Search

Sex differences are commonly observed in behaviors that are closely linked to adaptive function, but sex differences can also be observed in behavioral "building blocks" such as locomotor activity and reward processing. Modern neuroscientific inquiry, in pursuit of generalizable principles of functioning across sexes, has often ignored these more subtle sex differences in behavioral building blocks that may result from differences in these behavioral building blocks. A frequent assumption is that there is a default (often male) way to perform a behavior. This approach misses fundamental drivers of individual variability within and between sexes. Incomplete behavioral descriptions of both sexes can lead to an overreliance on reduced "single-variable" readouts of complex behaviors, the design of which may be based on male-biased samples. Here, we advocate that the incorporation of new machine-learning tools for collecting and analyzing multimodal "big behavior" data allows for a more holistic and richer approach to the quantification of behavior in both sexes. These new tools make behavioral description more robust and replicable across laboratories and species, and may open up new lines of neuroscientific inquiry by facilitating the discovery of novel behavioral states. Having more accurate measures of behavioral diversity in males and females could serve as a hypothesis generator for where and when we should look in the brain for meaningful neural differences.

Related Article from Isolating the Effects of Social Interactions on Cancer Biology

A major issue in neuroscience is the poor translatability of research results from preclinical studies in animals to clinical outcomes. Comparative neuroscience can overcome this barrier by studying multiple species to differentiate between species-specific and general mechanisms of neural circuit functioning. Targeted manipulation of neural circuits often depends on genetic dissection, and use of this technique has been restricted to only a few model species, limiting its application in comparative research. However, ongoing advances in genomics make genetic dissection attainable in a growing number of species. To demonstrate the potential of comparative gene editing approaches, we developed a viral-mediated CRISPR/Cas9 strategy that is predicted to target the oxytocin receptor ( Oxtr ) gene in >80 rodent species. This strategy specifically reduced OXTR levels in all evaluated species ( n = 6) without causing gross neuronal toxicity. Thus, we show that CRISPR/Cas9-based tools can function in multiple species simultaneously. Thereby, we hope to encourage comparative gene editing and improve the translatability of neuroscientific research.

The field of neuropsychopharmacology relies on behavioral assays to quantify behavioral processes related to mental illness and substance use disorders. Although these assays have been highly informative, sometimes laboratories have unpublished datasets from experiments that “didn’t work”. Often this is because expected outcomes were not observed in positive or negative control groups. While this can be due to experimenter error, an important alternative is that under-appreciated environmental factors can have a major impact on results. “Hidden variables” such as circadian cycles, husbandry, and social environments are often omitted in methods sections, even though there is a strong body of literature documenting their impact on physiological and behavioral outcomes. Applying this knowledge in a more critical manner could provide behavioral neuroscientists with tools to develop better testing methods, improve the external validity of behavioral techniques, and make better comparisons of experimental data across institutions. Here we review the potential impact of “hidden variables” that are commonly overlooked such as light-dark cycles, transport stress, cage ventilation, and social housing structure. While some of these conditions may not be under direct control of investigators, it does not diminish the potential impact of these variables on experimental results. We provide recommendations to investigators on which variables to report in publications and how to address “hidden variables” that impact their experimental results.

Social stressors are known to have strong negative impacts on mental health. There is a long history of preclinical social defeat stress studies in rodents focusing on males that has produced important insights into the neural mechanisms that modulate depression- and anxiety-related behavior. Despite these impressive results, a historical weakness of rodent social stress models has been an under-representation of studies in females. This is problematic because rates of depression and anxiety are higher in women versus men. Recently there has been a surge of interest in adapting social stress methods for female rodents. Here we review new rodent models that have investigated numerous facets of social stress in females. The different models have different strengths and weaknesses, with some model systems having stronger ethological validity with other models having better access to molecular tools to manipulate neural circuits. Continued use and refinement of these complementary models will be critical for addressing gaps in understanding the function of neural circuits modulating depression- and anxiety-related behavior in females.

