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.

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.

Whole-genome sequencing reveals the genetic mechanisms of domestication in classical inbred mice.

BACKGROUND: The laboratory mouse was domesticated from the wild house mouse. Understanding the genetics underlying domestication in laboratory mice, especially in the widely used classical inbred mice, is vital for studies using mouse models. However, the genetic mechanism of laboratory mouse domestication remains unknown due to lack of adequate genomic sequences of wild mice. RESULTS: We analyze the genetic relationships by whole-genome resequencing of 36 wild mice and 36 inbred strains. All classical inbred mice cluster together distinctly from wild and wild-derived inbred mice. Using nucleotide diversity analysis, Fst, and XP-CLR, we identify 339 positively selected genes that are closely associated with nervous system function. Approximately one third of these positively selected genes are highly expressed in brain tissues, and genetic mouse models of 125 genes in the positively selected genes exhibit abnormal behavioral or nervous system phenotypes. These positively selected genes show a higher ratio of differential expression between wild and classical inbred mice compared with all genes, especially in the hippocampus and frontal lobe. Using a mutant mouse model, we find that the SNP rs27900929 (T>C) in gene Astn2 significantly reduces the tameness of mice and modifies the ratio of the two Astn2 (a/b) isoforms. CONCLUSION: Our study indicates that classical inbred mice experienced high selection pressure during domestication under laboratory conditions. The analysis shows the positively selected genes are closely associated with behavior and the nervous system in mice. Tameness may be related to the Astn2 mutation and regulated by the ratio of the two Astn2 (a/b) isoforms.

Amphetamine exposure alters behaviors, and neuronal and neurochemical activation in the brain of female prairie voles.

Previous studies have shown that 3-day d-amphetamine (AMPH) treatment effectively induced conditioned place preferences (CPP) and impaired pair bonding behaviors in prairie voles (Microtus ochrogaster). Using this established animal model and treatment regimen, we examined the effects of the demonstrated threshold rewarding dose of AMPH on various behaviors and their potential underlying neurochemical systems in the brain of female prairie voles. Our data show that 3-day AMPH injections (0.2 mg/kg/day) impaired social recognition and decreased depressive-like behavior in females without affecting their locomotion and anxiety-like behaviors. AMPH treatment also decreased neuronal activation indicated by the labeling of the early growth response protein 1 (Egr-1) as well as the number of neurons double-labeled for Egr-1 and corticotrophin-releasing hormone (CRH) in the dentate gyrus (DG) of the hippocampus and paraventricular nucleus of the hypothalamus (PVN) in the brain. Further, AMPH treatment decreased the number of neurons double-labeled for Egr-1 and tyrosine hydroxylase (TH) but did not affect oxytocinergic neurons in the PVN or cell proliferation and neurogenesis markers in the DG. These data not only demonstrate potential roles of the brain CRH and dopamine systems in mediating disrupted social recognition and depressive-like behaviors by AMPH in female prairie voles, but also further confirm the utility of the prairie vole model for studying interactions between psychostimulants and social behaviors.

Behavioral, neurochemical, and neuroimmune changes associated with social buffering and stress contagion.

Social buffering can provide protective effects on stress responses and their subsequent negative health outcomes. Although social buffering is beneficial for the recipient, it can also have anxiogenic effects on the provider of the social buffering - a phenomena referred to as stress contagion. Social buffering and stress contagion usually occur together, but they have traditionally been studied independently, thus limiting our understanding of this dyadic social interaction. In the present study, we examined the effects of preventative social buffering and stress contagion in socially monogamous prairie voles (Microtus ochrogaster). We tested the hypothesis that this dynamic social interaction is associated with coordinated alterations in behaviors, neurochemical activation, and neuroimmune responses. To do so, adult male prairie voles were stressed via an acute immobilization restraint tube (IMO) either alone (Alone) or with their previously pair-bonded female partner (Partner) in the cage for 1 h. In contrast, females were placed in a cage containing either an empty IMO tube (Empty) or one that contained their pair-bonded male (Partner). Anxiety-like behavior was tested on the elevated plus maze (EPM) following the 60-mins test and brain sections were processed for neurochemical/neuroimmune marker labeling for all subjects. Our data indicate that females in the Partner group were in contact with and sniffed the IMO tube more, showed fewer anxiety-like behaviors, and had a higher level of oxytocin expression in the paraventricular nucleus of the hypothalamus (PVN) compared to the Empty group females. Males in the Partner group had lower levels of anxiety-like behavior during the EPM test, greater activation of corticotropin-releasing hormone expressing neurons in the PVN, lower activation of serotonin neurons in the dorsal raphe, and lower levels of microgliosis in the nucleus accumbens. Taken together, these data suggest brain region- and neurochemical-specific alterations as well as neuroinflammatory changes that may be involved in the regulation of social buffering and stress contagion behaviors.

Transcriptomic Regulations Underlying Pair-bond Formation and Maintenance in the Socially Monogamous Male and Female Prairie Vole.

