Peromyscus Californicus Research Articles

Are testosterone pulses a physiological mechanism for expanding activity beyond territories?

We ask whether artificially induced testosterone pulses (T-pulses), administered to males in the wild at the territory boundary, adjust location preferences within the territory. Multiple transient T-pulses occurring after social interactions in males can alter behaviour and spatial preferences. We previously found that T-pulses administered at the nest induce male California mice, a biparental and territorial species, to spend more time at the nest likely through conditioned place preferences. We hypothesized that T's reinforcing effects would increase future time by the T-injected males at the boundary and promote territorial defence. Contrary to predictions, T-pulses induced a decrease in male time at the boundary, and instead appeared to promote male territorial/home range expansion, accompanied by shorter sustained vocalizations (SVs) and decreased proportion of three SV bouts. Shorter SVs are associated with aggression in the laboratory. Furthermore, in response to T-male behavioural changes, uninjected female partners decreased boundary time. Our results suggest new functions for socially induced T-pulses, such as extending territorial boundaries/home ranges. Location preferences induced through reinforcing/rewarding mechanisms may be more plastic and dependent on physical and social contexts than previously thought. Moreover, the results suggest that location preferences produced through rewarding/reinforcing mechanisms can be viewed from adaptive perspectives to influence future behaviour.

Hypocretin in the nucleus accumbens shell modulates social approach in female but not male California mice

The hypocretin (Hcrt) system modulates arousal and anxiety-related behaviors and has been considered as a novel treatment target for stress-related affective disorders. We examined the effects of Hcrt acting in the nucleus accumbens shell (NAcSh) and anterodorsal bed nucleus of the stria terminalis (adBNST) on social behavior in male and female California mice (Peromyscus californicus). In female but not male California mice, infusion of Hcrt1 into NAcSh decreased social approach. Weak effects of Hcrt1 on social vigilance were observed in both females and males. No behavioral effects of Hcrt1 infused into the adBNST were observed. Analyses of sequencing data from California mice and Mus musculus NAc showed that Hcrtr2 was more abundant than Hcrtr1, so we infused the selective Hcrt receptor 2 antagonist into the NAcSh, which increased social approach in females previously exposed to social defeat. A calcium imaging study in the NAcSh of females before and after stress exposure showed that neural activity increased immediately following the expression of social avoidance but not during freezing behavior. This observation is consistent with previous studies that identified populations of neurons in the NAc that drive avoidance. Intriguingly, calcium transients were not affected by stress. These data suggest that hypocretin acting in the NAcSh plays a key role in modulating stress-induced social avoidance.

Inhibition of alloparental behavior by acute stress in virgin male California mice (Peromyscus californicus)

In many biparental mammals, such as California mice (Peromyscus californicus), fathers display affiliative behavior toward unfamiliar infants whereas reproductively naïve adult males show highly variable responses. Sources of this variability are not well understood, but evidence suggests that stress can either enhance or inhibit alloparental care. We evaluated immediate and delayed effects of acute stress on pup-directed behavior in adult virgin male California mice. Mice underwent three 10-minute tests with unfamiliar pups at 48-hour intervals. Stressed mice (N=22) received a subcutaneous oil injection immediately before tests 1 and 2, whereas controls (N=22) were left undisturbed. In controls, but not stressed mice, latency to approach the pup decreased and duration of alloparental behavior increased across the three tests. At each time point, stressed males were less likely than controls to perform alloparental behavior. Controls spent significantly more time performing alloparental behavior than stressed mice in tests 1 and 2 but not in test 3. Pup-directed aggression did not differ between the groups at any time point. These findings suggest that acute stress can both inhibit alloparental behavior in the short term and prevent the increase in alloparental behavior that typically occurs with repeated exposure to pups in virgin male California mice.

Mating system variation and gene expression in the male reproductive tract of Peromyscus mice.

