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Background: Stress-induced illnesses, like major depression, are among the leading causes of disability across the world. Consequently, there is a dire need for the validation of translationally-suited animal models incorporating social stress to uncover the etiology of depression. Prairie voles (Microtus ochrogaster) are more translationally relevant than many other rodent models as they display monogamous social and bi-parental behaviors. Therefore, we evaluated whether a novel social defeat stress (SDS) model in male prairie voles induces depression-relevant behavioral outcomes., Methods: Adult sexually-naïve male prairie voles experienced SDS bouts from a conspecific pair-bonded male aggressor, 10 min per day for 10 consecutive days. Non-stressed controls (same-sex siblings) were housed in similar conditions but never experienced physical stress. Twenty-four h later, voles were evaluated in social interaction, sucrose preference, and Morris water maze tests - behavioral endpoints validated to assess social withdrawal, anhedonia-related behavior, and spatial memory performance, respectively., Results: SDS-exposed voles displayed lower sociability and body weight, decreased preference for a sucrose solution, and impairment of spatial memory retrieval. Importantly, no differences in general locomotor activity were observed as a function of SDS exposure., Limitations: This study does not include female voles in the experimental design., Conclusions: We found that repeated SDS exposure, in male prairie voles, results in a depression-relevant phenotype resembling an anhedonia-like outcome (per reductions in sucrose preference) along with social withdrawal and spatial memory impairment - highlighting that the prairie vole is a valuable model with potential to study the neurobiology of social stress-induced depression-related outcomes., Competing Interests: Declaration of competing interest The authors declare no financial or non-financial conflicts of interest. The funding agency was not involved in the design of the experiments, data collection process, interpretation of the results, nor writing of the manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Birth is a critical period for the developing brain, a time when surging hormone levels help prepare the fetal brain for the tremendous physiological changes it must accomplish upon entry into the 'extrauterine world'. A number of obstetrical conditions warrant manipulations of these hormones at the time of birth, but we know little of their possible consequences on the developing brain. One of the most notable birth signaling hormones is oxytocin, which is administered to roughly 50% of laboring women in the United States prior to / during delivery. Previously, we found evidence for behavioral, epigenetic, and neuroendocrine consequences in adult prairie vole offspring following maternal oxytocin treatment immediately prior to birth. Here, we examined the neurodevelopmental consequences in adult prairie vole offspring following maternal oxytocin treatment prior to birth. Control prairie voles and those exposed to 0.25 mg/kg oxytocin were scanned as adults using anatomical and functional MRI, with neuroanatomy and brain function analyzed as voxel-based morphometry and resting state functional connectivity, respectively. Overall, anatomical differences brought on by oxytocin treatment, while widespread, were generally small, while differences in functional connectivity, particularly among oxytocin-exposed males, were larger. Analyses of functional connectivity based in graph theory revealed that oxytocin-exposed males in particular showed markedly increased connectivity throughout the brain and across several parameters, including closeness and degree. These results are interpreted in the context of the organizational effects of oxytocin exposure in early life and these findings add to a growing literature on how the perinatal brain is sensitive to hormonal manipulations at birth., Competing Interests: Conflict of interest CFF reports a financial interest in Animal Imaging Research, the company that makes the radio frequency electronics and holders for animal imaging. All other authors report no biomedical financial interests or potential conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: We used the highly prosocial prairie vole to test the hypothesis that higher-order brain structure-microarchitecture and functional connectivity (FC)-would differ between males from populations with distinctly different levels of prosocial behavior. Specifically, we studied males from Illinois (IL), which display high levels of prosocial behavior, and first generation males from Kansas dams and IL males (KI), which display the lowest level of prosocial behavior and higher aggression. Behavioral differences between these males are associated with overexpression of estrogen receptor alpha in the medial amygdala and bed nucleus of the stria terminalis and neuropeptide expression in the paraventricular nucleus., Methods: We compared apparent diffusion coefficient, fractional anisotropy, and blood oxygen level-dependent resting-state FC between males., Results: IL males displayed higher apparent diffusion coefficient in regions associated with prosocial behavior, including the bed nucleus of the stria terminalis, paraventricular nucleus, and anterior thalamic nuclei, while KI males showed higher apparent diffusion coefficient in the brainstem. KI males showed significantly higher fractional anisotropy than IL males in 26 brain regions, with the majority being in the brainstem reticular activating system. IL males showed more blood oxygen level-dependent resting-state FC between the bed nucleus of the stria terminalis, paraventricular nucleus, and medial amygdala along with other brain regions, including the hippocampus and areas associated with social and reward networks., Conclusions: Our results suggest that gray matter microarchitecture and FC may play a role the expression of prosocial behavior and that differences in other brain regions, especially the brainstem, could be involved. The differences between males suggests that this system represents a potentially valuable model system for studying emotional differences and vulnerability to stress and addiction., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: The goal of this study was to elucidate the fundamental connectivity-resting-state connectivity-within and between nodes in the olfactory and prosocial (PS) cores, which permits the expression of social monogamy in males; and how differential connectivity accounts for differential expression of prosociality and aggression., Methods: Using resting-state functional magnetic resonance imaging, we integrated graph theory analysis to compare functional connectivity between two culturally/behaviorally distinct male prairie voles (Microtusochrogaster)., Results: Illinois males display significantly higher levels of prosocial behavior and lower levels of aggression than KI (Kansas dam and Illinois sire) males, which are associated with differences in underlying neural mechanisms and brain microarchitecture. Shared connectivity 1) between the anterior hypothalamic area and the paraventricular nucleus and 2) between the medial preoptic area and bed nucleus of the stria terminalis and the nucleus accumbens core suggests essential relationships required for male prosocial behavior. In contrast, Illinois males displayed higher levels of global connectivity and PS intracore connectivity, a greater role for the bed nucleus of the stria terminalis and anterior hypothalamic area, which were degree connectivity hubs, and greater PS and olfactory intercore connectivity., Conclusions: These findings suggest that behavioral differences are associated with PS core degree of connectivity and postsignal induction. This transgenerational system may serve as powerful mental health and drug abuse translational model in future studies., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Social norms and legality surrounding the use of medical and recreational cannabis are changing rapidly. The prevalence of cannabis use in adolescence is increasing. The aim of this study was to assess any sex-based neurobiological effects of chronically inhaled, vaporised cannabis on adolescent female and male mice., Methods: Female and male mice were exposed daily to vaporised cannabis (10.3% Δ-9-tetrahydrocannabinol [THC] and 0.05% cannabidiol [CBD]) or placebo from postnatal day 23 to day 51. Following cessation of treatment, mice were examined for changes in brain structure and function using noninvasive multimodal magnetic resonance imaging (MRI). Data from voxel-based morphometry, diffusion weighted imaging and rest state functional connectivity were registered to and analysed with a 3D mouse atlas with 139 brain areas. Following imaging, mice were tested for their preference for a novel object., Results: The effects were sexually dimorphic with females showing a unique distribution and inverse correlation between measures of fractional anisotropy and apparent diffusion coefficient localised to the forebrain and hindbrain. In contrast males displayed significant increased functional coupling with the thalamus, hypothalamus and brainstem reticular activating system as compared with controls. Cannabis males also presented with altered hippocampal coupling and deficits in cognitive function., Conclusion: Chronic exposure to inhaled vaporised cannabis had significant effects on brain structure and function in early adulthood corroborating much of the literature. Females presented with changes in grey matter microarchitecture, while males showed altered functional connectivity in hippocampal circuitry and deficits in object recognition., (© 2022 Society for the Study of Addiction.)

