Prairie voles (Microtus ochrogaster) are highly social rodents that have become a valuable animal model for studying social attachment, pair bonding, parental care, and the neurobiological mechanisms underlying social behavior. In recent years, due in part to the publication of the prairie vole genome and deeper mechanistic understanding of their social behavior, prairie voles have become a more popular research model, especially for translational research. However, generating reliable and reproducible findings requires effective colony management, including thoughtful breeding strategies, consistent husbandry practices, and clear documentation. In this paper, we describe the demographic history of, and husbandry techniques employed for, our prairie vole breeding colony at the University of California, Davis from 2004 to 2020. Well-organized and transparent colony management allows for the preservation of informative behavioral traits in prairie voles and strengthens the impact of the prairie vole model across behavioral and biomedical science.

The increasing prevalence of cannabis use, including among pregnant women, highlights the critical need for a deeper understanding of prenatal cannabis exposure. This study aimed to develop a standardized cross-species inhalation exposure protocol to administer the principal psychoactive component of cannabis, Δ9-tetrahydrocannabinol (THC), to prairie voles (Microtus ochrogaster) and laboratory rats (Rattus norvegicus), and to investigate the distribution of THC in maternal and fetal tissues following prenatal exposure. Using an established e-cigarette system for delivering vaporized THC, we administered THC to pregnant prairie voles and rats. THC concentrations were measured in maternal plasma and fetal brain tissue using LC-MS/MS (liquid chromatography coupled with tandem mass spectrometry). We found that THC readily crossed the placental barrier in both species, resulting in significantly higher concentrations of THC in the fetal brain within the THC-exposed groups compared to the vehicle controls. Interspecies comparison revealed higher THC concentrations in rat fetal brain tissue compared to prairie voles. No significant effects of fetal position on THC levels were found for either species. The findings confirm placental transfer of THC and reveal species-specific patterns of THC distribution. Additional studies were then carried out in voles to compare plasma and brain THC levels in maternal and virgin adult prairie voles. Maternal brain THC concentrations were significantly higher than fetal brain concentrations in prairie voles. This study establishes a translational model for investigating prenatal cannabis exposure using an aerosolized administration method in voles compared to established methods in rats. The standardized protocol and results provide a foundation for future research into the developmental consequences of prenatal cannabis exposure and offer crucial insights for informing public health policies and clinical practices in response to the global increase in cannabis use.

Social relationships play a critical role in modulating stress responses, adjusting behavior, and regulating physiology. Changes in the social environment, including cohabitation and partner status, can shape behavioral and physiological outcomes, yet the extent of influence to physiological changes remains unclear. In this study, we characterized the complexity of relationships across different social contexts in the prairie vole (Microtus ochrogaster) across four different social contexts including: isolated voles, females paired with vasectomized males (BV), females paired with intact males (BI), and same-sex sibling pairs (SS). We investigated the establishment and development of these varied social relationships through the use of four behavioral testing paradigms: partner preference testing (PPT), separation distress (SD), social buffering (SB), and homecage observations (HCO). In the PPT, we found that BI, BV, and SS subjects all preferred spending time with their partner rather than a stranger. In SD, subjects spent more time in the nest when their partners were present than when alone, whereas grooming increased during isolation. In SB, affiliative behaviors were elevated in the presence of a partner. In the homecage, SS subjects spent more time huddling and lunging was elevated in BV groups compared to BI, suggesting differences in baseline social dynamics with the presence of pups. We used these behavioral measures to identify two sets of factors that describe relationship quality. Together, the findings underscore that social relationships are not a unified construct, but reflect multiple complex responses. This study highlights the importance of characterizing complex social organization across different relationship types.

Prairie voles (Microtus ochrogaster) are one of the few mammalian species that are monogamous and engage in the biparental rearing of their offspring. Biparental care impacts the quantity and quality of care the offspring receives. The increased attention by the father may translate to heightened tactile contact the offspring receives through licking and grooming. In the current study, we used electrophysiological multiunit recording techniques to define the organization of the perioral representation in the primary somatosensory area (S1) of prairie voles. Functional representations were related to myeloarchitectonic boundaries. Our results show that most of S1 is occupied by the representation of the contralateral mystacial whiskers and the lower and upper lips. The mystacial vibrissae representation encompassed a large portion of the caudolateral S1, while the representation of the lower and upper lips occupied a large portion of the rostrolateral aspect of S1. We found that neuronal populations representing the perioral structures tended to have small receptive fields relative to other body part representations on the head. The representation of the mystacial whiskers and perioral structures was coextensive with cytoarchitectonically defined barrel fields that extend from the caudolateral to a rostrolateral aspect of S1. We discuss our findings in the context of the magnification of behaviorally relevant sensory surfaces in other rodents, the ubiquity of the barrel systems in rodents, and behaviors associated with specialized sensory surfaces.