Genes involved in reproduction often evolve rapidly at the sequence level due to postcopulatory sexual selection (PCSS) driven by male-male competition and male-female sexual conflict, but the impact of PCSS on gene expression has been under-explored. Further, though multiple tissues contribute to male reproductive success, most studies have focused on the testes. To explore the influence of mating system variation on reproductive tract gene expression in natural populations, we captured adult males from monogamous Peromyscus californicus and polygynandrous P. boylii and P. maniculatus. We generated RNAseq libraries, quantified gene expression in the testis, seminal vesicle, epididymis, and liver, and identified 3627 mating system-associated differentially expressed genes (MS-DEGs), where expression shifted in the same direction in P. maniculatus and P. boylii relative to P. californicus. Gene expression variation was most strongly associated with mating behaviour in the seminal vesicles, where 89% of differentially expressed genes were MS-DEGs, including the key seminal fluid proteins Svs2 and Pate4. We also used published rodent genomes to test for positive and relaxed selection on Peromyscus-expressed genes. Though we did not observe more overlap than expected by chance between MS-DEGs and positively selected genes, 203 MS-DEGs showed evidence of positive selection. Fourteen reproductive genes were under tree-wide positive selection but convergent relaxed selection in P. californicus and Microtus ochrogaster, a distantly related monogamous species. Changes in transcript abundance and gene sequence evolution in association with mating behaviour suggest that male mice may respond to sexual selection intensity by altering aspects of sperm motility, sperm-egg binding and copulatory plug formation.

Effects of acute inhibition of dopamine β-hydroxylase on neural responses to pups in adult virgin male California mice (Peromyscus californicus)

The neural mechanisms underlying paternal care in biparental mammals are not well understood. The California mouse (Peromyscus californicus) is a biparental rodent in which virtually all fathers are attracted to pups, while virgin males vary widely in their behavior toward unrelated infants, ranging from attacking to avoiding to huddling and grooming pups. We previously showed that pharmacologically inhibiting the synthesis of the neurotransmitter norepinephrine (NE) with the dopamine β-hydroxylase inhibitor nepicastat reduced the propensity of virgin male and female California mice to interact with pups. The current study tested the hypothesis that nepicastat would reduce pup-induced c-Fos immunoreactivity, a cellular marker of neural activity, in the medial preoptic area (MPOA), medial amygdala (MeA), basolateral amygdala (BLA), and bed nucleus of the stria terminalis (BNST), brain regions implicated in the control of parental behavior and/or anxiety. Virgin males were injected with nepicastat (75 mg/kg, i.p.) or vehicle 2 hours prior to exposure to either an unrelated pup or novel object for 60 minutes (n = 4–6 mice per group). Immediately following the 60-minute stimulus exposure, mice were euthanized and their brains were collected for c-Fos immunohistochemistry. Nepicastat reduced c-Fos expression in the MeA and MPOA of pup-exposed virgin males compared to vehicle-injected controls. In contrast, nepicastat did not alter c-Fos expression in any of the above brain regions following exposure to a novel object. Overall, these results suggest that the noradrenergic system might influence MeA and MPOA function to promote behavioral interactions with pups in virgin males.

Sex differences in responses to aggressive encounters among California mice

Despite how widespread female aggression is across the animal kingdom, there remains much unknown about its neuroendocrine mechanisms, especially in females that engage in aggression outside the peripartum period. Although the impact of aggressive experience on steroid hormone responses have been described, little is known about the impact of these experiences on female behavior or the subsequent neuropeptide responses to performing aggression. In this study, we compared behavioral responses in both male and female adult California mice based on if they had 0, 1, or 3 aggressive encounters using a resident intruder paradigm. We measured how arginine vasopressin and oxytocin cells in the paraventricular nucleus responded to aggression using c-fos immunohistochemistry. We saw that both sexes disengaged from intruders with repeated aggressive encounters, but that on the final day of testing females were more likely to freeze when they encountered intruders compared to no aggression controls – which was not significant in males. Finally, we saw that percent of arginine vasopressin and c-fos co-localizations in the posterior region of the paraventricular nucleus increased in males who fought compared to no aggression controls. No difference was observed in females. Overall, there is evidence that engaging in aggression induces stress responses in both sexes, and that females may be more sensitive to the effects of fighting.