Formation of long-term pair-bonds is a complex process, involving multiple neural circuits and is context- and experience-dependent. While laboratory studies using prairie voles have identified the involvement of several neural mechanisms, efforts to translate these findings into predictable field outcomes have been inconsistent at best. Here we test the hypothesis that inhibition of oestrogen receptor alpha (ERα) in the medial amygdala of male prairie voles would significantly increase the expression of social monogamy in the field. Prairie vole populations of equal sex ratio were established in outdoor enclosures with males bred for high levels of ERα expression and low levels of prosocial behaviour associated with social monogamy. Medial amygdala ERα expression was knocked down in half the males per population. Knockdown males displayed a greater degree of social monogamy in five of the eight behavioural indices assessed. This study demonstrates the robust nature of ERα in playing a critical role in the expression of male social monogamy in a field setting.

This study was designed to assess the effects of daily psychostimulant exposure during juvenility and peri-adolescence on brain morphology and functional connectivity using multimodal magnetic resonance imaging. We hypothesized that long-term exposure to methylphenidate would enhance connectivity with the prefrontal cortex. Male rats were given daily injections of either methylphenidate (n=10), dextroamphetamine (n=10) or saline vehicle (n=10) from postnatal day 21 to 42. They were imaged between postnatal day 43 and 48. Voxel-based morphometry, diffusion weighted imaging, and resting state functional connectivity were used to quantify brain structure and function. Images from each modality were registered and analyzed, using a 3D MRI rat atlas providing site-specific data over 171 different brain areas. Following imaging, rats were tested for cognitive function using novel object preference. Long-lasting psychostimulant treatment was associated with only a few significant changes in brain volume and measures of anisotropy compared to vehicle. Resting state functional connectivity imaging revealed decreased coupling between the prefrontal cortex, basal ganglia and sensory motor cortices. There were no significant differences between experimental groups for cognitive behavior. In this exploratory study, we showed that chronic psychostimulant treatment throughout juvenility and preadolescence has a minimal effect on brain volume and gray matter microarchitecture, but significantly uncouples the connectivity in the cerebral/basal ganglia circuitry., Competing Interests: Craig Ferris has a financial interest in Animal Imaging Research, the company that makes the radiofrequency electronics and holders for animal imaging., (AJTR Copyright © 2021.)

Background: The phytocannabinoid cannabidiol (CBD) exhibits anxiolytic activity and has been promoted as a potential treatment for post-traumatic stress disorders. How does CBD interact with the brain to alter behavior? We hypothesized that CBD would produce a dose-dependent reduction in brain activity and functional coupling in neural circuitry associated with fear and defense., Methods: During the scanning session awake mice were given vehicle or CBD (3, 10, or 30 mg/kg I.P.) and imaged for 10 min post treatment. Mice were also treated with the 10 mg/kg dose of CBD and imaged 1 h later for resting state BOLD functional connectivity (rsFC). Imaging data were registered to a 3D MRI mouse atlas providing site-specific information on 138 different brain areas. Blood samples were collected for CBD measurements., Results: CBD produced a dose-dependent polarization of activation along the rostral-caudal axis of the brain. The olfactory bulb and prefrontal cortex showed an increase in positive BOLD whereas the brainstem and cerebellum showed a decrease in BOLD signal. This negative BOLD affected many areas connected to the ascending reticular activating system (ARAS). The ARAS was decoupled to much of the brain but was hyperconnected to the olfactory system and prefrontal cortex., Conclusion: The CBD-induced decrease in ARAS activity is consistent with an emerging literature suggesting that CBD reduces autonomic arousal under conditions of emotional and physical stress.

Psychostimulant abuse is associated with a variety of impairments in social functioning, including an increased frequency of depression and aggression and deficits in social cognition. Psychostimulants reduce social investigation in rats and mice; however, it is less clear how other forms of social behavior (e.g., prosocial behavior) are affected. Females are also generally more sensitive to the effects of psychostimulants on locomotion and stereotyped behavior, which suggests that females might also display greater disruption of prosocial behavior. In order to test the hypothesis that psychostimulants reduce prosocial behavior and that females are more vulnerable, we treated adult male and female prairie voles with methamphetamine for three days (0, 0.2 or 2.0mg/kg, i.p.) and examined effects on locomotion and alloparental behavior. The lower methamphetamine dose increased activity in the open field in males and reduced locomotion in females. Methamphetamine-treated males took longer to enter the pup chamber, but both sexes displayed reduced pup contact following treatment with the lower methamphetamine dose. The methamphetamine-induced reduction in prosocial behavior was not associated with changes in pup-directed aggression in males or females. In order to investigate potential mechanisms underlying these changes in behavior, we measured adrenal weights as a proxy for activation of the hypothalamic-pituitary-adrenal (HPA) axis. The higher methamphetamine dose increased adrenal weights. Collectively, these data demonstrate that methamphetamine administration reduces alloparental behavior in both sexes and that females are more sensitive to some of the effects of this drug (e.g., locomotion/stereotyped behavior and possibly stimulation of the HPA axis)., (Copyright © 2017 Elsevier Inc. All rights reserved.)

This study tested the hypotheses that maternal and paternal effects differentially influence expression of their offspring's adult behavior and underlying neural mechanisms. We predicted that maternal influences would be greater than paternal influences on male offspring. We tested these hypotheses by cross-breeding two phenotypically-, behaviorally- and neuroanatomically-distinct populations of prairie voles (Microtus ochrogaster) from Illinois, which are highly prosocial, and Kansas, which are significantly less prosocial. Females from each population were crossed with males from the other population. F 1 crosses were tested as adults to determine the effect of parentage on the expression of prosocial behavior and aggression, using a same-sex dyadic encounter and a heterosexual partner preference test, and for the expression of oxytocin (OT) and arginine vasopressin (AVP) in the paraventricular nucleus of the hypothalamus (PVN). As predicted, all significant differences in males, behavioral, OT and AVP immunoreactivity, were associated exclusively with maternal influences. There was a significant effect of treatment in the OT immunoreactivity of females. The effect of treatment in females' OT was associated with an interaction of population and sex, while same-sex social interactions differences were associated with population. Finally, in females, paternity influenced heterosexual bonds, with females with Illinois sires forming a partner preference. The results indicate that maternal influences dominate in male offspring, suggesting a parent-of-origin effect, while paternal effects are limited to selected prosocial behavioral expression in daughters., (Copyright © 2018. Published by Elsevier B.V.)

Objective: In this study, empathy is quantified using a novel social test. Empathy and prosocial behavior are linked to the expression of oxytocin in humans and rodent models. Specifically, prosocial behavior in prairie voles (Microtus ochrogaster) has been linked to the expression of oxytocin in the paraventricular nucleus of the hypothalamus. The animal's behavior was considered empathic if it spends significantly more time attempting to remove a loos fitting restraint (tether) from the stimulus animal than time in contact with a, simultaneously presented, non-social object similar to the tether. The behavioral data was cross-referenced with the number of neurons expressing oxytocin and arginine vasopressin, as well as the density of dopaminergic neurons (identified by the expression of tyrosine hydroxylase), in the paraventricular nucleus of the hypothalamus. These proteins influence empathic behavior in humans, non-human primates, rats, mice, and prairie voles., Results: The consistency between neuroanatomical mechanisms linked to empathy, and the durations of time spent engaging in empathic contact, support the prediction that the empathic contact in this test is a distinct prosocial behavior, lacking prior behavioral training or the naturally occurring ethological relevance of other prosocial behaviors, and is a measure of empathy.

