Species differences in OTR density in the NAcc have been associated with species differences in mating strategy (social monogamy vs polygamy) and alloparental behavior, suggesting that variation in OTR receptor expression may underlie species differences in social organization and behavior (Insel et al., 1991
; Young and Wang, 2004
; Olazabal and Young, 2006b
). Socially monogamous prairie voles have higher densities of OTR in the NAcc than non-monogamous meadow and montane voles, and pharmacological blockade of those receptors prevents mating-induced partner preference formation (Young et al., 2001
; Olazabal and Young, 2006b
). There is also significant individual variation in OTR density in the NAcc within prairie voles (). OTR density in this region is positively correlated with individual variation in alloparental behavior of adult sexually naïve female prairie voles (Young, 1999
; Olazabal 2006) and OTR antagonist administration into the NAcc eliminates this behavior (Olazabal and Young, 2006a
). Therefore, in this study we sought to directly test the relationship between receptor density in the NAcc and affiliative behavior in voles, by using AAV gene transfer.
Our results show that, as predicted, female prairie voles with elevated levels of OTR in the NAcc display accelerated partner preference formation compared to females with lower OTR density (CMV-GFP or shams). Contrary to our prediction, there was no difference in alloparental behavior between groups, suggesting differential mechanisms by which accumbal OTR regulates partner preference formation and alloparental behavior. Our results support the hypothesis that individual differences in OTR expression contribute to intra-species variation in some aspects of affiliative behavior. However, increasing OTR expression in the NAcc was not sufficient to induce partner preference formation in meadow voles, even after 72 hours of cohabitation, suggesting that the species differences in accumbal OTR alone are not sufficient to explain the species differences in the ability to form partner preferences. It is important to note that there were no group differences in mating behavior in any of parameters examined. Therefore, the enhanced partner preference in the experimental prairie voles cannot be attributed to increased sexual activity during the initial cohabitation period.
Adult female prairie voles show remarkable individual variation in their display of alloparental care. About 50% of sexually naïve females will spontaneously retrieve, lick/groom, and hover over pups presented to them (Lonstein and De Vries, 1999
; Bales and Carter, 2003
; Olazabal and Young, 2005
). There is also significant individual variation in OTR density in the NAcc among prairie voles (Young, 1999
). Females with higher densities of OTR in the NAcc are more likely to display alloparental responsiveness than animals with lower OTR in this area. Thus it was surprising that elevating OTR density in the NAcc of prairie voles did not enhance alloparental behavior. The fact that these animals did show accelerated partner preference formation suggest that the OTR derived from the viral vector transgene was functionally coupled to signal transduction pathways in the NAcc.
We hypothesize that individual variation in OTR activation in the NAcc during development may play a more important role in producing intra-species variation in alloparental behavior. The positive correlation in OTR density in the NAcc and alloparental behavior has been shown in juvenile prairie voles as well as adults (Olazabal and Young, 2006b
). Alloparental behavior in prairie voles appears to be particularly sensitive to perturbations during development. For example, perinatal exposure to OT alters alloparental behavior in female prairie voles (Bales et al., 2007
). Therefore, individuals with higher densities of OTR during development may experience increased OTR signaling in the NAcc, resulting in long-lasting neurochemical changes that increase the probability of displaying alloparental behavior as they become adults. If this hypothesis is correct, we would predict that increasing OTR expression in the NAcc neonatally would increase the frequency of alloparental behavior.
Another explanation for the failure of enhancing OTR expression in the NAcc to increase alloparental behavior is that variation in OTR expression in multiple brain regions may be necessary to produce the expected diversity in behavior. For example, OTR expression in the lateral septum is negatively correlated with alloparental behavior (Olazabal and Young, 2006a
). Finally, it is also possible that variation in hormone exposure or social experience influences OTR density in the NAcc in addition to altering alloparental behavior. For example, the presence or absence of the father during development or perinatal manipulation of steroid hormones can influence the display of alloparental responsiveness in female prairie voles (Roberts et al., 1996
; Roberts et al., 1998
; Lonstein and De Vries, 2000
In male prairie voles, vasopressin plays a critical role in the display of paternal behavior as well as partner preference formation, paralleling the role of oxytocin in females (Winslow et al., 1993
; Wang et al., 1994
). Site-specific pharmacological studies demonstrate that V1aR in the ventral pallidum, a major output of the NAcc, are critical for pair bond formation (Lim and Young, 2004
). Increasing V1aR in the ventral pallidum using viral vector mediated gene transfer accelerates partner preference formation of male prairie voles (Pitkow et al., 2001
), a finding that parallels the current study. Although over-expressing V1aR in the ventral pallidum of male meadow voles was not sufficient to induce paternal behavior, it did promote partner preference (Lim et al., 2004
); in contrast, in the present study overexpression of OTR in the NaCC did not stimulate partner preference formation in female meadow voles.
