Partner Preference Formation Research Articles

RNAi knockdown of oxytocin receptor in the nucleus accumbens inhibits social attachment and parental care in monogamous female prairie voles

Oxytocin modulates many aspects of social cognition and behaviors, including maternal nurturing, social recognition and bonding. Natural variation in oxytocin receptor (OXTR) density in the nucleus accumbens (NAcc) is associated with variation in alloparental behavior, and artificially enhancing OXTR expression in the NAcc enhances alloparental behavior and pair bonding in socially monogamous prairie voles. Furthermore, infusion of an OXTR antagonist into the NAcc inhibits alloparental behavior and partner preference formation. However, antagonists can promiscuously interact with other neuropeptide receptors. To directly examine the role of OXTR signaling in social bonding, we used RNA interference to selectively knockdown, but not eliminate, OXTR in the NAcc of female prairie voles and examined the impact on social behaviors. Using an adeno-associated viral vector expressing a short hairpin RNA (shRNA) targeting Oxtr mRNA, we reduced accumbal OXTR density in female prairie voles from juvenile age through adulthood. Females receiving the shRNA vector displayed a significant reduction in alloparental behavior and disrupted partner preference formation. These are the first direct demonstrations that OXTR plays a critical role in alloparental behavior and adult social attachment, and suggest that natural variation in OXTR expression in this region alone can create variation in social behavior.

Melanocortin Receptor Agonists Facilitate Oxytocin-Dependent Partner Preference Formation in the Prairie Vole.

The central melanocortin (MC) system has been widely studied for its effects on food intake and sexual behavior. However, the MC system, and more specifically the MC4 receptor (MC4R), also interacts with neurochemical systems that regulate socioemotional behaviors, including oxytocin (OT) and dopamine. In monogamous prairie voles, OT and dopamine interact to promote partner preference formation, a laboratory measure of an enduring social bond between mates. Here we investigated the effects of MC receptor activation on partner preference formation in prairie voles, as well as the interaction between the MC and OT systems during this process. Peripheral administration of the brain penetrant MC3/4R receptor peptide agonist, Melanotan II (MTII), and the highly selective, small-molecule MC4R agonist, Pf-446687, enhanced partner preference formation in the prairie vole, but not in the non-monogamous meadow vole. MTII-induced partner preferences were enduring, as they were present 1 week after drug manipulation. The prosocial effects of MCR agonists may be mediated, in part, through modulation of OT, as coadministration of an OT receptor antagonist prevented MTII-induced partner preferences. MTII also selectively activated hypothalamic OT neurons and potentiated central OT release. As OT has been shown to enhance some aspects of social cognition in humans, our data suggest that the MC4R may be a viable therapeutic target for enhancing social function in psychiatric disorders, including autism spectrum disorders and schizophrenia, potentially through activation of the OT system.

The effects of naloxone on courtship and pairing behaviour in male and female zebra finches: the importance of testing mechanisms using multiple paradigms

Opioids are implicated in social attachments, but their role in avian pair bonds is not well understood. The present study tested the effects of naloxone, an opioid antagonist, on pairing using both a forced-choice and a mixed-sex aviary paradigm. First, three doses of naloxone were systemically administered in males using a repeated measures forced-choice design, partner preference formation was tested on the second day. Males treated with 20 mg/kg sang less undirected song. Males treated with 10 mg/kg of naloxone sang less to the familiar partner than when treated with saline and were less likely to form a partner preference than were other treatments. In females, 10 mg/kg of naloxone in a forced-choice paradigm increased preference for the unfamiliar over the familiar male. Finally, males and females were administered either naloxone (10 mg/kg) or saline in a mixed-sex aviary. In females, naloxone increased pairing behaviours, but had no other effects in either sex. Our findings suggest that the effects of naloxone on pairing-related behaviours are context-dependent; male–male competition may decrease the effects of naloxone on male song and a choice of mates may increase affiliation in females in a semi-naturalistic paradigm, and increase preferences for an unfamiliar partner in a forced-choice paradigm. Our findings highlight the importance of using multiple paradigms to test mechanisms of behaviour. These findings contribute to our understanding of the mechanisms of monogamous relationships and suggest that opioids play a role in male courtship, female affiliation and partner preferences in both sexes of zebra finches, but that context is important.