This study tested the hypothesis that site-specific estrogen receptor alpha (ERα) expression is a critical factor in the expression of male prosocial behavior and aggression. Previous studies have shown that in the socially monogamous prairie vole (Microtus ochrogaster) low levels of ERα expression, in the medial amygdala (MeA), play an essential role in the expression of high levels of male prosocial behavior and that increasing ERα expression reduced male prosocial behavior. We used an shRNA adeno-associated viral vector to knock down/inhibit ERα in the MeA of the polygynous male meadow vole (M. pennsylvanicus), which displays significantly higher levels of ERα in the MeA than its monogamous relative. Control males were transfected with a luciferase expressing AAV vector. After treatment males participated in three social behavior tests, a same-sex dyadic encounter, an opposite-sex social preference test and an alloparental test. We predicted that decreasing MeA ERα would increase male meadow vole's prosocial behavior and reduce aggression. The results generally supported the hypothesis. Specifically, MeA knockdown males displayed lower levels of defensive aggression during dyadic encounters and increased levels of overall side-x-side physical contact with females during the social preference test, eliminating the partner preference observed in controls. There was no effect on pup interactions, with both treatments expressing low levels of alloparental behavior. Behaviors affected were similar to those in male prairie voles with increased ERα in the BST rather than the MeA, suggesting that relative changes of expression within these nuclei may play a critical role in regulating prosocial behavior., (Copyright © 2018 Elsevier B.V. All rights reserved.)

During development, microglia, the resident immune cells of the brain, play an important role in synaptic organization. Microglial colonization of the developing brain is sexually dimorphic in some regions, including nuclei critical for the coordination of social behavior, suggesting steroid hormones have an influencing role, particularly estrogen. By extension, microglial colonization may be vulnerable to endocrine disruption. Concerns have been raised regarding the potential for endocrine disrupting compounds (EDCs) to alter brain development and behavior. Developmental exposure to Bisphenol A (BPA), a ubiquitous EDC, has been associated with altered sociosexual and mood-related behaviors in various animal models and children. Through a comparison of the promiscuous Wistar rat (Rattus norvegicus) and the socially monogamous prairie vole (Microtus ochrogaster), we are the first to observe that developmental exposure to the synthetic estrogen ethinyl estradiol (EE) or BPA alters the sex-specific colonization of the hippocampus and amygdala by microglia., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Chronic stressors are generally considered to disrupt reproduction and inhibit mating. Here we test the hypothesis that a chronic stressor, specifically social isolation, can facilitate adaptive changes that enhance/accelerate reproductive effort. In general, monogamous species display high levels of prosociality, delayed sexual maturation, and greater parental investment in fewer, higher quality offspring compared with closely related polygynous species. We predicted that chronic social isolation would promote behavioral and neurochemical patterns in prairie voles associated with polygyny. Male and female prairie voles were isolated for four weeks and changes in mating behavior, alloparental care, estrogen receptor (ER) α expression and tyrosine hydroxylase (TH) expression in brain regions regulating sociosexual behavior were examined. In males, isolation accelerated copulation, increased ERα in the medial amygdala (MEApd) and bed nucleus of the stria terminalis (BSTpm), and reduced TH expression in the MEApd and BSTpm, but had no effect on alloparental behavior. In females, isolation resulted in more rapid estrus induction and reduced TH expression in the MEApd and BSTpm, but had no effect on estradiol sensitivity or ERα expression. The results support the hypothesis that ERα expression in the MEApd and BSTpm is a critical determinant of male copulatory behavior and/or mating system. The lack of change in alloparental behavior suggests that changes in prosocial behavior are selective and regulated by different mechanisms. The results also suggest that TH in the MEApd and BSTpm may play a critical role in determining mating behavior in both sexes., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

In microtine and dwarf hamsters low levels of estrogen receptor alpha (ERα) in the bed nucleus of the stria terminalis (BST) and medial amygdala (MeA) play a critical role in the expression of social monogamy in males, which is characterized by high levels of affiliation and low levels of aggression. In contrast, monogamous Peromyscus males display high levels of aggression and affiliative behavior with high levels of testosterone and aromatase activity. Suggesting the hypothesis that in Peromyscus ERα expression will be positively correlated with high levels of male prosocial behavior and aggression. ERα expression was compared within the social neural network, including the posterior medial BST, MeA posterodorsal, medial preoptic area (MPOA), ventromedial hypothalamus (VMH), and arcuate nucleus in two monogamous species, P. californicus and P. polionotus, and two polygynous species, P. leucopus and P. maniculatus. The results supported the prediction, with male P. polionotus and P. californicus expressing higher levels of ERα in the BST than their polygynous counter parts, and ERα expression was sexually dimorphic in the polygynous species, with females expressing significantly more than males in the BST in both polygynous species and in the MeA in P. leucopus. Peromyscus ERα expression also differed from rats, mice and microtines as in neither the MPOA nor the VMH was ERα sexually dimorphic. The results supported the hypothesis that higher levels of ERα are associated with monogamy in Peromyscus and that differential expression of ERα occurs in the same regions of the brains regardless of whether high or low expression is associated with social monogamy. Also discussed are possible mechanisms regulating this differential relationship.

Here, for the first time, the expression of estrogen receptor beta (ERβ) is characterized in the brains of the highly prosocial prairie vole (Microtus ochrogaster). ERβ immunoreactivity was compared in weanlings (postnatal Day 21) and adult males and females. The results indicate several major findings. First, unlike ERα, ERβ expression is not sexually dimorphic. Second, the adult pattern of ERβ-IR is established at the time of weaning, as there were no age-dependent effects on distribution. Finally, ERβ does not appear to be as widely distributed in voles compared with rats and mice. High levels of ERβ-IR were observed in several regions/nuclei within the medial pre-optic area, ventrolateral pre-optic nuclei, and in the hypothalamus, especially in the paraventricular and supraoptic nuclei. The visualization of ERβ in prairie voles is important as the socially monogamous prairie vole functions as a human relevant model system for studying the expression of social behavior and social deficit disorders. Future studies will now be able to determine the effect of treatments on the expression and/or development of ERβ in this highly social species., (© 2015 Wiley Periodicals, Inc.)

Sex- and species-specific patterns of estrogen receptor (ER)-α expression are established early in development, which may contribute to sexual differentiation of behavior and determine male social organization. The current study investigated the effects of ERα and ERβ activation during the second postnatal week on subsequent alloparental behavior and ERα expression in juvenile prairie voles. Male and female pups were treated daily with 17β-estradiol (E2, ERα/ERβ agonist), PPT (selective ERα agonist), DPN (selective ERβ agonist), or the oil vehicle on postnatal days (PD) 8-14. Alloparental behavior and ERα expression were examined at PD21. PPT treatment inhibited prosocial motivation in males and increased pup-directed aggression in both sexes. E2 and DPN had no apparent effect on behavior in either sex. PPT-treated males had increased ERα expression in the medial preoptic area (MPN), medial amygdala (MEApd) and bed nucleus of the stria terminalis (BSTpr). DPN treatment also increased ERα expression in males, but only in the BSTpr. Female ERα expression was unaffected by treatment. These results support the hypothesis that ERα activation in early life is associated with less prosocial patterns of central ERα expression and alloparental behavior in males. The lack of an effect of E2 on behavior suggests that ERβ may antagonize the effects of ERα on alloparental behavior. The results in DPN-treated males suggest that ERα in the MEApd, and not the BSTpr, may be a primary determinant of alloparental behavior in males., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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 (OT) has an organizational effect within the central nervous system and can have long-lasting effects on the expression of social behavior. OT has recently been implicated in modulating the release of serotonin through activation of receptors in the raphe nuclei. Here we test the hypothesis that OT can have an organizational effect on the serotonergic system. Male prairie voles received an intraperitoneal injection on postnatal day 1 with 3.0 or .3 µg OT, an OT antagonist, or a saline control. Brains were collected on day 21 and immunostained for serotonin. Serotonin axons were quantified in the anterior hypothalamus, cortical amygdala, medial amygdala, paraventricular nucleus of the hypothalamus, and ventromedial hypothalamus. Males treated with 3.0 µg OT displayed significantly higher serotonin axon length densities in the anterior hypothalamus, cortical amygdala, and the ventromedial hypothalamus than control males. These results support the hypothesis that OT has an organizational effect on the serotonin system during the neonatal period, and that these effects are site-specific., (Copyright © 2011 Wiley Periodicals, Inc.)