Pair bonding and disruption impact lung transcriptome in monogamous Peromyscus californicus

Social interactions affect physiological and pathological processes, yet their direct impact in peripheral tissues remains elusive. Recently we showed that disruption of pair bonds in monogamous Peromyscus californicus promotes lung tumorigenesis, pointing to a direct effect of bonding status in the periphery (Naderi et al., 2021). Here we show that lung transcriptomes of tumor-free Peromyscus are altered in a manner that depends on pair bonding and superseding the impact of genetic relevance between siblings. Pathways affected involve response to hypoxia and heart development. These effects are consistent with the profile of the serum proteome of bonded and bond-disrupted Peromyscus and were extended to lung cancer cells cultured in vitro, with sera from animals that differ in bonding experiences. In this setting, the species’ origin of serum (deer mouse vs FBS) is the most potent discriminator of RNA expression profiles, followed by bonding status. By analyzing the transcriptomes of lung cancer cells exposed to deer mouse sera, an expression signature was developed that discriminates cells according to the history of social interactions and possesses prognostic significance when applied to primary human lung cancers. The results suggest that present and past social experiences modulate the expression profile of peripheral tissues such as the lungs, in a manner that impacts physiological processes and may affect disease outcomes. Furthermore, they show that besides the direct effects of the hormones that regulate bonding behavior, physiological changes influencing oxygen metabolism may contribute to the adverse effects of bond disruption.

Decline in small mammal species richness in coastal-central California, 1997-2013.

The richness and composition of a small mammal community inhabiting semiarid California oak woodland may be changing in response to climate change, but we know little about the causes or consequence of these changes. We applied a capture-mark-recapture model to 17 years (1997-2013) of live trapping data to estimate species-specificabundances. The big-eared woodrat was the most frequently captured species in the area, contributing 58% of total captures. All small mammal populations exhibited seasonal fluctuations, whereas those of the California mouse, brush mouse, and pinyon mouse declined during the study period. We also applied a multispecies dynamic occupancy model to our small mammal detection history data to estimate species richness, occupancy (), detection (p), local extinction (), and colonization () probabilities, and to discern factors affecting these parameters. We found that decreased from 0.369 ± 0.088 in 1997 to 0.248 ± 0.054 in 2013; was lower during the dry season (May-September) than the wet season (October-April) and was positively influenced by total seasonal rainfall (slope parameter, = 0.859 ± 0.371; 95% CI = 0.132-1.587). Mean mammalian species richness decreased from 11.943 ± 0.461 in 1997 to 7.185 ± 0.425 in 2013. With highly variable climatic patterns expected in the future, especially increased frequency and intensity of droughts,itis important to monitor small mammal communities inhabiting threatened California oak woodlands.

Effects of reproductive status on behavioral and neural responses to isolated pup stimuli in female California mice

The transition to motherhood in mammals is marked by changes in females’ perception of and responsiveness to sensory stimuli from infants. Our understanding of maternally induced sensory plasticity relies most heavily on studies in uniparental, promiscuous house mice and rats, which may not be representative of rodent species with different life histories. We exposed biparental, monogamous California mouse (Peromyscus californicus) mothers and ovariectomized virgin females to one of four acoustic and olfactory stimulus combinations (Control: clean cotton and white noise; Call: clean cotton and pup vocalizations; Odor: pup-scented cotton and white noise; Call + Odor: pup-scented cotton and pup vocalizations) and quantified females’ behavior and Fos expression in select brain regions. Behavior did not differ between mothers and ovariectomized virgins. Among mothers, however, those exposed to the Control condition took the longest to sniff the odor stimulus, and mothers exposed to the Odor condition were quicker to sniff the odor ball compared to those in the Call condition. Behavior did not differ among ovariectomized virgins exposed to the different conditions. Fos expression differed across conditions only in the anterior hypothalamic nucleus (AHN), which responds to aversive stimuli: among mothers, the Control condition elicited the highest AHN Fos and Call + Odor elicited the lowest. Among ovariectomized virgin females, Call elicited the lowest Fos in the AHN. Thus, reproductive status in California mice alters females’ behavioral responses to stimuli from pups, especially odors, and results in the inhibition of defense circuitry in response to pup stimuli.