Acute stress is generally thought to impair performance on tasks thought to rely on selective attention. This effect has been well established for moderate to severe stressors, but no study has examined how a mild stressor—the most common type of stressor—influences selective attention. In addition, no study to date has examined how stress influences the component processes involved in overall selective attention task performance, such as controlled attention, automatic attentional activation, decision-making, and motor abilities. To address these issues, we randomly assigned 107 participants to a mild acute stress or control condition. As expected, the mild acute stress condition showed a small but significant increase in cortisol relative to the control condition. Following the stressor, we assessed attention with two separate flanker tasks. One of these tasks was optimized to investigate component attentional processes using computational cognitive modeling, whereas the other task employed mouse-tracking to illustrate how response conflict unfolded over time. The results for both tasks showed that mild acute stress decreased response time (i.e., increased response speed) without influencing accuracy or interference control. Further, computational modeling and mouse-tracking analyses indicated that these effects were due to faster motor action execution time for chosen actions. Intriguingly, however, cortisol responses were unrelated to any of the observed effects of mild stress. These results have implications for theories of stress and cognition, and highlight the importance of considering motor processes in understanding the effects of stress on cognitive task performance.

Oxytocin is a neuropeptide that can produce anxiolytic effects and promote social approach. However, emerging evidence shows that under some conditions, oxytocin can instead induce anxiety-related behaviors. These diverse effects of oxytocin appear to be mediated by circuit-specific actions. Recent data showed that inhibition of oxytocin receptors (OTRs) in the bed nucleus of the stria terminalis (BNST) was sufficient to increase social approach and decrease social vigilance in female California mice (Peromyscus californicus) exposed to social defeat stress. As a member of the G-protein coupled receptor family, OTRs can induce distinct downstream pathways by coupling to different G-protein isoforms. We show that infusion of carbetocin, a biased OTR-Gq agonist, in the BNST reduced social approach in both female and male California mice. In both females and males, carbetocin also increased social vigilance. To gain insight into cell types that could be mediating this effect, we analyzed previously published single-cell RNAseq data from the BNST and nucleus accumbens (NAc). In the NAc, we and others showed that OTR activation promotes social approach behaviors. In the BNST, Oxtr was expressed in over 40 cell types, that span both posterior and anterior subregions of the BNST. The majority of Oxtr-expressing neurons were GABAergic. In the anterior regions of BNST targeted in our carbetocin experiments, Cyp26b1-expressing neurons had high average Oxtr expression. In the NAc, most Oxtr+ cells were D1 dopamine receptor-expressing neurons and interneurons. These differences in Oxtr cell type distribution may help explain how activation of OTR in BNST versus NAc can have different effects on social approach and social vigilance.

Domesticated mice and rats have shown to be powerful model systems for biomedical research, but there are cases in which the biology of species is a poor match for the hypotheses under study. The California mouse (Peromyscus californicus) has unique physiological and behavioral traits and has emerged as a powerful model for studying sex differences in the biology of psychiatric disease, which is particularly relevant considering the new NIH guidelines that require the inclusion of sex as a biological variable. Despite its growing role in preclinical research, there is a lack of studies assessing species-specific housing needs, which presents a challenge for research facilities seeking to ensure good welfare and obtaining high-quality experimental data. Indeed, captive California mice present a high prevalence of stereotypic backflipping behavior, a common consequence of suboptimal housing and a potential source of experimental outcome variability. Using three different cage systems, the present studies show that increasing housing space as well as social and environmental complexity can delay the development of stereotypic behavior in male and female California mice. Critically, this reduction in stereotypy is accompanied by increased effect sizes of stress in an established model for social anxiety. These results suggest that increased cage size and enrichment could enhance welfare in California mice while simultaneously increasing the quality of behavioral experiments.

Women are more likely to suffer from stress-related affective disorders than men, but the underlying mechanisms of sex differences remain unclear. Previous works show that microRNA (miRNA) profiles are altered in stressed animals and patients with depression and anxiety disorders. In this study, we investigated how miRNA expression in the anterior bed nucleus of stria terminalis (BNST) was affected by social defeat stress in female and male California mice (Peromyscus californicus). We performed sequencing to identify miRNA transcripts in the whole brain and anterior BNST followed by qPCR analysis to compare miRNA expression between control and stressed animals. The results showed that social defeat stress induced sex-specific miRNA expression changes in the anterior BNST. Let-7a, let-7f and miR-181a-5p were upregulated in stressed female but not male mice. Our study provided evidence that social stress produces distinct molecular responses in the BNST of males and females.