Estrogen receptor alpha (ERalpha) typically masculinizes male behavior, while low levels of ERalpha in the medial amygdala (MeA) and the bed nucleus of the stria terminalis (BST) are associated with high levels of male prosocial behavior. In the males of the highly social prairie vole (Microtus ochrogaster), increasing ERalpha in the MeA inhibited the expression of spontaneous alloparental behavior and produced a preference for novel females. To test for the effects of increased ERalpha in the BST, a viral vector was used to enhance ERalpha expression in the BST of adult male prairie voles. Following treatment, adult males were tested for alloparental behavior with 1-3-day-old pups, and for heterosexual social preference and affiliation. Treatment did not affect alloparental behavior as 73% of ERalpha-BST males and 62.5% of control males were alloparental. Increasing ERalpha in the BST affected heterosexual affiliation, with ERalpha-BST males spending significantly less total time in side-by-side contact with females relative to time spent with control males. ERalpha-BST males did not show a preference for either the familiar or novel female. These findings differed significantly from those reported in ERalpha-MeA enhanced males, where ERalpha inhibited alloparental behavior and produced a preference for a novel female. The findings from this study suggest two things: first, that increased ERalpha in the BST decreases social affiliation and second, that altering ERalpha in different regions of the social neural circuit differentially impacts the expression of social behavior.

In most species, the effects of oxytocin (OT) on female reproductive behavior are dependent upon estrogen, which increases both OT and OT receptor expression. It is also becoming apparent that OT neurotransmission can influence estrogen signaling, especially during development, as neonatal OT manipulations in prairie voles alter ERalpha expression and estrogen-dependent behaviors. We tested the hypothesis that OT developmentally programs ERalpha expression and estrogen sensitivity in female Sprague-Dawley rats, a species previously used to establish the estrogen-dependence of OT signaling in adulthood. OT treatment for the first postnatal week significantly increased ERalpha-immunoreactivity in the ventromedial nucleus of the hypothalamus (VMH), but not in the medial preoptic area (MPOA). Conversely, neonatal OT antagonist (OTA) treatment significantly reduced ERalpha-immunoreactivity in the MPOA, but not in the VMH. Both treatments increased OT-immunoreactivity in the paraventricular nucleus of the hypothalamus (PVN) and reduced estrogen sensitivity, indicated by reduced sexual receptivity following chronic estradiol benzoate (EB) administration. Behavioral deficits in OTA-treated females were apparent during both paced and non-paced tests with 0.5 microg EB (but not 5.0 or 10.0 microg EB), whereas deficits in OT-treated females were only observed during the initial paced test with 0.5 and 5.0 microg EB (but not 10.0 microg EB). The current results demonstrate that OT can positively regulate ERalpha expression within the MPOA and VMH during development; however, endogenous OT selectively programs ERalpha expression within the MPOA. Thus, exogenous OT or OTA exposure during development may have long-term consequences on behavior through stable changes in ERalpha and OT expression.

Sex steroids play a significant role in organizing male social behavior, which is associated with low levels of pro-social behavior and high levels of aggression. However, the role of steroids in organizing behavior in highly social males is unclear. The authors tested the hypothesis that low levels of sex steroids facilitate the expression of pro-social behavior in male prairie voles (Microtus ochragaster), predicting that inhibition of testosterone and estradiol would reduce spontaneous-alloparental behavior. Treatment with the aromatase inhibitor 1,4,6-androstatriene-3,17-dione (ATD) or the androgen receptor blocker flutamide, days 8-14, significantly reduced the expression of alloparental behavior in 21-day old males. While both treatments reduced alloparental behavior and increased pup-directed aggression, there were differential treatment effects. Flutamide altered initial response, increasing latency to enter the pup cage and the likelihood of retreat from initial contact. ATD-treated males that were alloparental showed increases in sniffing and latencies to lick and huddle. Results indicate that endogenous steroids play a role in the development of male pro-social behavior and the effects of estrogens and androgens differ.

Oestrogen receptor (ER)alpha immunoreactivity in three brain regions relevant to maternal behaviour (medial preoptic area, bed nucleus of the stria terminalis and medial amygdala) was measured in two species of dwarf hamster that both mate during a postpartum oestrous but differ in expression of paternal behaviour. Male and female Phodopus campbelli and Phodopus sungorus were sampled as sexually naive adults, following mating to satiety, and as new parents. In all brain regions, females expressed higher levels of ER alpha than males. Species did not have an effect on ER alpha distribution except in the medial amygdala, where P. sungorus females had higher expression levels than all other groups. Behavioural status was not associated with altered ER alpha expression. These results were not expected for females and suggest that a primary activational role for oestrogen, acting through ER alpha in these regions, does not generalize to maternal behaviour in Phodopus. In males, these results are consistent with previous manipulations of the ER alpha ligand, oestrogen, and suggest that paternal behaviour in P. campbelli is likely to be regulated by developmental effects of oestrogen on the brain during early life (similar to Microtus ochrogaster), rather than through activation by oestrogen at the time of fatherhood (similar to Peromyscus californicus).

Studies using estrogen receptor alpha (ERalpha) knock-out mice indicate that ERalpha masculinizes male behavior. Recent studies of ERalpha and male prosocial behavior have shown an inverse relationship between ERalpha expression in regions of the brain that regulate social behavior, including the medial amygdala (MeA), and the expression of male prosocial behavior. These studies have lead to the hypothesis that low levels of ERalpha are necessary to "permit" the expression of high levels of male prosocial behavior. To test this, viral vectors were used to enhance ERalpha in male prairie voles (Microtus ochrogaster), which display high levels of prosocial behavior and low levels of MeA ERalpha. Adult male prairie voles were transfected with ERalpha in the MeA (MeA-ERalpha) or the caudate-putamen (ERalpha control) or luciferase (MeA-site-specific control), and 3 weeks later tested for spontaneous alloparental behavior and partner preference. Enhancing ERalpha in the MeA altered/reduced male prosocial behavior. Only one-third of MeA-ERalpha males, compared with all control males, were alloparental. MeA-ERalpha males also displayed a significant preference for a novel female. This is a critical finding because the manipulations of neuropeptides, oxytocin and vasopressin, can inhibit the formation of a partner preference, but do not lead to the formation of a preference for a novel female. The results support the hypothesis that low levels of ERalpha are necessary for high levels of male prosocial behavior, and provide the first direct evidence that site-specific ERalpha expression plays a critical role in the expression of male prosocial behavior.