The onset of parental care is associated with shifts in parents' perception of sensory stimuli from infants, mediated by neural plasticity in sensory systems. In new mothers, changes in auditory and olfactory processing have been linked to plasticity at several points along both sensory pathways, including cortical changes that are modulated, at least in part, by oxytocin. In males of biparental species, vasopressin, in addition to oxytocin, is important for modulating parental behavior; however, little is known about sensory plasticity in new fathers. We examined variation in the mRNA expression of oxytocin and vasopressin receptors (Oxtr and Avpr1a) in sensory cortices of virgin males, paired nonbreeding males, and new fathers in the biparental California mouse (Peromyscus californicus), and variation among cortices using the visual cortex for comparison. Reproductive status did not affect gene expression for either receptor, but compared to the visual cortex, expression of both receptors was higher in the left auditory cortex and lower in the anterior olfactory nucleus. Additionally, expression for both receptors was higher in the left auditory cortex compared to the right auditory cortex. While oxytocin and vasopressin receptor expression may remain stable across reproductive stages in male California mice, our findings provide support for auditory cortex lateralization, with the left auditory cortex possibly displaying higher sensitivity to both oxytocin and vasopressin compared to the right.

Cannabis is one of the most widely used psychoactive substances worldwide, with a growing interest in its potential therapeutic applications. In recent years, there has been a significant increase in cannabis use, driven by the progressive legalization and acceptance of recreational usage. Despite the expanding legalization and use of cannabis, the effects of this substance on various physiological systems and behaviors are not fully understood. Accumulating evidence suggests that cannabis exposure may elicit sex-specific effects, highlighting the importance of considering sex as a biological variable in cannabis research. Sex can affect many behavioral outcomes, thus these differences should be considered when looking at the continuation of cannabis legalization. Despite the growing recognition of the importance of sex differences in research, the current literature on cannabis use and its effects has not adequately addressed these differences. Understanding sex differences in cannabis use is crucial for developing treatment strategies and informing public health policies. This scoping review aims to address these gaps and highlight instances of sex-specific behavioral responses to cannabis exposure. The purpose of this review is to: 1) give an overview of cannabis, the endocannabinoid system, and sex-differences in scientific literature, 2) provide an overview of the current state of knowledge regarding sex differences in cannabis use, 3) examine how sex differences can influence the behavioral effects of cannabis use. This review will predominantly focus on tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis. By synthesizing the available literature, this scoping review seeks to identify gaps in our understanding and guide future research efforts in this field.

Oxytocin receptors (OTRs) within the extended amygdala and nucleus accumbens (NAc) have been implicated in modulating social behaviors, particularly following stress. The effects of OTR could be mediated by modulating the activity of pre-synaptic axon terminals or via receptors in post-synaptic neurons or glia. Using a viral-mediated CRISPR/Cas9 gene editing system in female California mice (Peromyscus californicus), we selectively knocked down OTR in the anteromedial bed nucleus of the stria terminalis (BNST) or NAc to examine their roles modulating social approach and vigilance behaviors. Knockdown of OTR in the BNST attenuated stress-induced decreases of social approach and had less robust effects on vigilance when interacting with a target mouse behind a wire barrier. In this large arena, where mice could control their proximity to a target mouse, BNST OTR knockdown also increased investigation of a non-social stimulus (empty cage). Behavioral effects of BNST OTR knockdown were weaker in the small arena where focal mice physically interacted with target mice. Interestingly, OTR knockdown in the NAc, reduced stress-induced social vigilance without affecting social approach. These effects could mediate altered encoding of socially aversive experiences, as knockdown manipulations were performed before stress exposure. Together, these results highlight effects of local OTR on social behavior that are region-specific.

