Transcriptomic analysis of paternal behaviors in prairie voles.

BACKGROUND: The importance of fathers' engagement in care and its critical role in the offspring's cognitive and emotional development is now well established. Yet, little is known on the underlying neurobiology due to the lack of appropriate animal models. In the socially monogamous and bi-parental prairie vole (Microtus ochrogaster), while 60-80% of virgin males show spontaneous paternal behaviors (Paternal), others display pup-directed aggression (Attackers). Here we took advantage of this phenotypic dichotomy and used RNA-sequencing in three important brain areas to characterize gene expression associated with paternal behaviors of Paternal males and compare it to experienced Fathers and Mothers. RESULTS: While Paternal males displayed the same range and extent of paternal behaviors as experienced Fathers, we observed structure-specific transcriptomic differences between parental behaviors phenotypes. Using differential expression, gene set expression, as well as co-expression network analyses, we found that phenotypic differences between Paternal males and Attackers were mainly reflected by the lateral septum (LS), and to a lower extent, the nucleus accumbens (NAc), transcriptomes. In the medial preoptic area (MPOA), the profiles of gene expression mainly reflected differences between females and males regardless of their parental behaviors phenotype. Functional enrichment analyses of those gene sets associated with Paternal males or Attackers in the LS and the NAc revealed the involvement of processes related to the mitochondria, RNA translation, protein degradation processes, as well as epigenetic regulation of gene expression. CONCLUSIONS: By leveraging the natural phenotypic differences in parental behaviors in virgin male prairie voles alongside fathers and mothers, we identified a marked structure- and phenotype-specific pattern of gene expression associated with spontaneous paternal behaviors independently from fatherhood and pair-bonding. The LS transcriptome related to the mitochondria, RNA translation, and protein degradation processes was thus highlighted as a primary candidate associated with the spontaneous display of paternal behaviors. Altogether, our observations further characterize the behavioral and transcriptomic signature of parental behaviors in the socially monogamous prairie vole and lay the groundwork to further our understanding of the molecular underpinnings of paternal behavior.

Population variation alters aggression-associated oxytocin and vasopressin expressions in brains of Brandt's voles in field conditions.

Density-dependent change in aggressive behavior contributes to the population regulation of many small rodents, but the underlying neurological mechanisms have not been examined in field conditions. We hypothesized that crowding stress and aggression-associated oxytocin (OT) and arginine vasopressin (AVP) in specific regions of the brain may be closely related to aggressive behaviors and population changes of small rodents. We analyzed the association of OT and AVP expression, aggressive behavior, and population density of Brandt's voles in 24 large semi-natural enclosures (0.48 ha each) in Inner Mongolia grassland. We tested the effects of population density on the OT/AVP system and aggressive behavior by experimentally manipulating populations of Brandt's voles in the grassland enclosures. High density was positively and significantly associated with more aggressive behavior, and increased expression of mRNA and protein of AVP and its receptor, but decreased expression of mRNA and protein of OT and its receptor in specific brain regions of the voles. Our study suggests that changes in OT/AVP expression are likely a result of the increased psychosocial stress that these voles experience during overcrowding, and thus the OT/AVP system can be used as indicators of density-dependent stressors in Brandt's voles.

Regulation of social behaviors by p-Stat3 via oxytocin and its receptor in the nucleus accumbens of male Brandt's voles (Lasiopodomys brandtii).

Social behavior plays a significant role in the formation of social structure and population regulation in both animals and humans. Oxytocin (OXT) and its receptor (OXTR) are well known for regulating social behaviors, but their upstream regulating factors are rarely investigated. We hypothesized that the phosphorylation of the signal transducer and activator of transcription 3 (p-Stat3) may regulate social and aggressive behaviors via the OXT system in the nucleus accumbens (NAc). To test this hypothesis, OXT, p-Stat3 inhibitor, OXTR antagonist, and OXT plus p-Stat3 inhibitor were infused, respectively, into the NAc in the brain of male Brandt's voles (Lasiopodomys brandtii) - a social rodent species in grassland of Inner Mongolia, China. Our data showed that blockage of p-Stat3-Tyr705 signaling pathway in the NAc not only increased aggressive behavior but also impaired social recognition of male Brandt's voles via its effects on the expression of local OXT and OXTR. These results have illustrated a novel signaling pathway of p-Stat3-Tyr705 in regulating social behaviors via the OXT system.