Background: Previous studies have demonstrated that neonatal manipulation of oxytocin (OT) has effects on the expression of estrogen receptor alpha (ER alpha) and the central production of oxytocin observed in juveniles (at weaning, 21 days of age). The goal of this study was to determine whether the effects of neonatal manipulation of OT last into adulthood, and if the effects differ from those observed during the early postnatal period. On the first day of life, prairie voles (Microtus ochrogaster) received one of three doses of OT (High, 3 microg; Med, 0.3 microg; Low, 0.03 microg), an OT antagonist, or isotonic saline. Another group was handled, but not injected. Then as adults, brains were collected, sectioned, and stained for ER alpha or OT using immunocytochemistry., Results: In females, treatment with OT increased the expression of ER alpha immunoreactivity in the ventral lateral septum (0.03 microg) and the ventromedial nucleus of the hypothalamus and central amygdala (0.3 microg). In males, OT antagonist increased ER alpha expression in the bed nucleus of the stria terminalis. There was no apparent effect of OT on the number of cells producing OT in the paraventricular nucleus of the hypothalamus., Conclusion: The current results suggest that neonatal manipulation of OT has long-term organizational effects on the expression of ER alpha in both males and females. The lack of effect on OT neurons in the paraventricular nucleus suggests that some developmental effects of OT previously observed in weanlings do not persist into adulthood. Developmental effects of OT on ER alpha patterns were sexually dimorphic, dose-dependent, and site-specific.

Oxytocin (OT) has been implicated in reproductive functions, induction of maternal behavior as well as endocrine and neuroendocrine regulation of the cardiovascular system. Here we demonstrate that neonatal manipulation of OT can modulate the mRNAs expression for OT receptor (OTR), atrial natriuretic peptide (ANP), endothelial nitric oxide synthase (eNOS) and estrogen receptor alpha (ERalpha) in the heart. On the first day of postnatal life, female and male rats were randomly assigned to receive one of the following treatments: (a) 50microl i.p. injection of 7microg OT; (b) 0.7microg of OT antagonist (OTA); or (c) isotonic saline (SAL). Hearts were collected either on postnatal day 1 or day 21 (D1 or D21) and the mRNAs expression of OTR, ANP, inducible NOS (iNOS), eNOS, ERalpha and estrogen receptor beta (ERbeta) were compared by age, treatment, and sex utilizing real time PCR. OT treatment significantly increased heart OTR, ANP and eNOS mRNAs expression on D1 in both males and females, ERalpha increased only in females. While there were significant changes in the relative expression of all types of mRNA between D1 and D21, there were no significant treatment effects observed in D21 animals. OTA treatment significantly decreased basal ANP and eNOS mRNAs expression on D1 in both sexes. The results indicate that during the early postnatal period OT can have an immediate effect on the expression OTR, ANP, eNOS, and ERalpha mRNAs and that these effects are mitigated by D21. Also with the exception of ERalpha mRNA, the effects are the same in both sexes.

Oxytocin (OT) is known for its role in reproduction. However, evidence has emerged suggesting its involvement in the regulation of the cardiovascular system. Here we examine the hypothesis that neonatal exposure to OT can have both short-term and long-lasting consequences on gene expression in heart tissue. On the first day of postnatal life, female and male prairie voles (Microtus ochrogaster) were randomly assigned to receive one of following treatments: 50 microl i.p. injection of (a) 3 microg OT (b) 0.3 microg of OT antagonist (OTA), or (c) isotonic saline (SAL). Hearts were collected on postnatal day 1 (D1, 2 h after injection), day 8 (D8), or day 21 (D21), and the mRNA expression for OT receptor (OTR), estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta as a function of age, treatment, and sex were measured using RT-PCR. Neonatal treatment with OT showed a marked increase in cardiac OTR mRNA expression on postnatal D1, but not D8 or D21, in both female and male animals. ERalpha increased as a function of OT treatment only in females. Although significant treatment effects were no longer detected in D8 or D21 animals, there were significant changes in the relative expression of all types of mRNA between D1 and D21 with age-related declines in OTR and ERbeta and increases in ERalpha Neonatal treatment with OTA showed no changes in cardiac OTR, ERalpha, or ERbeta mRNAs expression. The results indicate that during the early postnatal period OT can have rapid effects on the expression of OTR and ERalpha mRNAs and that these effects are mitigated by D8 or D21. Also, with the exception of ERalpha mRNA, the effects are the same in both sexes.

During neonatal development exogenous oxytocin increases ERalpha immunoreactivity in the hypothalamus of female prairie voles. The purpose of this study was to determine if the increase in ERalpha is associated with an increase in ERalpha mRNA expression and to determine if the effect is specific to ER subtype or if oxytocin also influences ERbeta mRNA expression. On the day of birth female prairie vole pups were treated with oxytocin, an oxytocin antagonist, or saline. Brains were collected and RT-PCR was used to determine the effect of treatment on ER mRNA production in the hypothalamus, hippocampus, and cortex. Within 2h of treatment oxytocin significantly increased ERalpha mRNA expression in the hypothalamus and hippocampus, but not the cortex, while inhibiting the effects of endogenous oxytocin reduced the expression of ERalpha mRNA in the hippocampus. Neonatal treatment did not affect the expression of ERbetamRNA. The results demonstrate that the effects of oxytocin treatment are region and ER subtype specific and that during the neonatal period oxytocin can affect the expression of ERalpha by altering message production. The regional specific changes in ERalpha mRNA expression in females are consistent with studies examining the behavioral and physiological effects of neonatal manipulation of oxytocin in females.

Reduced levels of estrogen receptor alpha (ERalpha) in the medial amygdala (MeA) and bed nucleus of stria terminalis (BST) have been hypothesized to play a significant role in the expression of male behaviors associated with monogamy. Therefore, the regulation of ERalpha could be a critical factor in determining male behavior and the evolution of monogamy. Central expression of ERalpha immunoreactivity was compared in hybrid offspring from crosses between two phenotypically distinct populations of prairie voles (Microtus ochrogaster). Illinois voles (IL) are socially monogamous and display low levels of ERalpha, while Kansas voles (KN) display some characteristics associated with polygyny and have higher levels of ERalpha. In offspring from hybrid crosses, the pattern of ERalpha expression was dependent upon parentage; the two types of hybrid crosses did not produce the same ERalpha pattern in the offspring. In the BST and MeA, hybrid males expressed ERalpha patterns consistent with those of males from their mother's population, while hybrid females had ERalpha patterns typical of females belonging to their father's population. The parental-specific patterns of ERalpha expression are suggestive of genomic imprinting, therefore, the vole ERalpha (Esr1) gene was cloned and sequenced, and examined for allele-specific expression. Results from this study indicate that while maternal factors may play a major role the expression of ERalpha in their male offspring, genomic imprinting is unlikely to be involved, suggesting another mechanism is responsible.

Previous studies have revealed that the neuropeptide hormone oxytocin (OT) has developmental effects on subsequent social behavior and on mechanisms underlying social behavior such as OT neurons and estrogen receptor alpha. This suggests that OT might also have developmental effects on neural responses to social stimuli. This was tested in socially monogamous prairie voles (Microtus ochrogaster) by manipulating OT on the first day of life and then assessing the response to a heterosexual pairing in adulthood. The response to cohabitation was assessed by quantifying neural activation in regions of the brain associated with sociosexual behavior and anxiety using c-Fos immunoreactivity. Additionally, immunocytochemistry was used to label OT and vasopressin neurons and plasma was assayed for both neuropeptides. Treatment effects were evident in females, but not in males. Blockade of OT receptors with an OT antagonist on the first day of life resulted in neural activation of the central amygdala in response to a pairing with a novel male in adulthood. The central amygdala does not normally express c-Fos after a heterosexual pairing in reproductively naïve prairie voles. Treatment effects also were observed in vasopressin immunoreactivity in the SON with OT-treated females showing a decrease.