Anxiety disorders are more common in women than men, and this difference arises during puberty. Increased secretion of gonadal hormones during puberty influences brain structure and function, but the extent to which hormones modulate anxiety-related brain circuits is unclear. The slow developing California mouse (Peromyscus californicus) is an ideal species for studying the effects of hormones on brain function during adolescence. In adults social defeat stress reduces social approach and increases vigilance in females but not males. Here we show this sex difference is absent in juvenile mice, and that prepubertal castration sensitizes adult males to social defeat. Since adult castration has no effect on stress sensitivity, our data show that gonadal hormones act during puberty to program behavioral responses to stress later in life. In adults, calcium imaging in the medioventral bed nucleus of the stria terminalis shows that threatening social contexts increase calcium transients. Furthermore, prepubertal castration generalizes these responses to less threatening social contexts. Prepubertal treatment with the non-aromatizable androgen dihydrotestosterone acts in males and females to reduce sensitivity to social defeat in adults. Together, these data indicate activation of androgen receptors during puberty are critical for programing behavioral responses to stress in adulthood, highlighting a possible mechanism contributing to sex differences in anxiety.Significance StatementPuberty is a key period when sex differences in anxiety emerges. Gonadal hormone release increases during this time but it is largely unknown how they impact brain circuits and behavior. We show that androgens play a key role in programming behavioral responses to social defeat stress. The bed nucleus of the stria terminalis responds to social threats and these responses are more generalized in males without gonadal hormone exposure during puberty. Our findings highlight the importance of pubertal androgens in determining adult behavioral responses to social stress.

Oxytocin increases the salience of both positive and negative social contexts and it is thought that these diverse actions on behavior are mediated in part through circuit-specific action. This hypothesis is based primarily on manipulations of oxytocin receptor function, leaving open the question of whether different populations of oxytocin neurons mediate different effects on behavior. Here we inhibited oxytocin synthesis in a stress-sensitive population of oxytocin neurons specifically within the medioventral bed nucleus of the stria terminalis (BNSTmv). Oxytocin knockdown prevented social stress-induced increases in social vigilance and decreases in social approach. Viral tracing of BNSTmv oxytocin neurons revealed fibers in regions controlling defensive behaviors, including lateral hypothalamus, anterior hypothalamus, and anteromedial BNST (BNSTam). Oxytocin infusion into BNSTam in stress naïve mice increased social vigilance and reduced social approach. These results show that a population of extrahypothalamic oxytocin neurons plays a key role in controlling stress-induced social anxiety behaviors.

Developmental exposure to endocrine disrupting chemicals (EDCs), e.g., bisphenol A (BPA) or genistein (GEN), causes longstanding epigenome effects. MicroRNAs (miRs) regulate which mRNAs will be translated to proteins and thereby serve as the final checkpoint in epigenetic control. Scant amount is known, however, whether EDCs affect neural miRNA (miR) patterns. We aimed to test the hypothesis that developmental exposure of California mice (Peromyscus californicus) to GEN, BPA, or both chemicals influences hypothalamic miR/small RNA profiles and ascertain the extent such biomolecular alterations correlate with behavioral and metabolic changes. California mice were developmentally exposed to GEN (250 mg/kg feed weight, FW), GEN (250 mg/kg FW)+BPA (5 mg/kg FW), low dose (LD) BPA (5 mg/kg FW), or upper dose (UD) BPA (50 mg/kg FW). Adult offspring were tested in a battery of behavioral and metabolic tests; whereupon, mice were euthanized, brains were collected and frozen, small RNAs were isolated from hypothalamic punches, and subsequently sequenced. California mice exposed to one or both EDCs engaged in one or more repetitive behaviors. GEN, LD BPA, and UD BPA altered aspects of ultrasonic and audible vocalizations. Each EDC exposure led to sex-dependent differences in differentially expressed miR/small RNAs with miR7–2, miR146, and miR148a being increased in all female and male EDC exposed groups. Current findings reveal that developmental exposure to GEN and/or BPA affects hypothalamic miR/small RNA expression patterns, and such changes correlate with EDC-induced behavioral and metabolic alterations. miR146 is likely an important mediator and biomarker of EDC exposure in mammals, including humans.