Parenting induces many neurological and behavioral changes that enable parents to rear offspring. Vasopressin plays an important role in this process via its effects on cognition, affect, and neuroplasticity, and in some cases, via interactions with decreased parental androgens. Thus far, the role of these hormones has been primarily studied in rodents. To address this gap, we explored vasopressin receptors and androgens in titi monkeys, a pair‐bonding and biparental primate species. In Studies 1 and 2, we used receptor autoradiography to correlate arginine vasopressin receptor 1a (AVPR1a) binding in the hippocampus (Study 1, n = 10) and the rest of the forebrain (Study 2, n = 23) with parental status, parental experience, parity, infant carrying, and pair affiliation. We found that parents exhibited lower AVPR1a binding than non‐parents throughout most brain regions assessed, with especially strong effects in the hippocampus (β = −.61), superior colliculus (β = −.88), lateral septum (β = −.35), and medial preoptic area (β = −.29). The other measures of parental experience also tended to be negatively associated with AVPR1a binding across different brain regions. In Study 3 (n = 44), we compared pre‐ and postpartum urinary androgen levels in parents and non‐parents and found that mothers exhibited a sustained androgen decrease across 3–4 months postpartum (relative to 3 months prepartum; β ranged from −.72 to −.62 for different comparisons). For males, we found that multiparous fathers exhibited decreased androgen levels at 1–2 weeks postpartum (β = −.25) and at 3–4 months postpartum (β = −.40) compared to the prepartum, indicating both immediate and long‐term reductions with subsequent paternal experience. Together, the results of this study suggest that decreases in AVPR1a binding and circulating androgens are associated with parental behavior and physiology in titi monkeys.

Strong social bonds are critical to human health; however, the mechanisms by which social bonds are formed and maintained are still being elucidated. The neurohormones oxytocin (OT) and vasopressin (AVP) are considered likely candidates. Primate females, both human and nonhuman, remain understudied populations. Here, we conducted a pharmacological study coupled with a behavioral partner preference test (PPT) to better understand the mechanistic basis of attachment in adult female titi monkeys (Plecturocebus cupreus). This pair-bonding species shares a conserved form of oxytocin with humans and is an excellent model organism to study the neural basis of social bonding. We performed intranasal administration of three doses of oxytocin (IN-OT), two doses of vasopressin (IN-AVP), one dose of an oxytocin antagonist (IN-OTA) and one dose of a saline treatment. We found that compared to the saline control, the IN-AVP treatment (lower dose, 40 IU/kg) decreased the time spent in proximity to the partner and increased lip-smacking toward the stranger. We found no effects of IN-OT or IN-OTA manipulation on partner preference. In contrast, low-dose IN-AVP weakened the partner preference in female titi monkeys.

Prairie voles are among a small group of mammals that display long-term social attachment between mating partners. Many pharmacological studies show that signaling via the oxytocin receptor (Oxtr) is critical for the display of social monogamy in these animals. We used CRISPR mutagenesis to generate three different Oxtr-null mutant prairie vole lines. Oxtr mutants displayed social attachment such that males and females showed a behavioral preference for their mating partners over a stranger of the opposite sex, even when assayed using different experimental setups. Mothers lacking Oxtr delivered viable pups, and parents displayed care for their young and raised them to the weanling stage. Together, our studies unexpectedly reveal that social attachment, parturition, and parental behavior can occur in the absence of Oxtr signaling in prairie voles.

Social monogamy is a reproductive strategy characterized by pair living and defense of a common territory. Pair bonding, sometimes displayed by monogamous species, is an affective construct that includes preference for a specific partner, distress upon separation, and the ability of the partner to buffer against stress. Many seahorse species show a monogamous social structure in the wild, but their pair bond has not been well studied. We examined the gene expression of lined seahorses (Hippocampus erectus) during and after the process of pairing in the laboratory as well as color change (luminance), a potential form of social communication and behavioral synchrony between pair mates. When a seahorse of either sex was interacting with its pair mate, their changes in luminance ("brightness") were correlated and larger than when interacting with an opposite-sex stranger. At the conclusion of testing, subjects were euthanized, RNA was extracted from whole brains and analyzed via RNA sequencing. Changes in gene expression in paired males versus those that were unpaired included processes governing metabolic activity, hormones and cilia. Perhaps most interesting is the overlap in gene expression change induced by pairing in both male seahorses and male prairie voles, including components of hormone systems regulating reproduction. Because of our limited sample size, we consider our results and interpretations to be preliminary, and prompts for further exploration. Future studies will expand upon these findings and investigate the neuroendocrine and genetic basis of these behaviors.