Thermo-TRPs and gut microbiota are involved in thermogenesis and energy metabolism during low temperature exposure of obese mice.

Ambient temperature and food composition can affect energy metabolism of the host. Thermal transient receptor potential ion channels (thermo-TRPs) can detect temperature signals and are involved in the regulation of thermogenesis and energy homeostasis. Further, the gut microbiota have also been implicated in thermogenesis and obesity. In the present study, we tested the hypothesis that thermo-TRPs and gut microbiota are involved in reducing diet-induced obesity (DIO) during low temperature exposure. C57BL/6J mice in obese (body mass gain >45%), lean (body mass gain <15%) and control (body mass gain <1%) groups were exposed to high (23±1°C) or low (4±1°C) ambient temperature for 28 days. Our data showed that low temperature exposure attenuated DIO, but enhanced brown adipose tissue (BAT) thermogenesis. Low temperature exposure also resulted in increased noradrenaline (NA) concentrations in the hypothalamus, decreased TRP melastatin 8 (TRPM8) expression in the small intestine, and altered composition and diversity of gut microbiota. In DIO mice, there was a decrease in overall energy intake along with a reduction in TRP ankyrin 1 (TRPA1) expression and an increase in NA concentration in the small intestine. DIO mice also showed increases in Oscillospira, [Ruminococcus], Lactococcus and Christensenella and decreases in Prevotella, Odoribacter and Lactobacillus at the genus level in fecal samples. Together, our data suggest that thermos-TRPs and gut microbiota are involved in thermogenesis and energy metabolism during low temperature exposure in DIO mice.

The ventromedial hypothalamic circuitry and male alloparental behaviour in a socially monogamous rodent species.

As prairie voles (Microtus ochrogaster) display spontaneous biparental care, and the ventromedial hypothalamus (VMH) has been implicated in reproductive behaviour, we conducted experiments to test the hypothesis that the VMH neurochemical circuitry is involved in alloparental behaviours in male prairie voles. We compared alloparental behaviours of adult, sexually naïve male and female voles-both displayed licking/grooming, huddling and retrieving behaviours towards conspecific pups. We also stained for the immediate-early gene encoded early growth protein Egr-1 in the vole brain. The pup-exposed animals showed levels of Egr-1 staining that was higher in the VMH but lower in the amygdala compared to animals exposed to a pup-sized piece of plastic (control). A retrograde tracer, Fluoro-Gold (FG), was injected into the VMH of male voles that were subsequently tested in the pup exposure or control condition. More FG/Egr-1 cells were detected for glutamatergic (GLU) staining in the ventral bed nucleus of the stria terminalis (BNSTv) and medial amygdala (MeA), whereas less FG/Egr-1 cells were stained for gamma-aminobutyric acid (GABA) in the MeA of the pup-exposed group compared to the control group. Further, the ratio of GLU:GABA expression in FG/Egr-1 projection neurons from both the BNSTv and MeA to the VMH was increased following pup exposure. Finally, pharmacological blockade of either dopamine D1 receptor or oxytocin receptor in the VMH impaired the onset of male alloparental behaviour. Together, these data suggest that the VMH may be involved in the onset of alloparental care and play a role in regulating social approach in male prairie voles.

GnRH expression and cell proliferation are associated with seasonal breeding and food hoarding in Mongolian gerbils (Meriones unguiculatus).

Seasonal brain plasticity contributes to a variety of physiological and behavioral processes. We hypothesized that variations in GnRH expression and cell proliferation facilitated seasonal breeding and food hoarding. Here, we reported seasonal changes in sexual and social behavior, GnRH expression and brain cell proliferation, and the role of photoperiod in inducing seasonal breeding and brain plasticity in Mongolian gerbils (Meriones unguiculatus). The gerbils captured in April and July had more mature sexual development, higher exploratory behavior, and preferred novelty much more than those captured in September. Male gerbils captured in April and July had consistently higher GnRH expression than those captured in September. GnRH expression was also found to be suppressed by food-induced hoarding behavior in the breeding season. Both subadult and adult gerbils from April and July had higher cell proliferation in SVZ, hypothalamus and amygdala compared to those in September. However, adult gerbils captured in September preferred familiar objects, and no seasonal differences were found in cell proliferation in hippocampal dentate gyrus among the three seasons. The laboratory study showed that photoperiod alone did not alter reproductive traits, behavior, cell proliferation or cell survival in the detected brain regions. These findings suggest that the structural variations in GnRH expression in hypothalamus and cell proliferation in hypothalamus, amygdala and hippocampus are associated with seasonal breeding and food hoarding in gerbils. It gives a new insight into the proximate physiological and neural basis for these seasonal life-history traits of breeding and food hoarding in small mammals.