Corticotropin-releasing factor receptor densities vary with photoperiod and sociality

Life in social groups relies on prosocial behaviors as well as on reduction of antisocial behaviors such as aggression and territoriality. The mechanisms supporting variation in behaviors that give rise to group living (sociality) are largely unknown. Female meadow voles exhibit natural seasonal variation in sociality: females are aggressive and territorial in summer, while in winter they share burrows and nest in mixed-sex groups. This behavioral shift is paralleled in the lab by day length-dependent variation in partner preference formation and social huddling. We exploit natural variation in meadow vole sociality in order to examine changes in neural pathways that coincide with environmental and behavioral variations.Mounting evidence suggests that the corticotropin-releasing factor system, encompassing multiple peptides and two receptor subtypes (CRF1 and CRF2), may play an important role in regulating social behaviors. We report day-length dependent variation in CRF1 and CRF2 receptor binding in female meadow voles, and relate these findings to previously collected oxytocin receptor (OTR) binding data and behavioral data for the same individuals. CRF1 receptor binding was greater in summer-like long day lengths (LD), particularly in the hippocampus, while CRF2 receptor binding was greater in winter-like short day lengths (SD) in the cingulate cortex and hippocampus. OTR varied with day length in the bed nucleus of the stria terminalis, nucleus accumbens, and hippocampus. SD voles huddled more extensively than LD voles, and greater huddling time was associated with more CRF1 receptor binding and less CRF2 receptor binding in subregions of the lateral septum. CRF2 receptor associations with behavior mirrored those of OTR in the lateral septum. Finally, estradiol treatment affected density of CRF receptors in multiple brain regions. CRF receptors and their ligands are promising candidates for enhancing understanding of the regulation of non-sexual social behavior between group living peers.

A novel model for neuroendocrine toxicology: neurobehavioral effects of BPA exposure in a prosocial species, the prairie vole (Microtus ochrogaster).

Impacts on brain and behavior have been reported in laboratory rodents after developmental exposure to bisphenol A (BPA), raising concerns about possible human effects. Epidemiological data suggest links between prenatal BPA exposure and altered affective behaviors in children, but potential mechanisms are unclear. Disruption of mesolimbic oxytocin (OT)/vasopressin (AVP) pathways have been proposed, but supporting evidence is minimal. To address these data gaps, we employed a novel animal model for neuroendocrine toxicology: the prairie vole (Microtus ochrogaster), which are more prosocial than lab rats or mice. Male and female prairie vole pups were orally exposed to 5-μg/kg body weight (bw)/d, 50-μg/kg bw/d, or 50-mg/kg bw/d BPA or vehicle over postnatal days 8-14. Subjects were tested as juveniles in open field and novel social tests and for partner preference as adults. Brains were then collected and assessed for immunoreactive (ir) tyrosine hydroxylase (TH) (a dopamine marker) neurons in the principal bed nucleus of the stria terminalis (pBNST) and TH-ir, OT-ir, and AVP-ir neurons in the paraventricular nucleus of the hypothalamus (PVN). Female open field activity indicated hyperactivity at the lowest dose and anxiety at the highest dose. Effects on social interactions were also observed, and partner preference formation was mildly inhibited at all dose levels. BPA masculinized principal bed nucleus of the stria terminalis TH-ir neuron numbers in females. Additionally, 50-mg/kg bw BPA-exposed females had more AVP-ir neurons in the anterior PVN and fewer OT-ir neurons in the posterior PVN. At the 2 lowest doses, BPA eliminated sex differences in PVN TH-ir neuron numbers and reversed this sex difference at the highest dose. Minimal behavioral effects were observed in BPA-exposed males. These data support the hypothesis that BPA alters affective behaviors, potentially via disruption of OT/AVP pathways.

Oxytocin reverses amphetamine-induced deficits in social bonding: evidence for an interaction with nucleus accumbens dopamine.