It has been hypothesized that site-specific reduction of estrogen receptor-alpha (ERalpha) is associated with the expression of male prosocial behaviors. Specifically, highly social males are predicted to express significantly lower levels of ERalpha than females and less social males in brain regions associated with prosocial behavior including the bed nucleus of the stria terminalis (BST) and the medial amygdala (MeA). This hypothesis was tested by comparing ERalpha immunoreactivity (IR) in three species of microtines, the polygynous montane (Microtus montanus) and meadow (M. pennsylvanicus) voles and the monogamous pine vole (M. pinetorum), and two species of cricetines that differ in the extent of social pair-bond formation, Siberian (Phodopus sungorus) and Djungarian (P. campbelli) hamsters. As predicted, ERalpha-IR was sexually dimorphic in the BST and MeA of the highly social species, with females expressing more ERalpha-IR cells than males. Male and female montane voles did not differ. Male and female meadow voles differed in the ventromedial hypothalamus, with females expressing more ERalpha-IR cells. Male pine voles expressed lower levels of ERalpha-IR in the MeA than male montane and meadow voles and in the BST relative to montane males. Male Djungarian hamsters, which show higher levels of parental care, had fewer ERalpha-IR cells in the BST than male Siberian hamsters. Results indicate that the distribution of ERalpha differs relative to the continuum of species-typical affiliative behavior and supports the hypothesis that ERalpha has a significant role in regulating species-specific social organization., (J. Comp. Neurol. 494:595-605, 2006. (c) 2005 Wiley-Liss, Inc.)

In adult females many of the effects of the neuropeptide oxytocin are steroid, and especially estrogen dependent. Here we demonstrate for the first time that neonatal manipulation of oxytocin can affect the expression of estrogen receptor alpha. On the first day of postnatal life male and female prairie voles (Microtus ochrogaster) were randomly assigned to receive one of four treatments; (a) 50 microl i.p. injection of 3 microg oxytocin (approximately 1 microg/g), (b) 0.3 microg of an oxytocin antagonist (approximately 0.1 microg/g), or (c) isotonic saline. A fourth group was handled, but not injected. On postnatal day 8 or 21, brain tissue was collected, fixed and sectioned. Free-floating sections were stained for estrogen receptor alpha using immunocytochemistry, and estrogen receptor alpha immunoreactive neurons were compared by age, treatment, and sex. To compare the temporal expression of estrogen receptor alpha an additional set of brains was collected from untreated males and females on the day of birth. The effects of oxytocin manipulations were age dependent, sexually dimorphic, and site-specific. While there were no significant treatment effects on postnatal day 8, by postnatal day 21 females that received oxytocin showed a significant increase in the number of cells expressing estrogen receptor alpha-immunoreactivity in the ventromedial nucleus of the hypothalamus. Treatment with oxytocin antagonist resulted in a significant decrease in estrogen receptor alpha-immunoreactivity in the medial preoptic area in postnatal day 21 females. While there were no significant effects in males, males treated with oxytocin antagonist trended toward a reduction in estrogen receptor alpha-immunoreactivity in the medial amygdala. The results indicate that oxytocin can have organizational effects on the expression of estrogen receptor alpha, that these effects are sexually dimorphic, and finally that during the preweaning period the development of estrogen receptor alpha is sexually dimorphic.

The purpose of this study was to determine the presence of estrogen receptor alpha (ERalpha) and the relationship between neurons that express ERalpha and produce vasopressin (AVP) in the paraventricular nucleus of the hypothalamus (PVN) in new world mice of the genus Peromyscus. Brains were collected from male and female Peromyscus californicus, Peromyscus leucopus, Peromyscus maniculatus, and Peromyscus polionotus, and double labeled for the expression of ERalpha and AVP immunoreactivity (IR). The number of cells expressing ERalpha-IR and AVP-IR was determined in the medial and posterior region of the PVN. The results indicate that Peromyscus is the first taxonomic group reported to have ERalpha widely distributed in the PVN, occurring in both medial and posterior regions of the PVN. While estrogen can regulate the production of AVP, AVP and ERalpha were rarely colocalized. There was, however, a significant inverse relationship between the number of cells that expressed ERalpha-IR and the number expressing AVP-IR. There were no sex differences in the expression of ERalpha-IR or AVP-IR.

In mammals the neonatal period is a time of significant social interaction. This is true even in solitary species as females spend a significant amount of time nursing and caring for their offspring. In social species interactions may also include the father, older siblings and extended family members. This period is a time of significant development, including organization of the central nervous system, and therefore a time when the degree and type of social interaction influences the development and expression of social behavior in adulthood. The purpose of this review is to examine the possible mechanisms for the epigenetic effects of early social experience on the subsequent expression of social behavior. We propose that social interactions during the neonatal period organize the subsequent expression of behavior by altering sensitivity to neuropeptides and steroids. Both neuropeptides (e.g. oxytocin and arginine vasopressin) and steroids (e.g. estrogen) regulate or influence the expression of behaviors such as affiliation, aggression, sociosexual behavior, parental behavior, and responses to stress. Therefore, changes in sensitivity to these hormones via reorganization of receptors or changes in hormone production and secretion are potentially powerful mechanisms through which early social experience can mold subsequent social behaviors.

During early neonatal development, oxytocin (OT) may influence the expression of adult behavior and physiology. Here we test the prediction that early postnatal exposure to OT or an oxytocin antagonist (OTA) can affect the subsequent expression of sexual receptivity and reproductive success of females. To test this hypothesis, female prairie voles (Microtus ochrogaster) received one of four treatments within 24 h of birth. Three groups received an intraperitoneal injection of OT, OTA, or isotonic saline. A fourth group was handled, but not injected. Around 75 days of age, females were paired with sexually experienced males for 72 h and sexual activity was recorded. Treatment had no effect on the probability of mating. Injection, regardless of treatment, reduced latency to mate compared with handled controls. OT and OTA treatment decreased mating bout frequency compared to saline and handled controls, while OTA treatment increased reproductive success, probability of successfully producing a litter. The results suggest that neonatally OT, both endogenous and exogenous, can affect the expression of adult female reproductive activity and that blocking the effects of endogenous OT during neonatal development can affect female reproductive success. Finally, the results suggest that a number of aspects of reproduction are regulated by OT during the postnatal period, but that the mechanism of action may differ depending upon the reproductive activity.

Estrogen (E) regulates a variety of male sociosexual behaviors. We hypothesize that there is a relationship between the distribution of estrogen receptor alpha (ERalpha) and the degree of male social behavior. To test this hypothesis, ERalpha immunoreactivity (IR) was compared in prairie voles (Microtus ochrogaster) from Illinois (IL), which are highly social, and Kansas (KN), which are less social. The expression of androgen receptors (AR) in males also was compared between populations. The expression of ERalpha and AR were compared in brains from KN and IL males and females using immunocytochemistry (ICC). There were significant intrapopulational differences, with males expressing less ERalpha-IR than females in the medial preoptic area, ventromedial nucleus, ventrolateral portion of the hypothalamus, and bed nucleus of the stria terminalis (BST). IL males also displayed less ERalpha-IR in the medial amygdala (MeA) than IL females. While IL males expressed significantly less ERalpha-IR in the BST and MeA than KN males, there was no difference in AR-IR. Differences in the pattern of ERalpha-IR between KN and IL males were behaviorally relevant, as low levels of testosterone (T) were more effective in restoring sexual activity in castrated KN males than IL males. The lack of difference in AR combined with lower expression of ERalpha-IR in IL males suggests that behavioral differences in response to T are associated with aromatization of T to E and that reduced sensitivity to E may facilitate prosocial behavior in males.