Sustained energy intake in lactating Swiss mice: a dual modulation process.

Limits to sustained energy intake (SusEI) during lactation are important because they provide an upper boundary below which females must trade off competing physiological activities. To date, SusEI is thought to be limited either by the capacity of the mammary glands to produce milk (the peripheral limitation hypothesis) or by a female's ability to dissipate body heat (the heat dissipation hypothesis). In the present study, we examined the effects of litter size and ambient temperature on a set of physiological, behavioral and morphological indicators of SusEI and reproductive performance in lactating Swiss mice. Our results indicate that energy input, energy output and mammary gland mass increased with litter size, whereas pup body mass and survival rate decreased. The body temperature increased significantly, while food intake (18 g day-1 at 21°C versus 10 g day-1 at 30°C), thermal conductance (lower by 20-27% at 30°C than 21°C), litter mass and milk energy output decreased significantly in the females raising a large litter size at 30°C compared with those at 21°C. Furthermore, an interaction between ambient temperature and litter size affected females' energy budget, imposing strong constraints on SusEI. Together, our data suggest that the limitation may be caused by both mammary glands and heat dissipation, i.e. peripheral limitation is dominant at room temperature, but heat dissipation is more significant at warm temperatures. Further, the level of the heat dissipation limits may be temperature dependent, shifting down with increasing temperature.

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.

Neuropeptidergic regulation of pair-bonding and stress buffering: Lessons from voles.

This article is part of a Special Issue "SBN 2014". Interpersonal attachment is a critical component of the human experience. Pair-bonding ameliorates the severity of several mental and physical diseases. Thus, a better understanding of how the central nervous system responds to and encodes social-buffering during stress is a valuable research enterprise. The prairie vole (Microtus ochrogaster), as a laboratory animal model, provides the gold standard for the investigation of the neurobiology underlying attachment. Furthermore, emerging research in voles, additional laboratory rodents, transgenic mice, primates, and humans has provided novel insight into the neurochemical mechanisms underlying the therapeutic effects of social bonds reducing anxiety, depression, and drug abuse liability. In the present review, we highlight the work from this burgeoning field and focus on the role(s) of the neuropeptides oxytocin (OT), vasopressin (AVP), and corticotrophin releasing hormone (CRH) mediating stress buffering. Together, the data suggest that OT underlies social bonding to reduce stress-induced psychological illness while AVP and CRH facilitate arousal to enhance autonomic reactivity, increasing susceptibility to adverse mental and physical health.

Fatherhood reduces the survival of adult-generated cells and affects various types of behavior in the prairie vole (Microtus ochrogaster ).

Motherhood has profound effects on physiology, neuronal plasticity, and behavior. We conducted a series of experiments to test the hypothesis that fatherhood, similarly to motherhood, affects brain plasticity (such as cell proliferation and survival) and various behaviors in the highly social prairie vole (Microtus ochrogaster). In Experiment 1, adult males were housed with their same-sex cage mate (control), single-housed (isolation), or housed with a receptive female to mate and produce offspring (father) for 6 weeks. Fatherhood significantly reduced cell survival (assessed by bromodeoxyuridine labeling), but not cell proliferation (assessed by Ki67-labeling), in the amygdala, dentate gyrus of the hippocampus, and ventromedial hypothalamus, suggesting that fatherhood affects brain plasticity. In Experiment 2, neither acute (20 min) nor chronic (20 min daily for 10 consecutive days) pup exposure altered cell proliferation or survival in the brain, but chronic pup exposure increased circulating corticosterone levels. These data suggest that reduced cell survival in the brain of prairie vole fathers was unlikely to be due to the level of pup exposure and display of paternal behavior, and may not be mediated by circulating corticosterone. The effects of fatherhood on various behaviors (including anxiety-like, depression-like, and social behaviors) were examined in Experiment 3. The data indicated that fatherhood increased anxiety- and depression-like behaviors as well as altered aggression and social recognition memory in male prairie voles. These results warrant further investigation of a possible link between brain plasticity and behavioral changes observed due to fatherhood.

Behavioral and physiological responses of female prairie voles (Microtus ochrogaster) to various stressful conditions.