We evaluated neuropathological consequences of fetal ZIKV exposure in rhesus monkeys, a translatable animal model for human neural development, by carrying out quantitative neuroanatomical analyses of the nearly full-term brains of fetuses infected with ZIKV and procedure-matched controls. For each animal, a complete cerebral hemisphere was evaluated using immunohistochemical (IHC) and neuroanatomical techniques to detect virus, identify affected cell types, and evaluate gross neuroanatomical abnormalities. IHC staining revealed the presence of ZIKV in the frontal lobe, which contained activated microglia and showed increased apoptosis of immature neurons. ZIKV-infected animals exhibited macrostructural changes within the visual pathway. Regional differences tracked with the developmental timing of the brain, suggesting inflammatory processes related to viral infiltration swept through the cortex, followed by a wave of cell death resulting in morphological changes. These findings may help explain why some infants born with normal sized heads during the ZIKV epidemic manifest developmental challenges as they age.

Social cognition is facilitated by oxytocin receptors (OXTR) in the hippocampus, a brain region that changes dynamically with pregnancy, parturition, and parenting experience. We investigated the impact of parenthood on hippocampal OXTR in male and female titi monkeys, a pair-bonding primate species that exhibits biparental care of offspring. We hypothesized that in postmortem brain tissue, OXTR binding in the hippocampal formation would differ between parents and non-parents, and that OXTR density would correlate with frequencies of observed parenting and affiliative behaviors between partners. Subjects were 10 adult titi monkeys. OXTR binding in the hippocampus (CA1, CA2/3, CA4, dentate gyrus, subiculum) and presubiculum layers (PSB1, PSB3) was determined using receptor autoradiography. The average frequency of partner affiliation ( Proximity , Contact , and Tail Twining ) and infant carrying were determined from longitudinal observations (5–6 per day). Analyses showed that parents exhibited higher OXTR binding than non-parents in PSB1 ( t (8) = − 2.33, p = 0.048), and that OXTR binding in the total presubiculm correlated negatively with Proximity ( r = − 0.88) and Contact ( r = − 0.91), but not Tail Twining or infant carrying. These results suggest that OXTR binding in the presubiculum supports pair bonding and parenting behavior, potentially by mediating changes in hippocampal plasticity.

In the decades since female social dominance was first described in strepsirrhine primates, researchers have sought to uncover the proximate and ultimate explanations for its development. In the females of various female-dominant species, androgens have been implicated as regulators of behavior and/or predictors of seasonal fluctuations in aggression (the ‘Female Masculinization Hypothesis’). Males, more generally, respond to changing social demands via seasonal fluctuations in androgen-mediated behavior (the ‘Challenge Hypothesis’), that may also entail changes in activation of the hypothalamic-pituitary-adrenal axis. Here, we explore if androgens, glucocorticoids, and intersexual behavior fluctuate seasonally in the female-dominant, blue-eyed black lemur (Eulemur flavifrons), with potential consequences for understanding female aggression and male deference. Across two studies conducted during the breeding and nonbreeding seasons, we assessed rates of mixed-sex, dyadic social behavior (aggression and affiliation) and concentrations of fecal glucocorticoid metabolites (Study 1) and serum sex hormones (androstenedione, testosterone, and estradiol; Study 2). Our results align with several predictions inspired by the Female Masculinization and Challenge Hypotheses for intersexual relations: During the breeding season, specifically, both aggression and androstenedione peaked in females, while female-initiated affiliation decreased, potentially to facilitate female resource access and reproductive control. By comparison, all target hormones (androgens, estrogen, and glucocorticoids) peaked in males, with glucocorticoid concentrations potentially increasing in response to the surge in female aggression, and unusually high estrogen concentrations year-round potentially facilitating male deference via male-initiated affiliation. These results suggest complex, seasonally and hormonally mediated behavior in Eulemur flavifrons.