Drug addiction has devastating consequences on social behaviors and can lead to the impairment of social bonding. Accumulating evidence indicates that alterations in oxytocin (OT) and dopamine (DA) neurotransmission within brain reward circuitry may be involved. We investigated this possibility, as well as the therapeutic potential of OT for drug-induced social deficits, using the prairie vole (Microtus ochrogaster)-a socially monogamous rodent that forms enduring pair bonds between adult mates. We demonstrate that repeated exposure to the commonly abused psychostimulant amphetamine (AMPH) inhibits the formation of partner preferences (an index of pair bonding) in female prairie voles. AMPH exposure also altered OT and DA neurotransmission in regions that mediate partner preference formation: it decreased OT and DA D2 receptor immunoreactivity in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAcc), respectively, and increased NAcc DA levels. Administration of OT directly into the mPFC of AMPH-exposed voles restored partner preferences, and altered NAcc DA levels, and this effect was dependent on OT receptor activation. Together, these data suggest that repeated AMPH exposure impairs pair bonding through an OT-mediated mechanism, and that OT and DA systems within brain reward circuitry may interact to mediate the complex relationship between drug abuse and social bonding. Further, these results provide empirical support for the idea that the central OT system may represent an important target for the treatment of social deficits in addiction.

Neonatal melanocortin receptor agonist treatment reduces play fighting and promotes adult attachment in prairie voles in a sex-dependent manner

The melanocortin receptor (MCR) system has been studied extensively for its role in feeding and sexual behavior, but effects on social behavior have received little attention. α-MSH interacts with neural systems involved in sociality, including oxytocin, dopamine, and opioid systems. Acute melanotan-II (MTII), an MC3/4R agonist, potentiates brain oxytocin (OT) release and facilitates OT-dependent partner preference formation in socially monogamous prairie voles. Here we examined the long-term impact of early-life MCR stimulation on hypothalamic neuronal activity and social development in prairie voles. Male and female voles were given daily subcutaneous injections of 10 mg/kg MTII or saline between postnatal days (PND) 1-7. Neonatally-treated males displayed a reduction in initiated play fighting bouts as juveniles compared to control males. Neonatal exposure to MTII facilitated partner preference formation in adult females, but not males, after a brief cohabitation with an opposite-sex partner. Acute MTII injection elicited a significant burst of the immediate early gene EGR-1 immunoreactivity in hypothalamic OT, vasopressin, and corticotrophin releasing factor neurons, when tested in PND 6-7 animals. Daily neonatal treatment with 1 mg/kg of a more selective, brain penetrant MC4R agonist, PF44687, promoted adult partner preferences in both females and males compared with vehicle controls. Thus, developmental exposure to MCR agonists lead to a persistent change in social behavior, suggestive of structural or functional changes in the neural circuits involved in the formation of social relationships.

Breaking bonds in male prairie vole: Long-term effects on emotional and social behavior, physiology, and neurochemistry

Social relationships are essential for many fundamental aspects of life while bond disruption can be detrimental to mental and physical health. Male prairie voles form enduring social bonds with their female partners, allowing the evaluation of partner loss on behavior, physiology, and neurochemistry. Males were evaluated for partner preference formation induced by 24h of mating, and half were separated from their partner for 4 wk. In Experiment 1, partner loss significantly increased anxiety-like behaviors in the elevated plus maze and light-dark box tests and marginally increased depressive-like behaviors in the forced swim test. In addition, while intruder-directed aggression is common in pair bonded prairie voles, separated males were affiliative and lacked aggression toward an unfamiliar female and an intruding male conspecific. Partner loss increased the density of oxytocin-immunoreactivity (-ir), vasopressin-ir, and corticotrophin-releasing hormone-ir cells in the paraventricular nucleus of the hypothalamus and oxytocin-ir cells in the supraoptic nucleus. Tyrosine hydroxylase-ir was not affected. In Experiment 2, partner preference was observed after 2 wk of partner loss but eliminated after 4 wk partner loss. Body weight gain and plasma corticosterone concentrations were elevated throughout the 4 wk. No effects were observed for plasma oxytocin or vasopressin. Together, partner loss elicits anxiety-like and depression-like behaviors, disrupts bond-related behaviors, and alters neuropeptide systems that regulate such behaviors. Thus, partner loss in male prairie voles may provide a model to better understand the behavior, pathology, and neurobiology underlying partner loss and grief.