Stressful life events elicit hypothalamic-pituitary-adrenal (HPA) axis activation, which may alter psychological states or behavioral routines. Therefore, the current study focused on the HPA axis response to better understand such manifestations in female prairie voles (Microtus ochrogaster). In Experiment 1, females were stressed for 1 h via one of the four stressors: exposure to a novel environment, immobilization ("plastic mesh"), brief social defeat, or prolonged social defeat. Following a 30-min recovery, the females received a 5-min elevated plus maze (EPM) test and, subsequently, blood was collected to measure plasma corticosterone concentrations. Only immobilization stress induced an anxiety-like behavioral response in the EPM test and elevated plasma corticosterone levels compared to the control groups. Corticosterone concentrations were also significantly elevated following exposure to prolonged social defeat compared to the control conditions, but not after novel environment stress or short social defeat. In Experiment 2, females were exposed to immobilization stress over 1, 3, or 7 days in a daily (predictable; pIMO) or irregular (unpredictable; uIMO) schedule. The biobehavioral stress response in females exposed to pIMO for 3 or 7 days did not differ significantly from controls, suggesting these females habituated. By comparison, females exposed to uIMO over 3 or 7 days did not habituate behaviorally or physiologically, even producing augmented corticosterone levels. In both experiments, positive correlations were found between corticosterone levels and anxiety-like behaviors in the EPM test. Together, our data suggest that the stress response by female prairie voles is dependent on stress intensity, source, previous experience, and predictability. Furthermore, the HPA axis response, as evident by corticosterone levels, is associated with the impact that these factors have on behavioral routine.

Nucleus accumbens dopamine mediates amphetamine-induced impairment of social bonding in a monogamous rodent species.

The prairie vole (Microtus ochrogaster) is a socially monogamous rodent species that forms pair bonds after mating, a behavior in which central dopamine (DA) has been implicated. Here, we used male prairie voles to examine the effects of drug exposure on pair bonding and related neural circuitry. In our first experiment, amphetamine (AMPH) motivated behavior was examined using a conditioned place preference (CPP) paradigm and was shown to be mediated by activation of D1-like DA receptors. Next, we examined the effects of repeated AMPH exposure on pair bonding. Intact and saline pretreated control males displayed mating-induced partner preferences, whereas males pretreated with AMPH at the doses effective to induce CPP failed to show mating-induced partner preferences. Such AMPH treatment also enhanced D1, but not D2, DA receptor expression in the nucleus accumbens (NAcc). Furthermore, pharmacological blockade of D1-like DA receptors in the NAcc rescued mating-induced partner preferences in AMPH-treated males. Together, our data indicate that repeated AMPH exposure may narrow the behavioral repertoire of male prairie voles via a DA receptor-specific mechanism in the NAcc, resulting in the impairment of pair bond formation.

Transcription and DNA methylation signatures of paternal behavior in hippocampal dentate gyrus of prairie voles.

In socially monogamous prairie voles (Microtus ochrogaster), parental behaviors not only occur in mothers and fathers, but also exist in some virgin males. In contrast, the other virgin males display aggressive behaviors towards conspecific pups. However, little is known about the molecular underpinnings of this behavioral dichotomy, such as gene expression changes and their regulatory mechanisms. To address this, we profiled the transcriptome and DNA methylome of hippocampal dentate gyrus of four prairie vole groups, namely attacker virgin males, parental virgin males, fathers, and mothers. While we found a concordant gene expression pattern between parental virgin males and fathers, the attacker virgin males have a more deviated transcriptome. Moreover, numerous DNA methylation changes were found in pair-wise comparisons among the four groups. We found some DNA methylation changes overlapping with transcription differences, across gene-bodies and promoter regions. Furthermore, the gene expression changes and methylome alterations are selectively enriched in certain biological pathways, such as Wnt signaling, which suggest a canonical transcription regulatory role of DNA methylation in paternal behavior. Therefore, our study presents an integrated view of prairie vole dentate gyrus transcriptome and epigenome that provides a DNA epigenetic based molecular insight of paternal behavior.

Chronic social defeat alters behaviors and neuronal activation in the brain of female Mongolian gerbils.