Oxytocin is currently being considered as a novel therapeutic for anxiety disorders due to its ability to promote affiliative behaviors. In the nucleus accumbens (NAc) activation of oxytocin receptors (OTR) promotes social approach (time spent near an unfamiliar individual). Here, we show that stressful social experiences reduce the expression of NAc OTR mRNA, coinciding with decreases in social approach. Social stressors also increase social vigilance, characterized as orienting to an unfamiliar individual without approaching. Vigilance is a key component of behavioral inhibition, a personality trait that is a risk factor for anxiety disorders. To understand whether NAc OTR can modulate both social approach and vigilance, we use pharmacological approaches to assess the impact of activation or inhibition of NAc OTR downstream pathways on these behaviors. First, we show that in unstressed male and female California mice, inhibition of OTR by an unbiased antagonist (L-368,899) reduces social approach but does not induce social vigilance. Next, we show that infusion of Atosiban, an OTR-Gq antagonist/OTR-Gi agonist, has the same effect in unstressed females. Finally, we show that Carbetocin, a biased OTR-Gq agonist, increases social approach in stressed females while simultaneously inhibiting social vigilance. Taken together these data suggest that OTR in the NAc differentially modulate social approach and social vigilance, primarily through an OTR-Gq mechanism. Importantly, pharmacological inhibition of OTR alone is insufficient to induce vigilance in unstressed mice, suggesting that mechanisms modulating social approach may be distinct from mechanisms modulating social vigilance.

Our review focuses on findings from mammals as part of a Special Issue "30th Anniversary of the Challenge Hypothesis". Here we put forth an integration of the mechanisms through which testosterone controls territorial behavior and consider how reproductive experience may alter these mechanisms. The emphasis is placed on the function of socially induced increases in testosterone (T) pulses, which occur in response to social interactions, as elegantly developed by Wingfield and colleagues. We focus on findings from the monogamous California mouse, as data from this species shows that reproductive status is a key factor influencing social interactions, site fidelity, and vigilance for offspring defense. Specifically, we examine differences in T pulses in sexually naïve versus sexually experienced pair bonded males. Testosterone pulses influence processes such as social decision making, the winner-challenge effect, and location preferences through rewarding effects of T. We also consider how social and predatory vigilance contribute to T pulses and how these interactions contribute to a territory centered around maximizing reproduction. Possible underlying mechanisms for these effects include the nucleus accumbens (rewarding effects of testosterone), hippocampus (spatial memories for territories), and the bed nucleus of the stria terminalis (social vigilance). The development of the challenge effect has provided an ideal framework for understanding the complex network of behavioral, environmental, physiological and neural mechanisms that ultimately relates to competition and territoriality across taxa. The opportunity to merge research on the challenge effect using both laboratory and field research to understand social behavior is unparalleled.

Oxytocin increases the salience of both positive and negative social contexts and it is thought that these diverse actions on behavior are mediated in part through circuit-specific action. This hypothesis is based primarily on manipulations of oxytocin receptor function, leaving open the question of whether different populations of oxytocin neurons mediate different effects on behavior. Here we inhibited oxytocin synthesis in a social stress-sensitive population of oxytocin neurons specifically within the medioventral bed nucleus of the stria terminalis (BNSTmv). Oxytocin knock-down prevented stress-induced increases in social vigilance and decreases in social approach. Viral tracing of BNSTmv oxytocin neurons revealed fibers in regions controlling defensive behaviors including lateral hypothalamus, anterior hypothalamus, and anteromedial BNST (BNSTam). Oxytocin infusion into BNSTam in stress naïve mice increased social vigilance and reduced social approach. These results show that a population of extra-hypothalamic oxytocin neurons play a key role in controlling stress-induced social anxiety behaviors.