Zika virus (ZIKV) is a mosquito‐transmitted flavivirus with a sin‐ gle‐stranded RNA that was responsible for a major outbreak in the Americas in 2015, with 30,000 cases reported in Brazil by January 30, 2016 (Faria et al., 2016). Over the course of outbreak, Zika spread throughout the Americas, and infection during pregnancy has been linked to microcephaly and congenital abnormalities (Mlakar et al., 2016). This is caused by a particular tropism ZIKV exhibits to the central nervous system, impairing the development of the fetal brain, generating cerebral calcifications, ventriculomegaly, intrauter‐ ine growth restriction, and in some cases, fetal demise. Congenital ZIKV infection was also linked to ocular abnormalities and blinding inflammatory disease in infants with or without reported microen‐ cephaly (Ventura & Ventura, 2018). Neurological manifestations were also reported in some adults, with most patients presenting Guillain–Barré syndrome, meningoencephalitis, or transverse myeli‐ tis (Da Silva, Frontera, De Filippis, & Do Nascimento, 2017). The substantial social and economic impact of ZIKV lead the World Health Organization to declare ZIKV a public health emergency of international concern (World Health Organization, 2018). Animal models of human ZIKV are urgently needed to determine pathogene‐ sis and long‐term effects of the virus in the development of the infant brain, as well as to generate treatments and vaccines to prevent in‐ fection, particularly in pregnant women. Several murine models have been developed and although mice show growth restriction and brain infection (Morrison & Diamond, 2017; Nem de Oliveira Souza et al., 2018), substantial differences in CNS development limits the transla‐ tional power of these findings. In contrast, nonhuman primates share many properties of neurological development with humans, and thus have emerged as a potentially powerful model to understand ZIKV pathology and to test candidate vaccines (Coffey, 2018). To establish a non‐human primate (NHP) model of ZIKV infec‐ tion, our group inoculated pregnant rhesus monkeys and their fe‐ tuses (Macaca mulatta) with a strain of ZIKV from Brazil in different gestational days to better understand developmental neuropathol‐ ogy in the fetal CNS (Coffey, 2018). In order to reveal how the virus impacts the developing fetal brain, we used microscopy techniques such as high‐resolution triple and quadruple immunofluorescence to study neuron and glial morphology and function. The micrograph in this cover shows astrocytic processes sur‐ rounding a blood vessel in the CNS, forming the blood brain barrier (BBB), as well as the red blood cells inside the vessel in the infected fetal monkey brain. It is unclear how the ZIKV accesses the brain, but it is suggested that an increase in BBB permeability potentiates viral dissemination and replication in the CNS (Daniels & Klein, 2015). One of our major goals has been to determine where ZIKV is pres‐ ent in the developing fetal brain, and then determine its impact on cellular development. We are also pursuing studies that we hope will elucidate the role of glial cells and neuroinflammation in the neuro‐ pathology caused by ZIKV infection. Together, we hope that these findings will shed light on fetal neuropathogenesis of ZIKV infection in a highly translational animal model of the disease that will ulti‐ mately allow us to test therapies and vaccines relevant for human health.

Oxytocin (OT) elicits weight loss in diet-induced obese (DIO) rodents, nonhuman primates and humans by reducing food intake and increasing energy expenditure. In addition to being important in the regulation of energy balance, OT is involved in social behaviors including parent-infant bonds, friendships, and pair bonds. However, the impact of social context on susceptibility to diet-induced obesity (DIO) and feeding behavior (including food sharing) has not been investigated in a rodent model that forms strong social bonds (i.e. prairie vole). Our goals were to determine in Prairie voles (Microtus ochrogaster) whether i) social context impacts susceptibility to DIO and ii) chronic intranasal OT reverses DIO. Voles were housed in divided cages with holes in the divider and paired with a same-sex animal with either the same food [high fat diet (HFD)/HFD, [low fat diet (LFD; chow)/chow], or the opposite food (HFD/chow or chow/HFD) for 19 weeks. HFD-fed voles pair-housed with voles maintained on the HFD demonstrated increased weight relative to pair-housed voles that were both maintained on chow. The study was repeated to determine the impact of social context on DIO susceptibility and body composition when animals are maintained on purified sugar-sweetened HFD and LFD to enhance palatability. As before, we found that voles demonstrated higher weight gain on the HFD/HFD housing paradigm, in part, through increased energy intake and the weight gain was a consequence of an increase in fat mass. However, HFD-fed animals housed with LFD-fed animals (and vice versa) showed intermediate patterns of weight gain and evidence of food sharing. Of translational importance is the finding that chronic intranasal OT appeared to reduce weight gain in DIO voles through a decrease in fat mass with no reduction in lean body mass. These effects were associated with transient reductions in food intake and increased food sharing. These findings identify a role of social context in the pathogenesis of DIO and indicate that chronic intranasal OT treatment reduces weight gain and body fat mass in DIO prairie voles, in part, by reducing food intake.

