted by intra-bulbar preadministration of 6-hydroxydopamine,vasopressin-induced increases in the retention timeof social memory were suppressed.59 This suggeststhat vasopressin’s effects on mitral cell inhibitionmay depend on catecholinergic input from thelocus coeruleus60 where, interestingly, vasopressinneurons were also recently identified using theeGFP–VP transgenic rat.61 Intrabulbar infusion ofvasopressin increases noradrenaline release in theolfactory bulbs of female sheep,62 indicating inter-actions between these two signals. The olfactorybulb also receives cholinergic input from the basalforebrain cholinergic system, specifically from thehorizontal limb of the diagonal band of Broca.63

Intrabulbar vasopressin infusion modulates acetyl-choline release,62 and chemical lesions of choliner-gic forebrain areas severely disrupts olfactory-basedoffspring recognition in the ewe.64 Modulation ofcholinergic inputs can also alter olfactory discrimi-nation in the rat.65 Therefore, vasopressin may act toalter acetylcholine release and thus modulate socialrecognition. It is likely that inputs from the piriformcortex also modulate this response.

The axonal targets of the vasopressin neuronsin the AON are not yet known, but this regionhas numerous connections with the MOBs andpiriform cortex.20,21,31,35 Therefore, if vasopressin-containing vesicles are targeted to the synapses at theaxon terminals of these neurons, then vasopressinfrom neurons in the AON may be released intothe olfactory bulb to facilitate social recognition inconjunction with locally released vasopressin. Al-ternatively, vasopressin signaling in the olfactorybulbs and AON might be independently involved



in processing social odor information at the twolocations.

However, we think it is likely that the dendritic re-lease of vasopressin is particularly important in thefiltering of social odor information in the olfactorybulbs and potentially the AON. In the hypothala-mus, very large amounts of vasopressin are releasedfrom the dendrites of magnocellular neurons,66 andalso from the dendrites of vasopressin neurons in thesuprachiasmatic nucleus.67 Importantly, dendriticrelease is not wholly activity dependent, but the de-gree to which it is activity dependent depends onthe previous experience of the neuron.68–70

How locally released vasopressin may facilitatethe recognition of complex odor bouquets, andthus social recognition, can be envisaged as follows.When an animal is exposed to the olfactory finger-print of a conspecific, a typical pattern of glomerularcell activation occurs.71 In the main olfactory sys-tem, this information passes from the mitral cellsand some external tufted cells to the AON, wherespecific olfactory signatures are integrated.33,72 Thisolfactory signal will activate some vasopressin cellsin the bulb, but little, if any, vasopressin may bereleased from their dendrites in response to thisfirst activation. However, either as a late responseto this initial activation, or as a response to a re-current signal from the AON, these neurons nowbecome “primed,” meaning that in their dendrites,vesicles that contain vasopressin are mobilized foractivity-dependent release.73 Then, if these cells areagain activated as a result of reexposure to the sameolfactory fingerprint, this mobilized dendritic vaso-pressin is released and blocks mitral cell activation—effectively “filtering out” recognized social stimuli.Whether vasopressin from the AON contributes tothis filtering at the level of the mitral cells or if addi-tional priming and/or filtering occurs at the level ofthe AON is unknown. We predict that vasopressinproduced in the AON acts to reinforce the selectivefiltering of complex odor profiles in the olfactorybulbs.

Facilitated recognition is translated in a reducedinvestigation time of a familiar conspecific. In thehypothalamus, priming lasts for at least 90 min-utes.70,73 In rats, the retention interval for successfulconspecific recognition lasts maximally 120 min-utes.74,75 The similar duration of hypothalamic den-dritic priming and the maximal retention intervalin social recognition tests suggests that in the ol-

factory bulb and the AON, priming likely occursover a similar frame as in the hypothalamus. How-ever, there is a significant difference in the retentioninterval between male (∼45 min) and female rats(∼120 min), and endogenous vasopressin signal-ing in sexually dimorphic limbic networks, such asthe septum, shortens the interval for recognition inmale rats.76,77 This suggests that, in males, althoughpriming of vasopressin release within the olfactorybulb and AON may promote signal filtering closeto the olfactory input, vasopressin acting in higherbrain areas may limit the duration of the memoryperformance, for example, by its impact on the gen-eration of emotions and control of motivation.78

This is consistent with studies showing that V1breceptor knockout mice lack motivation in tests ofsocial odor recognition.19 It may also be that a yetundiscovered sexual dimorphism in the expressionof V1b receptors in limbic regions, or even withinthe olfactory bulb or AON, underlies the sex differ-ences in motivation observed in social recognitiontests in rats. Regardless, we suggest that the socialodor memory created in these olfactory regions istransitory and only has fleeting utility (less than 120minutes). Longer term storage of social memoriesin male rats has been described under defined ex-perimental conditions,79,80 but it remains unknownwhether endogenous vasopressin-facilitated short-term memory plays a role in the formation of thesememories. In this context it is worth noting thatsystemic injections of different synthetic vasopressinanalogues have been shown to promote social recog-nition after a 24-h retention interval.81 How en-dogenous vasopression may be involved in the con-solidation of temporary social odor memory intolong-term memory requires additional studies.