Kappa opioid receptor activation has been linked to stress and anxiety behavior, thus leading to kappa antagonists being popularized in research as potential anxiolytics. However, while these findings may hold true in standard models, the neuromodulatory effects of social defeat may change the behavioral outcome of kappa opioid receptor activation. Previous research has shown that social defeat can lead to hyperactivity of serotonergic neurons in the dorsal raphe nucleus, and that inhibition of this increase blocks the social deficits caused by defeat. Kappa opioid receptor activation in the dorsal raphe nucleus works to decrease serotonergic activity. We injected the kappa opioid receptor U50,488 directly into the dorsal raphe nucleus of male and female, defeat and control adult California mice. Here we show evidence that U50,488 induces anxiety behavior in control male California mice, but helps relieve it in defeated males. Consistent with previous literature, we find little effect in females adding evidence that there are marked and important sex differences in the kappa opioid system.

Although prior research has examined how early adversity and chronic stress exposure relate to hypothalamic-pituitary-adrenal (HPA) axis responses to acute stress, to date, no studies have examined how stressors occurring over the entire lifespan predict such responses. To address this issue, we recruited 61 healthy young adults and measured their exposure to 55 different types of acute life events and chronic difficulties occurring over the lifespan. In addition, we characterized differences in participants' HPA axis responses to acute stress by measuring their salivary cortisol and DHEA responses to the Trier Social Stress Test for Groups. Greater cumulative stress exposure was associated with a blunted cortisol response, but a heightened DHEA response, to the acute stressor. Moreover, it was participants' exposure to these stressors (i.e., lifetime count), not their perceived severity, which predicted their cortisol and DHEA responses to acute stress. Furthermore, differential effects were observed by stress exposure domain. Notably, only adulthood and marital/partner stressors significantly predicted cortisol responses to acute stress, whereas stress was more uniformly associated with DHEA responses to the acute stressor. These results thus reveal how cumulative stress exposure is associated with HPA axis responsivity to acute stress, while highlighting the fact that different stressors may have substantially different associations with these biological outcomes.

Kappa opioid receptors (KOR) are considered to be a promising therapeutic target for stress-induced psychiatric disorders such as anxiety and depression. Preclinical data show that KOR antagonists have greater efficacy if administered before stressful experiences as opposed to afterwards. However, almost all of these studies use long-acting antagonists, leaving it unclear whether inhibition of KOR after stress is required for efficacy. Here we show that administration of the short-acting KOR antagonist AZ-MTAB before episodes of social defeat stress block the induction of anhedonia (both males and females) and social avoidance responses (females) that persist two weeks after stress. In both males and females pre-stress AZ-MTAB treatment also blunted anticipatory autogrooming behavior immediately prior to the third episode of defeat. In contrast when AZ-MTAB was administered two weeks after defeat (immediately before behavior testing) in female California mice, it was ineffective at reversing anhedonia and social avoidance. These results suggest that short-acting KOR antagonists may have greater therapeutic potential if administered before exposure to psychosocial stressors.