Histone deacetylase inhibitors facilitate partner preference formation in female prairie voles

In the socially monogamous prairie vole (Microtus ochrogaster), mating induces enduring pair-bonds initiated by partner preference formation and regulated by a variety of neurotransmitters including oxytocin, vasopressin, and dopamine. Here we examined potential epigenetic mechanisms mediating pair-bond regulation. We show that the histone deacetylase inhibitors sodium butyrate and TrichoStatin A (TSA) facilitate partner preference formation in female prairie voles in the absence of mating. This was associated with a specific up-regulation of oxytocin (OTR) and vasopressin V1a receptors (V1aR) in the nucleus accumbens, through an increase in histone acetylation at their respective promoter. Furthermore, TSA-facilitated partner preference was prevented by OTR or V1aR blockade in the nucleus accumbens. Importantly, mating-induced partner preference triggered the same epigenetic regulation of OTR and V1aR gene promoters as TSA. These observations thus indicate that TSA and mating facilitate partner preference through epigenetic events, providing the first direct evidence for an epigenetic regulation of pair-bonding.

μ-Opioid Receptors within Subregions of the Striatum Mediate Pair Bond Formation through Parallel Yet Distinct Reward Mechanisms

The prairie vole is a socially monogamous rodent that is an excellent animal model for studies of the neurobiology of social attachment. Such studies have demonstrated that activation of reward circuitry during social interactions facilitates pair bond formation. Within this circuitry, μ-opioid receptors (MORs) modulate naturally rewarding behavior in an anatomically segregated manner; MORs located throughout the striatum (dorsal striatum, NAc core, and the entire NAc shell) are implicated in general motivational processes, whereas those located specifically within the dorsomedial NAc shell mediate positive hedonics (and are referred to as a "hedonic hotspot"). The purpose of the present study was to determine whether MORs within these distinct subregions differentially mediate pair bond formation. We first used receptor autoradiography to compare MOR binding densities between these regions. MOR binding was significantly higher in the NAc core and dorsomedial NAc shell compared with the ventral NAc shell. We next used partner preference testing to determine whether MORs within these subregions differentially mediate pair bonding. Blockade of MORs using 1 or 3 μg of H-d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2 within the dorsal striatum decreased mating during the cohabitation period and inhibited partner preference formation. In contrast, blockade of MORs within dorsomedial NAc shell inhibited partner preference formation without effecting mating behavior, whereas other regions were not involved. Thus, MORs within the dorsal striatum mediate partner preference formation via impairment of mating, whereas those in the dorsomedial NAc shell appear to mediate pair bond formation through the positive hedonics associated with mating.

Neuroanatomical distribution of μ-opioid receptor mRNA and binding in monogamous prairie voles (Microtus ochrogaster) and non-monogamous meadow voles (Microtus pennsylvanicus)

The opiate system has long been implicated in the rewarding properties of social interactions. In particular, the μ-opioid receptor (MOR) mediates multiple forms of social attachment, including the attachment of offspring to the mother and social bonding between mates. We have previously shown that MOR in the caudate-putamen is involved in partner preference formation in monogamous prairie voles. Here, using in situ hybridization and receptor autoradiography, we mapped in detail the distribution of MOR mRNA and ligand binding in monogamous prairie vole brains and compared MOR binding density with that of promiscuous meadow vole brains. Comparison of MOR binding in these closely related species with distinctly different social behavior revealed that while the distribution of MOR is similar, prairie voles have significantly higher densities of MOR than meadow voles in a majority of regions in the forebrain, including the caudate-putamen, nucleus accumbens shell, lateral septum and several thalamic nuclei, including the anteroventral and anteromedial thalamic nuclei. These differences in MOR expression between prairie and meadow voles could potentially contribute to species differences in behavior, including social attachment.