Female parenting is obligate in mammals, but fathering behavior among mammals is rare. Only 3–5% of mammalian species exhibit biparental care, including humans, and mechanisms of fathering behavior remain sparsely studied. However, in species where it does exist, paternal care is often crucial to the survivorship of offspring. The present study is the first to identify new gene targets linked to the experience of fathering behavior in a biparental species using RNA sequencing. In order to determine the pattern of gene expression within the medial preoptic area that is specifically associated with fathering behavior, we identified differentially expressed genes in male prairie voles ( Microtus ochrogaster) that experienced one of three social conditions: virgin males, pair bonded males, and males with fathering experience. Differentially expressed genes from each comparison (i.e., Virgin vs Paired, Virgin vs Fathers, and Paired vs Fathers) were evaluated using the Gene Ontology enrichment analysis, and Kegg pathways analysis to reveal metabolic pathways associated with specific differentially expressed genes. Using these tools, we identified a group of genes that are differentially expressed in voles with different amounts of social experience. These genes are involved in a variety of processes, with particular enrichment in genes associated with immune function, metabolism, synaptic plasticity, and the remodeling of dendritic spines. The identification of these genes and processes will lead to novel insights into the biological basis of fathering behavior.

Early experience and social context interact to alter the phenotype of complex social behaviors. These early experiences can also result in alterations to cortical organization and connections. Given the ability of the neuropeptide oxytocin (OT) to modulate social and reproductive behavior, OT is likely involved in these cortical processes. However, little is known about the distribution of OT and OT receptors (OTR) within the neocortex. Using autoradiographic and neuroanatomical techniques, we characterized the cortical distribution of OT receptors (OTR) in prairie voles, a socially monogamous rodent species. We found that OTR density was low in the primary sensory areas (including primary somatosensory and auditory regions) but was quite high in association regions (including temporal and parietal association areas, and prelimbic regions). In the primary motor area as well as the temporal and parietal association areas, we observed differences in OTR density across cortical layers. Specifically, cortical layers 2/3 and 5 exhibited greater OTR density than layer 4. Our results point to a role for OT in integrating sensory and motor in the prairie vole brain, providing a complementary mechanism for the modulation of social interactions. Given the ability of early social experience and developmental manipulations of OT to affect the brain and behavior, these results suggest a novel mechanism for how OT may influence cortical organization.

Early-life sensory experiences have a profound effect on brain organization, connectivity, and subsequent behavior. In most mammals, the earliest sensory inputs are delivered to the developing brain through tactile contact with the parents, especially the mother. Prairie voles (Microtus ochrogaster) are monogamous and, like humans, are biparental. Within the normal prairie vole population, both the type and the amount of interactions, particularly tactile contact, that parents have with their offspring vary. The question is whether these early and pervasive differences in tactile stimulation and social experience between parent and offspring are manifest in differences in cortical organization and connectivity. To address this question, we examined the cortical and callosal connections of the primary somatosensory area (S1) in high-contact (HC) and low-contact (LC) offspring using neuroanatomical tracing techniques. Injection sites within S1 were matched so that direct comparisons between these two groups could be made. We observed several important differences between these groups. The first was that HC offspring had a greater density of intrinsic connections within S1 compared with LC offspring. Additionally, HC offspring had a more restricted pattern of ipsilateral connections, whereas LC offspring had dense connections with areas of parietal and frontal cortex that were more widespread. Finally, LC offspring had a broader distribution of callosal connections than HC offspring and a significantly higher percentage of labeled callosal neurons. This study is the first to examine individual differences in cortical connections and suggests that individual differences in cortical connections may be related to natural differences in parental rearing styles associated with tactile contact.