Domesticated mice and rats have shown to be powerful model systems for biomedical research, but there are cases in which the biology of species is a poor match for the hypotheses under study. The California mouse (Peromyscus californicus) has unique traits that make it an ideal model for studying biological mechanisms underlying human-relevant behaviors such as intra-female aggression, biparental care, and monogamy. Indeed, peer-reviewed scientific publications using California mouse as a model for behavioral research have more than doubled in the past decade. Critically, behavioral outcomes in captive animals can be profoundly affected by housing conditions, but there is very limited knowledge regarding species-specific housing needs in California mice. Currently, California mouse investigators have to rely on guidelines aimed for more common laboratory species that show vastly different physiology, behavior, and/or ecological niche. This not only could be suboptimal for animals’ welfare, but also result in lack of standardization that could potentially compromise experimental reproducibility and replicability across laboratories. With the aim of assessing how different housing systems can affect California mouse behavior both in the home cage as well as the open field and social interaction tests before and after social defeat stress, here we tested three different caging systems: 1. Standard mouse cage, 2. Large cage, and 3. Large cage + environmental enrichment (EE), which focused on increasing vertical complexity based on observations that California mice are semiarboreal in the wild. We found that the effects of housing were largely sex specific: compared to standard cages, in females large + EE reduced home cage stereotypic-like backflipping and rearing behaviors, while large cage increased social interactions. In males, the large+EE cage reduced rearing and digging but did not significantly affect backflipping behavior. Interestingly, while there were no significant differences in the open field and social interaction pre-stress behaviors, large and large+EE housing increased the sensitivity of these tests to detect stress induced phenotypes in females. Together, these results suggest that increasing social and environmental complexity affects home cage behaviors in male and female California mice without interfering with, but rather increasing the magnitude of, the effects of defeat stress on the open field and social interaction tests.

The majority of mammalian species are uniparental, with the mother solely providing care for young conspecifics, although fathering behaviours can emerge under certain circumstances. For example, a great deal of individual variation in response to young pups has been reported in multiple inbred strains of laboratory male mice. Furthermore, sexual experience and subsequent cohabitation with a female conspecific can induce caregiving responses in otherwise indifferent, fearful or aggressive males. Thus, a highly conserved parental neural circuit is likely present in both sexes; however, the extent to which infants are capable of activating this circuit may vary. In support of this idea, fearful or indifferent responses toward pups in female mice are linked to greater immediate early gene (IEG) expression in a fear/defensive circuit involving the anterior hypothalamus compared to that in an approach/attraction circuit involving the ventral tegmental area. However, experience with infants, particularly in combination with histone deacetylase inhibitor (HDACi) treatment, can reverse this pattern of pup-induced activation of fear/defence circuitry and promote approach behaviour. Thus, HDACi treatment may increase the transcription of primed/poised genes that play a role in the activation and selection of a maternal approach circuit in response to pup stimuli. In the present study, we investigated whether HDACi treatment would impact behavioural response selection and associated IEG expression changes in virgin male mice that are capable of ignoring, attacking or caring for pups. The results obtained indicate that systemic HDACi treatment induces spontaneous caregiving behaviour in non-aggressive male mice and alters the pattern of pup-induced IEG expression across a fear/defensive neural circuit.

Social vigilance is a behavioral strategy commonly used in adverse or changing social environments. In animals, a combination of avoidance and vigilance allows an individual to evade potentially dangerous confrontations while monitoring the social environment to identify favorable changes. However, prolonged use of this behavioral strategy in humans is associated with increased risk of anxiety disorders, a major burden for human health. Elucidating the mechanisms of social vigilance in animals could provide important clues for new treatment strategies for social anxiety. Importantly, during adolescence the prevalence of social anxiety increases significantly. We hypothesize that many of the actions typically characterized as anxiety behaviors begin to emerge during this time as strategies for navigating more complex social structures. Here, we consider how the social environment and the pubertal transition shape neural circuits that modulate social vigilance, focusing on the bed nucleus of the stria terminalis and prefrontal cortex. The emergence of gonadal hormone secretion during adolescence has important effects on the function and structure of these circuits, and may play a role in the emergence of a notable sex difference in anxiety rates across adolescence. However, the significance of these changes in the context of anxiety is still uncertain, as not enough studies are sufficiently powered to evaluate sex as a biological variable. We conclude that greater integration between human and animal models will aid the development of more effective strategies for treating social anxiety.