The CRF system and social behavior: a review

The corticotropin-releasing factor (CRF) system plays a key role in a diversity of behaviors accompanying stress, anxiety and depression. There is also substantial research on relationships between social behaviors and the CRF system in a variety of taxa including fish, birds, rodents, and primates. Some of these relationships are due to the broad role of CRF and urocortins in stress and anxiety, but these peptides also modulate social behavior specifically. For example, the social interaction (SI) test is often used to measure anxiety-like behavior. Many components of the CRF system including CRF, urocortin1, and the R1 receptor have been implicated in SI, via general effects on anxiety as well as specific effects depending on the brain region. The CRF system is also highly responsive to chronic social stressors such as social defeat and isolation. Animals exposed to these stressors display a number of anxiety- and stress-related behaviors, accompanied by changes in specific components the CRF system. Although the primary focus of CRF research on social behavior has been on the deleterious effects of social stress, there are also insights on a role for CRF and urocortins in prosocial and affiliative behaviors. The CRF system has been implicated in parental care, maternal defense, sexual behavior, and pair bonding. Species differences in the ligands and CRF receptors have been observed in vole and bird species differing in social behavior. Exogenous administration of CRF facilitates partner preference formation in monogamous male prairie voles, and these effects are dependent on both the CRF R1 and R2 receptors. These findings are particularly interesting as studies have also implicated the CRF and urocortins in social memory. With the rapid progress of social neuroscience and in understanding the complex structure of the CRF system, the next challenge is in parsing the exact contribution of individual components of this system to specific social behaviors.

Chronic Intranasal Oxytocin Causes Long-Term Impairments in Partner Preference Formation in Male Prairie Voles

Oxytocin (OT) is a hormone shown to be involved in social bonding in animal models. Intranasal OT is currently in clinical trials for use in disorders such as autism and schizophrenia. We examined long-term effects of intranasal OT given developmentally in the prairie vole (Microtus ochrogaster), a socially monogamous rodent, often used as an animal model to screen drugs that have therapeutic potential for social disorders. We treated voles with one of three dosages of intranasal OT, or saline, from day 21 (weaning) through day 42 (sexual maturity). We examined both social behavior immediately following administration, as well as long-term changes in social and anxiety behavior after treatment ceased. Group sizes varied from 8 to 15 voles (n = 89 voles total). Treatment with OT resulted in acute increases in social behavior in male voles with familiar partners, as seen in humans. However, long-term developmental treatment with low doses of intranasal OT resulted in a deficit in partner preference behavior (a reduction of contact with a familiar opposite-sex partner, used to index pair-bond formation) by male voles. Long-term developmental treatment with OT may show results different to those predicted by short-term studies, as well as significant sex differences and dosage effects. Further animal study is crucial to determining safe and effective strategies for use of chronic intranasal OT, especially during development.

Neuroendocrine and Behavioural Responses to Exposure to an Infant in Male Prairie Voles

Paternal behaviour and pair-bond formation are defining characteristics of social monogamy. However, in comparison to pair-bonding, the endocrine factors associated with the male care of young are not well studied. In the present study, plasma concentrations of oxytocin, vasopressin and corticosterone (CORT) were measured in reproductively naïve male prairie voles as a function of exposure to an infant or control manipulations (i.e. handling or exposure to a wooden dowel). Plasma oxytocin concentrations were transiently elevated within 10 min of pup exposure. Although plasma CORT concentration typically increases after handling, after 10 min of pup exposure, the concentration of plasma CORT was not increased, suggesting an attenuation of CORT release by pup exposure. Group differences in the concentrations of plasma hormones were no longer detected at 20 or 60 min after treatment. These patterns of rapid change in the concentrations of plasma oxytocin and CORT were observed in both juvenile and adult males but not detected after control procedures. Plasma vasopressin, assessed only in adult males, did not vary as a function of pup exposure or other manipulations. In the paraventricular nucleus of the hypothalamus, pup exposure also increased activation (as assessed by the measurement of c-Fos) of neurones that stained for either oxytocin or vasopressin, whereas it decreased c-Fos expression in neurones stained for corticotrophin-releasing hormone. In addition, brief pup exposure (20 min) facilitated subsequent partner preference formation when alloparental males and pup attackers were considered as a group. In the context of other studies, these data support the hypothesis that neuroendocrine changes associated with male alloparental behaviour are related to those implicated in pair-bonding.