BACKGROUND: The ability to form enduring social bonds is characteristic of human nature, and impairments in social affiliation are central features of severe neuropsychiatric disorders including autism spectrum disorder and schizophrenia. Owing to its ability to form long-term pair-bonds, the socially monogamous prairie vole has emerged as an excellent model to study the neurobiology of social attachment. Despite the enduring nature of the bond, however, surprisingly few genes have been implicated in the pair-bonding process in either sex. METHODS: Male and female prairie voles (Microtus ochrogaster) were cohabitated with an opposite-sex partner for 24 hours or 3 weeks, and transcriptomic regulations in the nucleus accumbens were measured by RNA sequencing. RESULTS: We found sex-specific response patterns despite similar behavioral indicators of pair-bond establishment. Indeed, 24 hours of cohabitation with an opposite-sex partner induced widespread transcriptomic changes that remained sustained to some extent in females after 3 weeks but returned to baseline before a second set of regulations in males. This led to a highly sexually biased nucleus accumbens transcriptome at 3 weeks related to processes such as neurotransmission, protein turnover, and DNA transcription. In particular, we found sex-specific alterations of mitochondrial dynamics following cohabitation, with a shift toward fission in males. CONCLUSIONS: In addition to identifying the genes, networks, and pathways involved in the pair-bonding process in the nucleus accumbens, our work illustrates the vast extent of sex differences in the molecular mechanisms underlying pair-bonding in prairie voles and paves the way to further our understanding of the complex social bonding process.

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.

Post-weaning Social Isolation in Male and Female Prairie Voles: Impacts on Central and Peripheral Immune System.

The socially monogamous prairie vole (Microtus ochrogaster) offers a unique opportunity to examine the impacts of adolescent social isolation on the brain, immune system, and behavior. In the current study, male and female prairie voles were randomly assigned to be housed alone or with a same-sex cagemate after weaning (i.e., on postnatal day 21-22) for a 6-week period. Thereafter, subjects were tested for anxiety-like and depressive-like behaviors using the elevated plus maze (EPM) and Forced Swim Test (FST), respectively. Blood was collected to measure peripheral cytokine levels, and brain tissue was processed for microglial density in various brain regions, including the Nucleus Accumbens (NAcc), Medial Amygdala (MeA), Central Amygdala (CeA), Bed Nucleus of the Stria Terminalis (BNST), and Paraventricular Nucleus of the Hypothalamus (PVN). Sex differences were found in EPM and FST behaviors, where male voles had significantly lower total arm entries in the EPM as well as lower latency to immobility in the FST compared to females. A sex by treatment effect was found in peripheral IL-1ß levels, where isolated males had a lower level of IL-1ß compared to cohoused females. Post-weaning social isolation also altered microglial density in a brain region-specific manner. Isolated voles had higher microglial density in the NAcc, MeA, and CeA, but lower microglial density in the dorsal BNST. Cohoused male voles also had higher microglial density in the PVN compared to cohoused females. Taken together, these data suggest that post-weaning social housing environments can alter peripheral and central immune systems in prairie voles, highlighting a potential role for the immune system in shaping isolation-induced alterations to the brain and behavior.

Density-induced social stress alters oxytocin and vasopressin activities in the brain of a small rodent species.

It is known that social stress could alter oxytocin (OT) and arginine-vasopressin (AVP) expression in specific regions of brains which regulate the aggressive behavior of small rodents, but the effects of density-induced social stress are still unknown. Brandt's voles (Lasiopodomys brandtii) are small herbivores in the grassland of China, but the underlying neurological mechanism of population regulation is still unknown. We tested the effects of housing density of Brandt's voles on OT/AVP system with physical contact (allowing aggression) and without physical contact (not allowing aggression) under laboratory conditions. Then, we tested the effects of paired-aggression (no density effect) of Brandt's voles on OT/AVP system under laboratory conditions. We hypothesized that high density would increase aggression among animals which would then increase AVP but reduce OT in brains of animals. Our results showed that high housing density induced more aggressive behavior. We found high-density-induced social stress (with or without physical contact) and direct aggression significantly 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 voles. The results suggest that density-dependent change of OT/AVP systems may play a significant role in the population regulation of small rodents by altering density-dependent aggressive behavior.

Social isolation alters behavior, the gut-immune-brain axis, and neurochemical circuits in male and female prairie voles.

The absence of social support, or social isolation, can be stressful, leading to a suite of physical and psychological health issues. Growing evidence suggests that disruption of the gut-immune-brain axis plays a crucial role in the negative outcomes seen from social isolation stress. However, the mechanisms remain largely unknown. The socially monogamous prairie vole (Microtus ochrogaster) has been validated as a useful model for studying negative effects of social isolation on the brain and behaviors, yet how the gut microbiome and central immune system are altered in isolated prairie voles are still unknown. Here, we utilized this social rodent to examine how social isolation stress alters the gut-immune-brain axis and relevant behaviors. Adult male and female prairie voles (n = 48 per sex) experienced social isolation or were cohoused with a same-sex cagemate (control) for six weeks. Thereafter, their social and anxiety-like behaviors, neuronal circuit activation, neurochemical expression, and microgliosis in key brain regions, as well as gut microbiome alterations from the isolation treatment were examined. Social isolation increased anxiety-like behaviors and impaired social affiliation. Isolation also resulted in sex- and brain region-specific alterations in neuronal activation, neurochemical expression, and microgliosis. Further, social isolation resulted in alterations to the gut microbiome that were correlated with key brain and behavioral measures. Our data suggest that social isolation alters the gut-immune-brain axis in a sex-dependent manner and that gut microbes, central glial cells, and neurochemical systems may play a critical, integrative role in mediating negative outcomes from social isolation.