Sexual differentiation of neural mechanisms of stress sensitivity during puberty.

Anxiety disorders are a major public health concern and current treatments are inadequate for many individuals. Anxiety is more common in women than men and this difference arises during puberty. Sex differences in physiological stress responses may contribute to this variability. During puberty, gonadal hormones shape brain structure and function, but the extent to which these changes affect stress sensitivity is unknown. We examined how pubertal androgens shape behavioral and neural responses to social stress in California mice (Peromyscus californicus), a model species for studying sex differences in stress responses. In adults, social defeat reduces social approach and increases social vigilance in females but not males. We show this sex difference is absent in juveniles, and that prepubertal castration sensitizes adult males to social defeat. Adult gonadectomy does not alter behavioral responses to defeat, indicating that gonadal hormones act during puberty to program behavioral responses to stress in adulthood. Calcium imaging in the medioventral bed nucleus of the stria terminalis (BNST) showed that social threats increased neural activity and that prepubertal castration generalized these responses to less threatening social contexts. These results support recent hypotheses that the BNST responds to immediate threats. Prepubertal treatment with the nonaromatizable androgen dihydrotestosterone acts in males and females to reduce the effects of defeat on social approach and vigilance in adults. These data indicate that activation of androgen receptors during puberty is critical for programming behavioral responses to stress in adulthood.

Effects of Acute Stress on Parental Behavior in Reproductively Naïve Male California Mice

Effects of Acute Stress on Parental Behavior in Reproductively Naïve Male California Mice

Behavioral convergence in defense behaviors in pair bonded individuals correlates with neuroendocrine receptors in the medial amygdala

Monogamous, pair-bonded animals coordinate intra-pair behavior for spatially separated challenges including territorial defense and nest attendance. Paired California mice, a monogamous, territorial and biparental species, approach intruders together or separately, but often express behavioral convergence across intruder challenges. To gain a more systems-wide perspective of potential mechanisms contributing to behavioral convergence across two conspecific intruder challenges, we conducted an exploratory study correlating behavior and receptor mRNA (Days 10 and 17 post-pairing). We examined associations between convergence variability in pair time for intruder-oriented behaviors with a pair mRNA index for oxytocin (OXTR), androgen (AR), and estrogen alpha (ERα) receptors within the medial amygdala (MeA) and the anterior olfactory nucleus (AON), brain regions associated with social behavior. An intruder behavior index revealed a bimodal distribution of intruder-related behaviors in Challenge 1 and a unimodal distribution in Challenge 2, suggesting population behavioral convergence, but no significant correlations with neuroendocrine measures. However, OXTR, AR, and ERα mRNA in the MeA were positively associated with convergence in individual intruder-related behaviors, suggesting multiple mechanisms may influence convergence. Mice could also occupy the nest during intruder challenges and convergence in nest attendance was positively correlated with MeA OXTR. At an individual level, nest attendance was positively associated with MeA ERα. Vocalizations were positively associated with AR and ERα mRNA. No positive associations were found in the AON. Overall, neuroendocrine receptors were implicated in convergence of a monogamous pair’s defense behavior, highlighting the potential importance of the MeA as part of a circuit underlying convergence.