Enhaced D2-type receptor activity facilitates the development of conditioned same-sex partner preference in male rats

Animal models have shown that the neural bases of social attachment, sexual preference and pair bonds, depend on dopamine D2-type receptor and oxytocin activity. In addition, studies have demonstrated that cohabitation can shape partner preference via conditioning. Herein, we used rats to explore the development of learned same-sex partner preferences in adulthood as a result of cohabitation during enhanced D2 activity. Experimental Wistar males (N=20), received saline or the D2 agonist (quinpirole) and were allowed to cohabitate during 24h, with a stimulus male partner that bore almond scent on the back as conditioned stimulus. This was repeated every 4days, for a total of three trials. Four days later they were drug-free tested for partner preference between the scented male partner and a sexually receptive female. Sexual partner preference was analyzed by measuring frequency and latency for appetitive and consummatory sexual behaviors, as well as non-contact erections. Social preference was also analyzed by measuring the frequency and latency of visits, body contacts and time spent together. Results indicated that only quinpirole-treated males displayed sexual and social preference for the scented male over the sexually receptive female. They spent more time together, displayed more body contacts, more female-like proceptive behaviors, and more non-contact erections. Accordingly, conditioned males appeared to be more sexually aroused and motivated by the known male than by a receptive female. We discuss the implications of this animal model on the formation of learned homosexual partner preferences.

Behavioral effects of progesterone on pair bonding and partner preference in the female zebra finch (Taeniopygia guttata)

Progesterone is a sex steroid known to be involved in reproduction, but its role in pair relationships is not well understood. This study explored the effects of exogenous progesterone (P4) on courtship and pairing behaviors in female zebra finches (Taeniopygia guttata) in two separate experiments: the first focused on courtship and initial pair formation and the second examined the effects on pair maintenance. In these experiments, we tested the hypothesis that P4 increases pairing behaviors and consequently influences their partner preference. In Experiment 1, animals engaged in significantly more pairing behaviors when they were treated with P4 than when they received the vehicle. However, this effect was not partner-specific, since the association index (a marker for female partner preference) did not differ between treatment conditions. In Experiment 2, females were given two weeks to form a pair and then injected with P4 or vehicle. Pairs were observed that day and the subsequent day to determine if P4 caused a decrease in mate-directed behavior and an increase in extra pair behavior. P4 did not affect the quality of the pair relationship and did not increase extra pair behavior. These results suggest that P4 influences the overall quantity of initial pairing behaviors and may slightly increase the likelihood of partner preference formation over short time courses. However, P4 does not alter a previously established bond, suggesting there are likely separate mechanisms for initial pairing behaviors and pair maintenance.

Neonatal exposure to the D1 agonist SKF38393 inhibits pair bonding in the adult prairie vole

The monogamous prairie vole displays developmental sensitivity to early pharmacological manipulation in a number of species-typical social behaviors. The long-term consequences of altering the neonatal dopamine system are not well characterized. This study examined whether early manipulation of the dopamine system, a known mediator of adult prairie vole social behavior, during neonatal development would affect adult aggressive and attachment behaviors. Eight-day-old pups were given a single treatment with either 1 mg/kg of SKF38393 (D1 agonist), quinpirole (D2 agonist), SCH23390 (D1 antagonist), eticlopride (D2 antagonist), or saline vehicle. As adults, animals received tests for intrasexual aggression and partner preference. Activation of D1-like receptors in pups impaired partner preference formation, but had no effect on aggression. Other neonatal treatments had no effect on their behavior as adults. To determine whether D1 activation in pups induced changes in dopamine receptor expression, we performed autoradiography on striatal tissue from a second cohort of saline-treated and SKF38393-treated animals. Although sex differences were observed, we found no treatment differences in D1 or D2 receptor binding in any striatal subregion. This study shows that exposure to a single early pharmacological alteration of dopamine receptor activity may have long-term effects on the social behavior of prairie voles.