Oxytocin (OT) modulates adult mammalian sexual behavior, sperm production and transport, and steroidogenesis; however, the consequences of developmental manipulations of oxytocin have received little attention. The purpose of this experiment was to determine whether neonatal exposure to OT, an oxytocin antagonist (OTA), saline (SAL), or handling (HAN)-only would have long-term effects on reproductive potential in male prairie voles (Microtus ochrogaster). Adult males were observed for 24 h with a sexually receptive female and sexual behavior was recorded. Females were subsequently lavaged and smears were examined for sperm. Reproductive parameters including motility of epididymal sperm, testis weight, and plasma androgen levels were in the normal range. OT-treated males that did not mate within the first 30 min did not mate at all, and in comparison to controls, a higher proportion of those OT-treated and OTA-treated males that did mate did not transfer sperm to the females. OTA-treated males also had significantly higher testicular sperm concentrations than HAN-only males, and significantly lower epididymal sperm concentrations. These differences suggest that in males, developmental manipulations of OT may have the potential to influence the subsequent expression of sexual behavior and sperm transport.

Early postnatal manipulations of oxytocin have long-term behavioral and physiological consequences; the present study examined the hypothesis that oxytocin or its absence influences the subsequent expression of either oxytocin or arginine vasopressin in the CNS. On postnatal day 1 female and male prairie voles (Microtus ochrogaster) received a single i.p. injection of oxytocin (3 microg), oxytocin antagonist (0.3 microg), or 50 microl of isotonic saline or were only handled. On postnatal days 1, 8 and 21, brains were fixed, sectioned and stained for oxytocin or vasopressin immunoreactivity and analyzed as a function of age, treatment and sex. Both oxytocin and vasopressin immunoreactivity were observed on day 1 in the supraoptic and paraventricular nuclei (PVN) of the hypothalamus. Numbers of oxytocin and vasopressin neurons increased with age in both nuclei. Females treated on postnatal day 1 with oxytocin or oxytocin antagonist displayed a significant increase in oxytocin immunoreactivity on day 21 in the PVN. In contrast, males treated with antagonist tended to have decreased vasopressin immunoreactivity in the same region. These results revealed that the effects of neonatal manipulation of oxytocin are age-dependent, site-specific and sexually dimorphic. The long-lasting effects of neonatal exposure to exogenous oxytocin and oxytocin antagonist indicate a role for oxytocin in the development of the CNS during the neonatal period, affecting the development of the oxytocinergic system in females and the vasopressinergic system in males. The developmental effects observed suggest one possible mechanism by which neonatal exposure to oxytocin or neonatal inhibition of endogenous oxytocin produces long-lasting behavioral and physiological alterations and could play a role in the development of male- and female-typical behavior.

Centrally administered arginine vasopressin induces the formation of partner preferences in male prairie voles (Microtus ochrogaster). The expression of many vasopressin-regulated behaviours is testosterone dependent. In this study, we tested the hypothesis that early exposure to gonadal steroids are necessary to establish the typical response of adult male prairie voles to exogenous vasopressin, predicting that adult males which were castrated neonatally would not form partner preferences in response to centrally administered vasopressin. We also examined the effect of neonatal castration on the expression of vasopressin (V1a) receptors. Voles were castrated on the day of birth (NEOCAST), sham-castrated on the day of birth (NEOSHAM) or castrated as adults (ADULTCAST). With the exception of one group of neonatal sham males (NEOSHAM CON), which served as a control for the effects of vasopressin, as adults, all males received a 1- micro l intracerebroventricular injection of vasopressin (100 ng) in artificial cerebrospinal fluid. In addition, 2 weeks before testing, one group of neonatally castrated males received an implant of testosterone propionate (NEOCAST + TP). Between 60 and 90 days of age, an internal cannula was placed in the lateral cerebral ventricle and, 24 h later, males were injected with vasopressin. Subsequently, after an additional 15 min, males were cohabitated with a female 'partner' for 1 h. Immediately following cohabitation, males were placed in a Y-shaped partner preference test apparatus for 3 h, in which the male had access to the 'partner' and a novel female, 'stranger.' Time spent with the partner versus the stranger was compared within and between treatments. The results were found to support our hypothesis as the NEOSHAM and ADULTCAST males formed partner preferences, spending more time with the partner, and they spent significantly more time with their partner than did NEOSHAM CON, NEOCAST or NEOCAST + TP males. Replacement of testosterone in neonatally castrated males did not restore partner preference formation in response to vasopressin in adult males. Finally, neonatal castration did not affect the distribution of V1a receptors.

Neonatal exposure to exogenous oxytocin (OT) can have long-term effects on the subsequent expression of adult behavior and physiology. Here, we test the prediction that early postnatal exposure to OT can affect the timing of sexual maturation in females, as indicated by the age of vaginal opening and the onset of first estrus. To test this hypothesis, female Sprague-Dawley rats received one of four treatments beginning on the day of birth and continuing for the next 6 days. Three groups received an intraperitoneal injection of one of the following: OT (1 mug/g), an OT antagonist (OTA, 0.1 mug/g) or isotonic saline (vehicle control). The fourth group was handled but not injected. Females were then examined to determine the day of vaginal opening and first estrus. The potential effects of OT on body weight were also measured, with females being weighed on postnatal days 1-7, 70, 91 and 136. Treatment with OT significantly delayed the age of vaginal opening and the onset of first estrus. There was no effect on weight. Results indicate that early exposure to OT can affect the timing and development of female sexual maturation.

Both exogenous and endogenous oxytocin (OT) are associated with an attenuated stress response. Increased levels of OT in the early postnatal period have been shown to affect behavior and physiology in rodents, and these effects last into adulthood, suggesting an organizational role for OT during development. We investigated the effects of neonatal exposure to OT on the development of the stress response in male and female prairie voles (Microtus ochrogaster). OT or an OT antagonist (OTA) was administered either on postnatal day 1 (single, D1) or days 1-7 (repeated, D1-7) and then on day 8 the response to social isolation was assessed by quantifying ultrasonic vocalizations (USVs) and measuring plasma corticosterone (CORT). Treatment effects were observed only in females. A single treatment with OTA was associated with a decrease in vocalizations, while repeated treatment produced an increase in vocalizations. A single treatment with either saline or OTA increased basal CORT. The results suggest that endogenous OT may be involved in the development of the stress response in females.

Early postnatal exposure to both exogenous and endogenous oxytocin (OT) can have long-term effects on behavior and physiology, although the mechanisms of these effects are not known. c-Fos expression was used to investigate the immediate neural effects of neonatal manipulations of OT in male and female prairie voles. On the day of birth prairie vole pups received an intraperitoneal injection of OT, a selective OT antagonist (OTA), or saline (vehicle control), while an additional group was handled but not injected. One hour after treatment brains were collected and fixed via spinning immersion and immunocytochemistry was then used to label for c-Fos immunoreactivity (IR). There were significant differences between males and females. Handled only females displayed significantly higher levels of c-Fos IR in the mediodorsal thalamic nucleus (MD) than males while handled males had higher c-Fos IR in the paraventricular nucleus of the hypothalamus than females. Exogenous OT stimulated neuronal activity in the supraoptic nucleus (SON) in males, while treatment with OTA increased Fos IR in the SON and was associated with reduced Fos IR in the MD in females. The results indicate that neuronal activity and responses to OT are sexually dimorphic in newborn prairie voles. In females changes in Fos expression were stimulated by treatment with OTA, suggesting that endogenous OT affects cellular activity while males responded to exogenous OT.