Monogamy or monogamish? Re-examining monogamy in Peromyscus californicus

California mice have been widely recognized as one of the few examples of ‘true’ genetic monogamy in mammals and are one of only four mammalian species considered to be both genetically and socially monogamous. The mating system of this species, first described by David O. Ribble (1991), was initially investigated in a single population by integrating both behavioral data and DNA fingerprinting to classify P. californicus as monogamous. Here, we investigated the parentage of field sampled litters of California mice across 4 populations using both classic field methods and modern microsatellite analyses. We putatively identified male-female mouse pairs in the field using capture localities and transfer of fluorescent pigment between individuals. We then used microsatellite loci to genotype pregnant adult females, their embryos, and the adult males identified in the field as the partners of those females. We identified occurrences of extra-pair paternity in 3 out of the 4 populations of California mice, calling in to question the designation of this species as genetically monogamous (Figure 1 and Table 1). We suggest a careful re-examination of the mating system of this species using modern molecular methods to analyze a greater number of samples representing multiple sampling localities. Future studies of this species should prove particularly informative regarding the correlates of extra-pair mating and, hence, the adaptive bases for the maintenance of male-female pair bonds in the absence of true genetic monogamy.

Paternal deprivation induces vigilance-avoidant behavior and accompanies sex-specific alterations in stress reactivity and central proinflammatory cytokine response in California mice (Peromyscus californicus).

Early-life stress (ELS) can increase anxiety, reduce prosocial behaviors, and impair brain regions that facilitate emotional and social development. This knowledge greatly stems from assessing disrupted mother-child relationships, while studies investigating the long-term effects of father-child relationships on behavioral development in children are scarce. However, available evidence suggests that fathers may uniquely influence a child's behavioral development in a sex-specific manner. Rodent models examining mother-offspring interaction demonstrate relationships among ELS, neuroinflammatory mediators, and behavioral development; yet, the role paternal care may play in neuroimmune functioning remains unreported. Using the biparental California mouse (Peromyscus californicus), we examined to what extent paternal deprivation impairs social and anxiety-like behaviors, augments peripheral corticosterone (CORT) response, and alters central proinflammatory cytokine production following an acute stressor in adulthood. Biparentally reared and paternally deprived (permanent removal of the sire 24h post-birth) adult mice were assessed for sociability, preference for social novelty, social vigilance, and social avoidance behaviors, followed by novelty-suppressed feeding (NSF) testing for general anxiety-like behavior. Following an acute stressor, circulating CORT concentrations and region-specific proinflammatory cytokine concentrations were determined via radioimmunoassay and Luminex multianalyte analysis, respectively. In response to a novel same-sex conspecific, social vigilance behavior was associated with reduced sociability and increased avoidance in paternally deprived mice-an effect not observed in biparentally reared counterparts. Yet, in response to a familiar same-sex conspecific, social vigilance persisted but only in paternally deprived females. The latency to consume during NSF testing was not significantly altered by paternal deprivation. In response to an acute physical stressor, lower circulating CORT concentrations were observed in paternally deprived females. Compared to control-reared males, paternal deprivation increased hypothalamic interleukin-1β, but decreased hippocampal IL-6 protein concentration. Greater social vigilance behavior was demonstrated in paternally deprived mice while they avoided social interaction with a novel same-sex conspecific; however, in response to a familiar same-sex conspecific, paternal deprivation increased social vigilance behavior but only in females. It is possible that different neurobiological mechanisms underlie these observed behavioral outcomes as sex-specific central proinflammatory cytokine and stress responsivity were observed in paternally deprived offspring.