Opioid Receptors: Binding that Ties

Prairie voles form stable, monogamous mating pairs, and are a valuable model for understanding the neurobiology of enduring partner relationships. The report by Burkett et al (2011) investigates the role of μ-opioid receptors (MOR) in partner preference formation in prairie voles. The authors found that systemic naltrexone treatment of female prairie voles during initial exposure to a male reduced subsequent mating bouts and nonsexual socialization with this familiar partner, when a choice test including a novel male was performed afterwards. The authors then targeted two regions in the basal ganglia, the shell of the nucleus accumbens, and the caudate putamen, with direct infusions of a selective MOR antagonist to determine if MOR in either region was necessary for partner preference. They found that MOR in the dorsal striatum, but not the shell of the nucleus accumbens, modulated partner preference formation, suggesting a role for dorsal striatal MOR in this complex social behavior. Radioligand binding and in situ hybridization data supported these results, as MOR expression was higher in the dorsal striatum than in nucleus accumbens.

Increasing oxytocin receptor expression in the nucleus accumbens of pre-pubertal female prairie voles enhances alloparental responsiveness and partner preference formation as adults

Oxytocin receptors (OXTR) in the nucleus accumbens (NAcc) promote alloparental behavior and partner preference formation in female prairie voles. Within the NAcc there is significant individual variation in OXTR binding and virgin juvenile and adult females with a high density of OXTR in the NAcc display an elevated propensity to engage in alloparental behavior toward novel pups. Over-expression of OXTR in the NAcc of adult female prairie voles using viral vector gene transfer facilitates partner preference formation, but has no effect on alloparental behavior, even though OXTR antagonists infused into the NAcc blocks both behaviors. We therefore hypothesized that long-term increases in OXTR signaling during development may underlie the relationship between adult OXTR density in the NAcc and alloparental behavior. To test this hypothesis, we used viral vector gene transfer to increase OXTR density in the NAcc of prepubertal, 21day old female prairie voles and tested for both alloparental behavior and partner preference formation as adults. Consistent with a developmental impact of OXTR signaling, adults over-expressing OXTR from weaning display both increased alloparental behavior and partner preference formation. Thus, the relatively acute impact of elevated OXTR signaling in the NAcc on partner preference formation previously reported appears to be dissociable from the effects of longer term, developmentally relevant OXTR signaling necessary for modulating alloparental behavior. These results are consistent with the hypothesis that oxytocin can have both long-term “organizational” effects as well as acute “activational” effects on affiliative behaviors.

Activation of μ-Opioid Receptors in the Dorsal Striatum is Necessary for Adult Social Attachment in Monogamous Prairie Voles

Despite significant evidence that opioids are involved in attachment by mediating social reward and motivation, the role of opioids in the formation of adult social attachments has not been explored. We used the socially monogamous prairie vole (Microtus ochrogaster) to explore the role of endogenous opioids in social bonding by examining partner preference formation in female prairie voles. We hypothesized that μ-opioid receptors (MORs) in the striatum have a critical role in partner preference formation. We therefore predicted that peripheral administration of an opioid receptor antagonist would inhibit partner preference formation, and more specifically, that μ-opioid selective receptor blockade within the striatum would inhibit partner preference formation. To test our hypotheses, we first administered the non-selective opioid antagonist naltrexone peripherally to females during an 18-h cohabitation with a male and later tested the female with a partner preference test (PPT). Females showed a dose schedule-dependent decrease in partner preference in the PPT, with females in the continuous dose group displaying stranger preferences. Next, we administered microinjections of the MOR selective antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) into either the nucleus accumbens shell (NAS) or the caudate-putamen (CP) immediately before a 24-h cohabitation with a male, and later tested the female with a PPT. Females receiving CTAP into the CP, but not the NAS, showed no preference in the PPT, indicating an inhibition of partner preference formation. We show here for the first time that MORs modulate partner preference formation in female prairie voles by acting in the CP.