Oxytocin (OT) is widely known for promoting social interactions, but there is growing appreciation that it can sometimes induce avoidance of social contexts. The social salience hypothesis posed an innovative solution to these apparently opposing actions by proposing that OT enhances the salience of both positive and negative social interactions. The mesolimbic dopamine system was put forth as a likely system to evaluate social salience owing to its well-described role in motivation. Evidence from several sources supports the premise that OT acting within the nucleus accumbens and ventral tegmental area facilitates social reward and approach behavior. However, in aversive social contexts, additional pathways play critical roles in mediating the effects of OT. Recent data indicate that OT acts in the bed nucleus of the stria terminalis to induce avoidance of potentially dangerous social contexts. Here, we review evidence for neural circuits mediating the effects of OT in appetitive and aversive social contexts. Specifically, we propose that distinct but potentially overlapping circuits mediate OT-dependent social approach or social avoidance. We conclude that a broader and more inclusive consideration of neural circuits of social approach and avoidance is needed as the field continues to evaluate the potential of OT-based therapeutics.

INTRODUCTION:Hantaviruses are a group of globally distributed rodent-associated viruses, some of which are responsible for human morbidity and mortality. Sin Nombre orthohantavirus, a particularly virulent species of hantavirus associated with Peromyscus spp. mice, is actively monitored by the Department of Public Health in California (CDPH). Recently, CDPH documented high (40%) seroprevalence in a potentially novel reservoir species, the cactus mouse (Peromyscus eremicus) in Death Valley National Park. METHODS:This study was performed in the extremely isolated Mojave Desert Amargosa River valley region of southeastern Inyo County, California, 105 km from Death Valley, approximately over the same time interval as the CDPH work in Death Valley (between 2011 and 2016). Similar rodent species were captured as in Death Valley and were tested for select hantaviruses using serology and RT-PCR to assess risk to human health and the conservation of the endemic endangered Amargosa vole. RESULTS:Among 192 rodents tested, including 56 Peromyscus spp., only one seropositive harvest mouse (Reithrodontomys megalotis) was detected. DISCUSSION:These data highlight the heterogeneity in the prevalence of hantavirus infection even among nearby desert communities and suggest that further studies of hantavirus persistence in desert environments are needed to more accurately inform the risks to public health and wildlife conservation.

Stress generally hurts many aspects of memory, but an interesting finding to emerge from the stress and memory literature is that stress that occurs shortly after learning (i.e., post-encoding stress) usually benefits memory. Although this effect is well established, the biological mechanisms underpinning this effect are not—especially in humans. We addressed this gap in the present study by collecting saliva samples from 80 participants who were randomized to a post-encoding stress (i.e., cold pressor for 3 min) or control task (i.e., warm water for 3 min) and 48 h later completed a recognition memory task. Saliva was collected both prior to and 15 min after the offset of (18 min after the onset of) the stress/control manipulation. Drawing on animal and human work, we examined how five stress-responsive biomarkers—cortisol, salivary α-amylase, progesterone, estradiol, and the proinflammatory cytokine interleukin (IL)-1β, all assessed in saliva—related to the effects of stress on memory. We found that stress enhanced recollection of negative images and that these effects were selectively related to salivary IL-1β. Moreover, we found that the beneficial effects of stress on memory were statistically mediated by salivary IL-1β. We found no robust associations—either linear or quadratic—between memory and any other biomarker, nor did we find significant interactions between biomarkers in predicting memory. These results suggest that immune system activity indexed by salivary IL-1β may play an important role in contributing to post-encoding stress effects on human memory.

Social monogamy, typically characterized by the formation of a pair bond, increased territorial defense, and often biparental care, has independently evolved multiple times in animals. Despite the independent evolutionary origins of monogamous mating systems, several homologous brain regions and neuropeptides and their receptors have been shown to play a conserved role in regulating social affiliation and parental care, but little is known about the neuromolecular mechanisms underlying monogamy on a genomic scale. Here, we compare neural transcriptomes of reproductive males in monogamous and nonmonogamous species pairs of Peromyscus mice, Microtus voles, parid songbirds, dendrobatid frogs, and Xenotilapia species of cichlid fishes. We find that, while evolutionary divergence time between species or clades did not explain gene expression similarity, characteristics of the mating system correlated with neural gene expression patterns, and neural gene expression varied concordantly across vertebrates when species transition to monogamy. Our study provides evidence of a universal transcriptomic mechanism underlying the evolution of monogamy in vertebrates.