Ovarian steroids and oxytocin (OT) have been implicated in the regulation of social behaviors. The purpose of the present study was to examine hormonal substrates of aggression and affiliation in the female Mongolian gerbil (Meriones unguiculatus), a highly social, monogamous rodent. Sexually naive adult females were paired with sexually experienced males for 48 h and their interactions videotaped. Females were gonadally intact and tested during vaginal estrus (INT) or ovariectomized and observed after the following treatments, administered by means of sc injections: EBEB (7 days of estradiol-benzoate); EBP (2 days of EB followed by progesterone), SALEB (saline, days 1-5 then 2 days of EB), OTEB (OT for days 1-5 then 2 days of EB); OTOIL (OT for days 1-5 then 2 days of OIL); or SALOIL (saline days 1-5 then 2 days of OIL). During the first hour of pairing INT females displayed higher levels of affiliation and lower levels of sniffing and agonistic behavior than SALOIL females. All hormonal treatments reduced agonistic behaviors when compared to SALOIL, although none of the hormonal treatments restored affiliation to INT levels. During the 48-h test overt aggression varied by treatment with INT, EBEB, EBP, and OTEB females displaying lower levels than SALOIL, while all groups displayed similar levels of affiliation. The results indicate that OT and E play a significant role in regulating male-directed aggressive behavior in females and that the presence of ovarian hormones as well as OT can increase affiliation during initial contact. Over a sustained period of cohabitation social cues appear to be more important in regulating affiliation than gonadal hormones.

Cohabitation of sexually nai;ve male and female prairie voles (Microtus ochrogaster) triggers a cascade of physiological changes that result in the formation of stable pair bonds. In the present study we used the expression of c-Fos protein to identify CNS regions activated during initial social contact in heterosexual, male/male and female/female pairs. Sexually naive males and females were randomly assigned to one of five groups: control- no cohabitation, or cohabitation for 1 h with an unrelated opposite sex, an unrelated same sex, an unfamiliar same sex sibling, or removal for 24 h and then repaired with the familiar sibling. Heterosexual pairing resulted in significant increases in c-Fos immunoreactivity (IR) in the posterodorsal and posteroventral medial amygdala (MeA), bed nucleus of the stria terminalis, medial preoptic nucleus, ventrolateral portion of the ventromedial nucleus of the hypothalamus (VMN-VL) in males and females, and the periventricular nucleus of the thalamus in males only. c-Fos IR during intrasexual cohabitation varied with the relationship of the experimental animal to the stimulus animal. Males cohabited with an unfamiliar unrelated male expressed significantly more c-Fos IR in the central amygdala (CeA). While females cohabited with an unfamiliar female (related or unrelated) also displayed increased c-Fos IR in the CeA, this increase was accompanied by an increase in c-Fos IR in the VMN-VL and MeA. The results from this study suggest that early neuronal activation associated with heterosexual cohabitation is similar in both sexes, while neuronal activation is sexually dimorphic in response to intrasexual cohabitation.

Although patterns of aggression and affiliation may play a major role in social organization, the mechanisms underlying these behaviors are not well understood. The purpose of this study was to examine the effects of social and hormonal experience on female-female aggression and affiliation in prairie voles, Microtus ochrogaster. Prairie voles exhibit the traits of social monogamy and tend to live in communal families structured around a male-female pair. It is rare for two unrelated females within a family to successfully reproduce. In this study, the social and/or hormonal experiences of female prairie voles were varied and female-female aggression and affiliation were measured during dyadic encounters with unfamiliar, nonaggressive females. An increase in aggression and decline in affiliative behaviors toward a stimulus female was observed during pregnancy and following male-cohabitation, with or without mating. Pairing with another female did not result in changes in either aggressive or affiliative behaviors toward the stimulus female. Female-female aggression increased and affiliative behaviors declined, with a maximal effect following approximately 8-12 days of male cohabitation. Similar patterns of change were seen in both ovariectomized and gonadally intact females, and treatment with estradiol and subsequent sexual experience did not significantly alter the tendency of females to show aggression or affiliative contact. Social experiences associated with prolonged cohabitation with a male facilitate the induction of female-female aggression; however, ovarian hormones, pregnancy or mating are not essential to induce aggression.

This study tested the hypothesis that intraspecific variations in mating systems are correlated with differences in the capacity of peripheral arginine vasopressin (AVP) to facilitate partner preferences. It has been hypothesized that differences in environmental conditions, Kansas being more xeric than Illinois, are responsible for some of the intraspecific differences in the mating systems between Kansas (KN) and Illinois (IL) prairie voles. We predicted that prairie voles from KN would be more behaviorally sensitive to peripheral AVP than prairie voles from IL. To test this hypothesis 60- to 120-day-old male and female, lab-reared, prairie voles originating from KN and IL received three subcutaneous injections of AVP or isotonic saline. Animals were then placed with an adult member of the opposite sex, designated a "partner," for a 1-hour period of cohabitation and subsequently tested for preference for the familiar partner versus a comparable stranger. Only KN males treated with AVP displayed a significant preference for the partner. Using the same experimental paradigm we also examined the ability of peripheral oxytocin (OT) to facilitate partner preference in KN prairie voles. OT facilitated partner preference in females, but not males. This finding was consistent with previous results describing the effects of peripheral OT in IL prairie voles. We also examined the hypothesis that the differential response of KN and IL males would be associated with differences in the distribution of AVP (V1a) receptors. However, there was no apparent difference in the distribution of V(1a) receptors between KN and IL males. The results of this study indicate that there is both intraspecific and intersexual variation in the regulation of social behavior in prairie voles. In addition, these findings suggest that the proximate causes of intraspecific variation may be predicted by knowledge of the habitat of origin., (Copyright 2001 Academic Press.)

Centrally administered oxytocin (OT) facilitates social behaviors including the partner preferences that characterize the monogamous social system of prairie voles. In contrast peripherally administered OT generally has been ineffective in influencing central processes including behavior. OT from the posterior pituitary gland is released in pulses into the peripheral circulation. We hypothesized that peripherally administered OT, if delivered in repeated injections mimicking these pulses, would influence behavior. Male and female prairie voles received three subcutaneous injections of OT, a single injection of OT, or isotonic saline. Animals then were placed with an adult member of the opposite sex, designated as a "partner," for a 1-h period of cohabitation, and subsequently tested for preference for the familiar partner versus a comparable stranger. Females treated with pulses of peripheral OT (1, 5, or 20 microg) displayed a significant preference for the partner compared to control females, while females receiving a lower dose of OT (0.1 microg) or a single injection (20 microg) did not. There was also a significant within-group effect as pulsed OT-treated females spent more time with the partner when compared to the stranger, while control females spent equal amounts of time with the partner and stranger. Peripheral pulses of OT were no longer effective in inducing partner preferences when females were pretreated with a selective OT receptor antagonist, administered either peripherally or centrally. In contrast to females, peripheral treatment with OT did not facilitate the formation of partner preferences in males., (Copyright 2000 Academic Press.)

The purpose of this study was to determine whether pretreatment with oxytocin could mimic the effects of social contact and enhance sexual receptivity in female prairie voles. Female prairie voles require prolonged exposure to males to become sexually active and oxytocin has been shown to play a major role in the establishment of social bonds between males and females. Therefore, we hypothesized that prior exposure to exogenous oxytocin, in the absence of males, would enhance sexual activity in females. Two experiments were conducted to test this hypothesis. Experiment 1 examined the capacity of oxytocin to enhance sexual behaviour in females undergoing natural oestrus. Sexually naive female prairie voles received a daily subcutaneous injection of 20 microg oxytocin or isotonic saline for 5 days before being placed with a sexually experienced male for 48 h. Females treated with oxytocin were significantly more likely to mate during this period than saline-treated females. In experiment 2 the ability of oxytocin to increase subsequent sensitivity of sexually naive females to oestradiol was tested. Females that received oxytocin pretreatment, as in experiment 1, followed by oestradiol displayed a significant increase in sexual receptivity when compared to females treated with saline and oestradiol or oestradiol only. The results supported the hypothesis that prior exposure to oxytocin can mimic the effects of social contact, and can facilitate sexual receptivity by increasing the sensitivity of females to very low doses of oestradiol.