Chronic social defeat has been found to be stressful and to affect many aspects of the brain and behaviors in males. However, relatively little is known about its effects on females. In the present study, we examined the effects of repeated social defeat on social approach and anxiety-like behaviors as well as the neuronal activation in the brain of sexually naïve female Mongolian gerbils (Meriones unguiculatus). Our data indicate that repeated social defeats for 20 days reduced social approach and social investigation, but increased risk assessment or vigilance to an unfamiliar conspecific. Such social defeat experience also increased anxiety-like behavior and reduced locomotor activity. Using ΔFosB-immunoreactive (ΔFosB-ir) staining as a marker of neuronal activation in the brain, we found significant elevations by social defeat experience in the density of ΔFosB-ir stained neurons in several brain regions, including the prelimbic (PL) and infralimbic (IL) subnuclei of the prefrontal cortex (PFC), CA1 subfields (CA1) of the hippocampus, central subnuclei of the amygdala (CeA), the paraventricular nucleus (PVN), dorsomedial nucleus (DMH), and ventrolateral subdivision of the ventromedial nucleus (VMHvl) of the hypothalamus. As these brain regions have been implicated in social behaviors and stress responses, our data suggest that the specific patterns of neuronal activation in the brain may relate to the altered social and anxiety-like behaviors following chronic social defeat in female Mongolian gerbils.

Effects of Group Size on Behavior, Reproduction, and mRNA Expression in Brains of Brandt's Voles.

For social animals, a moderate group size is greatly important to maintain their reproductive success. However, the underlying neurobiological mechanism of group size on behavior and reproduction has rarely been investigated. In this study, we examined the effects of group size (1, 2, 4 pairs of adult male and female voles raised per cage) on behavior and reproduction. Meanwhile, the mRNA expression of stress and reproduction response-related genes in male brains was detected. We found that Brandt's voles (Lasiopodomys brandtii) in the large-sized group fight more severely than those in the small-sized group. Meanwhile, male voles were more anxious than females. The average number of embryos and litters per female in the medium-sized group was significantly higher than that of large-sized group. In male voles, stress- or reproduction-response mRNA expressions were more related to final group size or final density due to death caused by fighting. Our results indicated that a moderate group size was beneficial to the reproductive output of Brandt's voles. Our study highlights the combined effects of stress- or reproduction-related gene expression or behavior in regulating the fitness of voles with different group sizes.

Limosilactobacillus reuteri administration alters the gut-brain-behavior axis in a sex-dependent manner in socially monogamous prairie voles.

Research on the role of gut microbiota in behavior has grown dramatically. The probiotic L. reuteri can alter social and stress-related behaviors - yet, the underlying mechanisms remain largely unknown. Although traditional laboratory rodents provide a foundation for examining the role of L. reuteri on the gut-brain axis, they do not naturally display a wide variety of social behaviors. Using the highly-social, monogamous prairie vole (Microtus ochrogaster), we examined the effects of L. reuteri administration on behaviors, neurochemical marker expression, and gut-microbiome composition. Females, but not males, treated with live L. reuteri displayed lower levels of social affiliation compared to those treated with heat-killed L. reuteri. Overall, females displayed a lower level of anxiety-like behaviors than males. Live L. reuteri-treated females had lower expression of corticotrophin releasing factor (CRF) and CRF type-2-receptor in the nucleus accumbens, and lower vasopressin 1a-receptor in the paraventricular nucleus of the hypothalamus (PVN), but increased CRF in the PVN. There were both baseline sex differences and sex-by-treatment differences in gut microbiome composition. Live L. reuteri increased the abundance of several taxa, including Enterobacteriaceae, Lachnospiraceae NK4A136, and Treponema. Interestingly, heat-killed L. reuteri increased abundance of the beneficial taxa Bifidobacteriaceae and Blautia. There were significant correlations between changes in microbiota, brain neurochemical markers, and behaviors. Our data indicate that L. reuteri impacts gut microbiota, gut-brain axis and behaviors in a sex-specific manner in socially-monogamous prairie voles. This demonstrates the utility of the prairie vole model for further examining causal impacts of microbiome on brain and behavior.

Social bonding decreases the rewarding properties of amphetamine through a dopamine D1 receptor-mediated mechanism.