Interestingly, oxytocin has similar effects as vaso-pressin on social recognition in the olfactory bulb.Interbulbar administration of oxytocin also in-creases retention time in a social recognition test,52

and, as for vasopressin, noradrenaline is requiredfor this effect.59 Oxytocin also reduces mitral cellfiring in rats, much like vasopressin,20,82 and in-creases bulbar noradrenaline release in multiparousewes62 and male rats.83 Oxytocin producing neu-rons, however, have not been described in the olfac-tory bulbs or AON. Oxytocin receptors are foundin the olfactory bulb,84 and selective antagonism ofthese receptors blocks oxytocin-induced increasesin retention time in a social discrimination test.83



Oxytocin receptor mRNA has also been describedin all regions of the AON.49 It may be postulatedthat vasopressin acts on oxytocin receptors to medi-ate at least some of its effects on social recognition,as the oxytocin receptor has only a 10-fold greateraffinity for oxytocin than vasopressin.85 However,as pharmacological blockade of V1a receptors andsilencing V1a receptor mRNA reduced the retentionof social memories,20 it is likely that vasopressin isacting via vasopressin receptors and, in particular,the V1a receptor. Nevertheless, future studies mustaddress the relative contribution of vasopressin andoxytocin receptor activation in the olfactory bulband AON on social odor processing.

The mechanisms underlying vasopressin-mediated social odor recognition in rats may betranslatable to other taxa. Vasopressin/vasotocindistributions are fairly well conserved across manyvertebrates86 and the functionality of the brainregions where these neuropeptides are found is alsoconserved.87,88 However, to date, there have been noother species where vasopressin has been describedin the olfactory bulbs or AON. Despite the apparentconservation of neural vasopressin/vasotocinsystems, there are a number of studies showingspecies-specific diversity in the expression ofvasopressin-sensitive social behavior, even whenthe species compared are closely related.5,7,89,90

Recent work suggests that neural vasopressinsystems are likely targets of selective pressure.89,91

Therefore, extending our findings relating tovasopressin-mediated social odor recognition toother species, including humans, must be done withcare. That being said, the potential interspecificplasticity of vasopressin’s actions on complexsocial behavior makes it an incredibly exciting andimportant peptide for comparative study.

Human studies

Recently, primary research has explored the roleof vasopressin in the modulation of human be-havior. For example, Coccaro et al. in 1998 foundthat levels of vasopressin in the cerebrospinal fluidwere positively correlated with aggressive behav-ior in humans.92 This finding could be easilylinked to the known role that vasopressin plays inmodulating animal aggression.2,7,93,94 There havealso been numerous studies examining how poly-morphisms in microsatellites associated with theV1a receptor gene correlate with various com-

plex human behaviors. Such polymorphisms havebeen linked with differences in human creativ-ity, novelty seeking, harm avoidance, pair-bonding,and altruism.10–13 Studies have also found an in-triguing association between specific V1a receptormicrosatellites and autism, a condition often accom-panied by atypical social behavior.95–97 These find-ings, although intriguing, are not well understoodmechanistically.

Here, we have proposed a model of a behaviorallyrelevant, temporally and spatially specific facilita-tion of vasopressin release by dendritic primingmechanisms in olfactory processing, similar to thatobserved within the hypothalamus. This model maybe of clinical interest. The AON is also one of the firstsites of visible pathology in Parkinson’s disease,98 adisease primarily characterized by deficits in motorcontrol but that also involves abnormal social cog-nition.99,100 Interestingly, these deficits include animpaired interpretation of emotion in faces,7,100,101

a behavioral trait that is modulated by intranasaladministration of vasopressin.102–104 The priming-induced facilitation of vasopressin release after re-peated social stimuli provides a general frameworkfor explaining the behavioral effects of vasopressinwithin higher brain areas, such as the amygdala andseptum, which are involved in generating emotions.

Conclusions

Vasopressin produced by distinct populations ofneurons in the olfactory system is involved in theprocessing of conspecific odor cues and in so-cial recognition. Future studies should address themechanism(s) of action of these neuronal popula-tions, and, particularly, the potential contribution ofpriming-induced vasopressin signaling in the for-mation of social memory. Clinical studies shouldcontinue to extend these findings to humans to re-veal the potential consequences of altered facilitatedneuropeptide release, as it contributes to the etiol-ogy of neurodegenerative diseases and autism.

Conflicts of interest

The authors declare no conflicts of interest.

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Vasopressin and social odor processing in the olfactory bulb and anterior olfactory nucleus

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