Agonistic behaviors and neuronal activation in sexually naïve female Mongolian gerbils.

Agonistic interaction is important for establishing social hierarchy and determining access to limited resources. Although there are substantial studies investigating the neural mechanisms of aggressive or defensive behavior in male rodents, little attention has been paid to the mechanisms underlying agonistic behaviors in females. In the present study, we depicted patterns of agonistic behaviors in sexually naïve female Mongolian gerbils (Meriones unguiculatus) and examined the neuronal activation in the brain by Fos-immunoreactive (Fos-ir) staining. We found that the winner-loser relationship was established rapidly. Winners displayed higher levels of aggression, environmental exploration, scent marking, and self-grooming, but less defensive behavior, in comparison to losers. Several patterns of Fos-ir expression emerged following agonistic interactions. Winners had the number of Fos-ir cells in the ventrolateral subnucleus of the ventromedial hypothalamus (VMHvl) and dorsal periaqueductal grey (PAGd) more than the controls but less than the losers. Losers also had more Fos-ir cells in the paraventricular nucleus of the hypothalamus (PVN), anterior medial (BSTam) and anteriolateral (BSTal) subnuclei of the bed nucleus of the stria terminalis (BST), and the ventral subnucleus of the lateral septum (LSv), as well as less Fos-ir cells in the dentate gyrus of the hippocampus (DG), compared to the controls. In addition, the number of Fos-ir cells showed similar increases in the principal nucleus (BSTpr) and interfascicular nucleus (BSTif) of the BST and amygdala (AMYG) in both the winners and losers, compared to the controls. Together, these data illustrate the patterns of altered neuronal activation in a behavior-, social status-, and brain region-specific manner, implicating potential roles of the brain neural circuit in mediating agonistic interactions in female Mongolian gerbils.

Hormonal Regulation of Mammalian Adult Neurogenesis: A Multifaceted Mechanism.

Adult neurogenesis-resulting in adult-generated functioning, integrated neurons-is still one of the most captivating research areas of neuroplasticity. The addition of new neurons in adulthood follows a seemingly consistent multi-step process. These neurogenic stages include proliferation, differentiation, migration, maturation/survival, and integration of new neurons into the existing neuronal network. Most studies assessing the impact of exogenous (e.g., restraint stress) or endogenous (e.g., neurotrophins) factors on adult neurogenesis have focused on proliferation, survival, and neuronal differentiation. This review will discuss the multifaceted impact of hormones on these various stages of adult neurogenesis. Specifically, we will review the evidence for hormonal facilitation (via gonadal hormones), inhibition (via glucocorticoids), and neuroprotection (via recruitment of other neurochemicals such as neurotrophin and neuromodulators) on newly adult-generated neurons in the mammalian brain.

Role of Long Noncoding RNA Gas5 in Cocaine Action.

BACKGROUND: Long noncoding RNAs (lncRNAs) are a class of transcribed RNA molecules greater than 200 nucleotides in length. Although lncRNAs do not encode proteins, they play numerous functional roles in gene expression regulation. lncRNAs are notably abundant in brain; however, their neural functions remain largely unknown. METHODS: We examined the expression of the lncRNA Gas5 in nucleus accumbens (NAc), a key brain reward region, of adult male mice after cocaine administration. We then performed viral-mediated overexpression of Gas5 in NAc neurons to determine its role in addiction-related behaviors. We also carried out RNA sequencing to investigate Gas5-mediated transcriptomic changes. RESULTS: We demonstrated that repeated short-term or long-term cocaine administration decreased expression of Gas5 in NAc. Viral-mediated overexpression of Gas5 in NAc neurons decreased cocaine-induced conditioned place preference. Likewise, Gas5 overexpression led to decreased cocaine intake, decreased motivation, and compulsive-like behavior to acquire cocaine, and it facilitated extinction of cocaine-seeking behavior. Transcriptome profiling identified numerous Gas5-mediated gene expression changes that are enriched in relevant neural function categories. Interestingly, these Gas5-regulated gene expression changes significantly overlap with chronic cocaine-induced transcriptome alterations, suggesting that Gas5 may serve as an important regulator of transcriptional responses to cocaine. CONCLUSIONS: Altogether, our study demonstrates a novel lncRNA-based molecular mechanism of cocaine action.

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.

Metagenome-Assembled Genome Sequences of Five Strains from the Microtus ochrogaster (Prairie Vole) Fecal Microbiome.

The prairie vole (Microtus ochrogaster) is an important model for the study of social monogamy and dual parental care of offspring. Characterization of specific host species-microbe strain interactions is critical for understanding the effects of the microbiota on mood and behavior. The five metagenome-assembled genome sequences reported here represent an important step in defining the prairie vole microbiome.

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.