Although the protective effects of social bonds on drug use/abuse have been well documented, we know little about the underlying neural mechanisms. Using the prairie vole (Microtus ochrogaster)--a socially monogamous rodent that forms long-term pair bonds after mating--we demonstrate that amphetamine (AMPH) conditioning induced a conditioned place preference (CPP) in sexually naive (SN), but not pair-bonded (PB), males. Although AMPH treatment induced a similar magnitude of dopamine release in the nucleus accumbens (NAcc) of SN and PB males, it had differential effects on NAcc D1 receptor (D1R) binding. Specifically, AMPH treatment increased D1R binding in SN, but decreased D1R binding in PB males. NAcc D1R, but not D2 receptor, antagonism blocked AMPH-induced CPP in SN males and NAcc D1R activation before AMPH conditioning enabled AMPH-induced CPP in PB males. Together, our data demonstrate that pair-bonding experience decreases the rewarding properties of AMPH through a D1R-mediated mechanism.

The neurobiology of pair bonding: insights from a socially monogamous rodent.

The formation of enduring relationships between adult mates (i.e., pair bonds) is an integral aspect of human social behavior and has been implicated in both physical and psychological health. However, due to the inherent complexity of these bonds and the relative rarity with which they are formed in other mammalian species, we know surprisingly little about their underlying neurobiology. Over the past few decades, the prairie vole (Microtus ochrogaster) has emerged as an animal model of pair bonding. Research in this socially monogamous rodent has provided valuable insight into the neurobiological mechanisms that regulate pair bonding behaviors. Here, we review these studies and discuss the neural regulation of three behaviors inherent to pair bonding: the formation of partner preferences, the subsequent development of selective aggression toward unfamiliar conspecifics, and the bi-parental care of young. We focus on the role of vasopressin, oxytocin, and dopamine in the regulation of these behaviors, but also discuss the involvement of other neuropeptides, neurotransmitters, and hormones. These studies may not only contribute to the understanding of pair bonding in our own species, but may also offer insight into the underlying causes of social deficits noted in several mental health disorders.

Salubrious effects of oxytocin on social stress-induced deficits.

Social relationships are a fundamental aspect of life, affecting social, psychological, physiological, and behavioral functions. While positive social interactions can attenuate stress and promote health, the social environment can also be a major source of stress when it includes social disruption, confrontation, isolation, or neglect. Social stress can impair the basal function and stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis, impairing function of multiple biological systems and posing a risk to mental and physical health. In contrast, social support can ameliorate stress-induced physiological and immunological deficits, reducing the risk of subsequent psychological distress and improving an individual's overall well-being. For better clinical treatment of these physiological and mental pathologies, it is necessary to understand the regulatory mechanisms of stress-induced pathologies as well as determine the underlying biological mechanisms that regulate social buffering of the stress system. A number of ethologically relevant animal models of social stress and species that form strong adult social bonds have been utilized to study the etiology, treatment, and prevention of stress-related disorders. While undoubtedly a number of biological pathways contribute to the social buffering of the stress response, the convergence of evidence denotes the regulatory effects of oxytocin in facilitating social bond-promoting behaviors and their effect on the stress response. Thus, oxytocin may be perceived as a common regulatory element of the social environment, stress response, and stress-induced risks on mental and physical health. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.

Social isolation impairs adult neurogenesis in the limbic system and alters behaviors in female prairie voles.

Disruptions in the social environment, such as social isolation, are distressing and can induce various behavioral and neural changes in the distressed animal. We conducted a series of experiments to test the hypothesis that long-term social isolation affects brain plasticity and alters behavior in the highly social prairie vole (Microtus ochrogaster). In Experiment 1, adult female prairie voles were injected with a cell division marker, 5-bromo-2'-deoxyuridine (BrdU), and then same-sex pair-housed (control) or single-housed (isolation) for 6 weeks. Social isolation reduced cell proliferation, survival, and neuronal differentiation and altered cell death in the dentate gyrus of the hippocampus and the amygdala. In addition, social isolation reduced cell proliferation in the medial preoptic area and cell survival in the ventromedial hypothalamus. These data suggest that long-term social isolation affects distinct stages of adult neurogenesis in specific limbic brain regions. In Experiment 2, isolated females displayed higher levels of anxiety-like behaviors in both the open field and elevated plus maze tests and higher levels of depression-like behavior in the forced swim test than controls. Further, isolated females showed a higher level of affiliative behavior than controls, but the two groups did not differ in social recognition memory. Together, our data suggest that social isolation not only impairs cell proliferation, survival, and neuronal differentiation in limbic brain areas, but also alters anxiety-like, depression-like, and affiliative behaviors in adult female prairie voles. These data warrant further investigation of a possible link between altered neurogenesis within the limbic system and behavioral changes.