SARS-CoV-2 infects multiple species of North American deer mice and causes clinical disease in the California mouse

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the virus that causes coronavirus disease-19 (COVID-19), emerged in late 2019 in Wuhan, China and its rapid global spread has resulted in millions of deaths. An important public health consideration is the potential for SARS-CoV-2 to establish endemicity in secondary animal reservoirs outside of Asia or acquire adaptations that result in new variants with the ability to evade the immune response and reinfect the human population. Previous work has shown that North American deer mice (Peromyscus maniculatus) are susceptible and can transmit SARS-CoV-2 to naïve conspecifics, indicating its potential to serve as a wildlife reservoir for SARS-CoV-2 in North America. In this study, we report experimental SARS-CoV-2 susceptibility of two additional subspecies of the North American deer mouse and two additional deer mouse species, with infectious virus and viral RNA present in oral swabs and lung tissue of infected deer mice and neutralizing antibodies present at 15 days post-challenge. Moreover, some of one species, the California mouse (P. californicus) developed clinical disease, including one that required humane euthanasia. California mice often develop spontaneous liver disease, which may serve as a comorbidity for SARS-CoV-2 severity. The results of this study suggest broad susceptibility of rodents in the genus Peromyscus and further emphasize the potential of SARS-CoV-2 to infect a wide array of North American rodents.

Fatherhood increases attraction to sensory stimuli from unrelated pups in male California mice, Peromyscus californicus

Fatherhood increases attraction to sensory stimuli from unrelated pups in male California mice, Peromyscus californicus

Acute intranasal oxytocin dose enhances social preference for parents over peers in male but not female peri-adolescent California mice (Peromyscus californicus)

Peri-adolescence is a critical developmental stage marked by profound changes in the valence of social interactions with parents and peers. We hypothesized that the oxytocin (OXT) and vasopressin (AVP) systems, known for influencing social behavior, would be involved in the maintenance and breaking of bonding behavior expressed by very early peri-adolescent males and females. In rodents, OXT is associated with mother–pup bonding and may promote social attachment to members of the natal territory. AVP, on the other hand, can act in contrasting ways to OXT and has been associated with aggression and territoriality. Specifically, we predicted that in peri-adolescent male and female juveniles of the biparental and territorial California mouse (Peromyscus californicus), a) OXT would increase the social preferences for the parents over unfamiliar age-matched peers (one male and one female), and b) AVP would break the parent-offspring bond and either increase time in the neutral chamber and/or approach to their unfamiliar and novel peers. We examined anxiety and exploratory behavior using an elevated plus maze and a novel object task as a control. Peri-adolescent mice were administered an acute intranasal (IN) treatment of 0.5 IU/kg IN AVP, 0.5 IU/kg IN OXT, or saline control; five minutes later, the behavioral tests were conducted. As predicted, we found that IN OXT enhanced social preference for parents; however, this was only in male and not female peri-adolescent mice. IN AVP did not influence social preference in either sex. These effects appear specific to social behavior and not anxiety, as neither IN OXT nor AVP influenced behavior during the elevated plus maze or novel object tasks. To our knowledge, this is the first evidence indicating that OXT may play a role in promoting peri-adolescent social preferences for parents and delaying weaning in males.

Post-mating parental behavior trajectories differ across four species of deer mice.

Among species, parental behaviors vary in their magnitude, onset relative to reproduction, and sexual dimorphism. In deer mice (genus Peromyscus), while most species are promiscuous with low paternal care, monogamy and biparental care have evolved at least twice under different ecological conditions. Here, in a common laboratory setting, we monitored parental behaviors of males and females of two promiscuous (eastern deer mouse P. maniculatus and white-footed mouse P. leucopus) and two monogamous (oldfield mouse P. polionotus and California mouse P. californicus) species from before mating to after giving birth. In the promiscuous species, females showed parental behaviors largely after parturition, while males showed little parental care. In contrast, both sexes of monogamous species performed parental behaviors. However, while oldfield mice began to display parental behaviors before mating, California mice showed robust parental care behaviors only postpartum. These different parental-care trajectories in the two monogamous species align with their socioecology. Oldfield mice have overlapping home ranges with relatives, so infants they encounter, even if not their own, are likely to be closely related. By contrast, California mice disperse longer distances into exclusive territories with possibly unrelated neighbors, decreasing the inclusive fitness benefits of caring for unfamiliar pups before parenthood. Together, we find that patterns of parental behaviors in Peromyscus are consistent with predictions from inclusive fitness theory.