There are several potential explanations for the failure of female meadow voles with elevated OTR in the NAcc to form partner preferences. First, species differences in OT release within the NAcc during mating may differ between female prairie voles and meadow voles. Although OTR localization differs between the species, both prairie voles and meadow voles have OT-immunoreactive fibers in the NAcc (Ross and Young, unpublished data). In vivo
microdialysis experiments have shown that mating stimulates OT release in the NAcc of female prairie voles, but parallel studies have not been performed in meadow voles (C.D. Cole and Young, unpublished data). It is possible that infusion of OT into CMV-OTR treated animals would facilitate partner preference formation in meadow voles. However, it should be noted that in rats and sheep, vaginocervical stimulation increases central OT release (Kendrick et al., 1986
; Sansone et al., 2002
). Therefore it is likely that meadow voles are already experiencing a rise in accumbal OT with mating. Another explanation for the failure of NAcc OTR expression to stimulate partner preference formation in female meadow voles is that species differences in OTR expression in other brain regions are also necessary for pair bonding. For example, OTR density is also higher in the prefrontal cortex and lateral amygdala in prairie voles compared to nonmonogamous vole species (Insel et al., 1991
; Young et al., 1996
; Smeltzer et al., 2006
). Therefore, elevating OTR expression in multiple sites may be necessary for stimulating mating-induced partner preferences in meadow voles. Finally, it is possible that multiple neurochemical differences between the species are responsible for species differences in behavior (e.g. dopamine, corticotropin releasing factor)(Gingrich et al., 2000
; Liu and Wang, 2003
; Smeltzer et al., 2006
; Lim et al., 2007
There are several important caveats of our experimental approach that warrant discussion. First, the CMV-OTR likely increased OTR expression in all cell types in the injected area, including neuronal populations that normally do not respond to OT. However, it is possible that the transgenic OTR resulted in greater signaling in neurons that normally express endogenous OTR because of enhanced sensitization to OT released onto those neurons, or the presence of the appropriate downstream signaling molecules. Secondly, the area of transgene expression produced by viral vector infusion was not uniformly expressed over the entire rostral-caudal or medio-lateral extent of the NAcc. In the CMV-OTR females, OTR expression was consistently elevated in the shell and adjacent core regions of the NAcc. However, it should be noted that shell of the NAcc has been most implicated in the regulation of partner preference formation and OTR density in this same region is more highly correlated with alloparental behavior than the core region.
This is the first study to demonstrate conclusively that variation in OTR expression in the brain can contribute to variation in social behavior. OT has been widely implicated in the regulation of several behaviors, including social information processing and memory, mate choice, maternal nurturing and attachment (Dantzer et al., 1987
; Kendrick, 2000
; Ferguson et al., 2001
; Kavaliers et al., 2003
). There is now clear evidence that OT modulates human social cognition as well, including interpersonal trust, eye gaze, facial memory, and emotion perception (Kosfeld et al., 2005
; Domes et al., 2007
; Guastella et al., 2008
; Savaskan et al., 2008
). OT administration increases the retention of social cognition in a voice intonation task in autistic subjects (Hollander et al., 2007
), and several genetic studies have reported modest associations between non-coding polymorphisms of the OTR gene and autism spectrum disorder (Wu et al., 2005
; Jacob et al., 2007
; Lerer et al., 2007
; Yrigollen et al., 2008
). There is limited information on the distribution of OTR, and nothing is known regarding individual variation in OTR density in the human brain. Our results suggest that variation in OTR density in specific brain regions may contribute to individual differences in social cognitive function in humans.