Effects of Parenthood on Neural Responses to Pup-Related Cues

The onset of parental care in female mammals is associated with plasticity in neural processing of infant-related sensory stimuli, which enhances mothers’ ability to detect and care for their offspring; however, little is known about sensory plasticity in fathers. We tested the hypothesis that parenthood alters neural responses to olfactory and auditory stimuli from infants in male and female California mice (Peromyscus californicus), a biparental rodent. Virgins and new parents of both sexes were exposed to a combination of a chemosensory stimulus (pup-scented or unscented cotton [control]) and an auditory stimulus (pup vocalizations or white noise [control]). Brains were collected one hour later and stained immunohistochemically for Fos, an index of neural activity. We quantified Fos in the main olfactory bulbs (MOB), a region essential to receiving olfactory information, and medial preoptic area (MPOA), a region critical for parental behavior. We predicted that Fos in MOB and MPOA would be greater in parents than virgins, especially after exposure to pup stimuli. We found that in females, MPOA and MOB Fos did not differ between virgins and mothers or across treatment groups. In contrast, fathers had lower expression of Fos in MOB but higher expression in MPOA, compared to virgin males. Moreover, Fos in MPOA was higher in males exposed to pup vocalizations and pup scent compared to those exposed exclusively to pup vocalizations. Fos in MPOA was also higher in males exposed to scent or both scent and vocalization stimuli compared to males exposed to control stimuli. These findings suggest that the onset of parenthood alters activity in the MOB and MPOA, especially in response to pup vocalizations and scents, in males but not females in this biparental rodent.

Sex-specific effects of neonatal paternal deprivation on microglial cell density in adult California mouse (Peromyscus californicus) dentate gyrus

Adverse early-life experiences are risk factors for psychiatric disease development, resulting in stress-related neuronal modeling and neurobehavioral changes. Stressful experiences modulate the immune system, contributing to neuronal damage in higher cortical regions, like the hippocampus. Moreover, early-life stressors dysregulate the function of microglia, the resident immune cells of the brain, in the developing hippocampus. Paternal deprivation, an early-life stressor in many biparental species, facilitates sex-dependent inhibitions in hippocampal plasticity, but parental contributors to these sex-specific outcomes are unknown. Also, neurobiological mechanisms contributing to impairments in hippocampal neuroplasticity are less known. Thus, our goals were to 1) determine whether parental behavior is altered in maternal females following removal of the paternal male, 2) assess the effects of paternal deprivation on dentate gyrus (DG) volume and microglia proliferation, and 3) determine if early-life experimental handling mitigates sex-specific reductions in DG cell survival. California mice were born to multiparous breeders and reared by both parents (biparental care) or by their mother alone (i.e., father removed on postnatal day 1; paternal deprivation). One cohort of offspring underwent offspring retrieval tests for eight days beginning on postnatal day 2. On PND 68, these offspring (and a second cohort of mice without behavioral testing) were euthanized and brains visualized for bromodeoxyuridine (BrdU) and neuron-specific class III beta-tubulin (TuJ-1) or ionized calcium binding adaptor molecule 1 (Iba1). While mate absence did not impair maternal retrieval, paternal deprivation reduced DG volume, but Iba1+ cell density was only higher in paternally-deprived females. Neither sex or paternal deprivation significantly altered the number of BrdU+ or Tuj1+ cells in the DG – an absence of a reduction in cell survival may be related to daily handing during early offspring retrieval tests. Together, these data suggest that paternal deprivation impairs hippocampal plasticity; however, sex and early environment may influence the magnitude of these outcomes.