Social interactions play a key role in modulating the impact of stressful experiences. In some cases, social interactions can result in social buffering, the process in which the presence of one individual reduces the physiological and behavioral impact of stress in another individual. On the other hand, there is growing evidence that a key initiating factor of social buffering behaviors is the initiation of an anxiogenic state in the individual that was not directly exposed to the stress. This is referred to as stress contagion (a form of emotion contagion). Both processes involve the transmission of social information, suggesting that contagion and buffering could share similar neural mechanisms. In general, mechanistic studies of contagion and buffering are considered separately, even though behavioral studies show that a degree of contagion is usually necessary for social buffering behaviors to occur. Here we consider the extent to which the neuropeptides corticotropin releasing hormone and oxytocin are involved in contagion and stress buffering. We also assess the importance that frontal cortical areas such as the anterior cingulate cortex and infralimbic cortex play in these behavioral processes. We suggest that further work that directly compares neural mechanisms during stress contagion and stress buffering will be important for identifying what appear to be distinct but overlapping circuits mediating these processes.

© 2015 Society of Biological Psychiatry Background Oxytocin (OT) is considered to be a stress-buffering hormone, dampening the physiologic effects of stress. However, OT can also be anxiogenic. We examined acute and long-lasting effects of social defeat on OT neurons in male and female California mice. Methods We used immunohistochemistry for OT and c-fos cells to examine OT neuron activity immediately after defeat (n = 6–9) and 2 weeks (n = 6–9) and 10 weeks (n = 4–5) later. We quantified Oxt messenger RNA with quantitative polymerase chain reaction (n = 5–9). Intranasal OT was administered to naïve and stressed mice tested in social interaction and resident-intruder tests (n = 8–14). Results Acute exposure to a third episode of defeat increased OT/c-fos colocalizations in the paraventricular nucleus of both sexes. In the medioventral bed nucleus of the stria terminalis, defeat increased Oxt messenger RNA, total OT neurons, and OT/c-fos colocalizations in female mice but not male mice. Intranasal OT failed to reverse stress-induced social withdrawal in female mice and reduced social interaction behavior in female mice naïve to defeat. In contrast, intranasal OT increased social interaction in stressed male mice and reduced freezing in the resident-intruder test. Conclusions Social defeat induces long-lasting increases in OT production and OT/c-fos cells in the medioventral bed nucleus of the stria terminalis of female mice but not male mice. Intranasal OT largely reversed the effects of stress on behavior in male mice, but effects were mixed in female mice. These results suggest that changes in OT-sensitive networks contribute to sex differences in behavioral responses to stress.

Psychosocial stress influences cognitive abilities, such as long-term memory retrieval. However, less is known about the effects of stress on cognitive flexibility, which is mediated by different neurobiological circuits and could thus be regulated by different neuroendocrine pathways. In this study, we randomly assigned healthy adults to an acute stress induction or control condition and subsequently assessed participants' cognitive flexibility using an open-source version of the Wisconsin Card Sort task. Drawing on work in rodents, we hypothesized that stress would have stronger impairing effects on cognitive flexibility in men than women. As predicted, we found that stress impaired cognitive flexibility in men but did not significantly affect women. Our results thus indicate that stress exerts sex-specific effects on cognitive flexibility in humans and add to the growing body of research highlighting the need to consider sex differences in effects of stress.

Exposure to acute stress can impact performance on numerous cognitive abilities, but little is known about how acute stress affects real-world decision-making ability. In the present study, we induced acute stress with a standard laboratory task involving uncontrollable socio-evaluative stress and subsequently assessed decision-making ability using the Adult Decision Making Competence index. In addition, we took baseline and post-test saliva samples from participants to examine associations between decision-making competence and adrenal hormones. Participants in the stress induction group showed enhanced decision-making competence, relative to controls. Further, although both cortisol and dehydroepiandrosterone (DHEA) reactivity predicted decision-making competence when considered in isolation, DHEA was a significantly better predictor than cortisol when both hormones were considered simultaneously. Thus, our results show that exposure to acute stress can have beneficial effects on the cognitive ability underpinning real-world decision-making and that this effect relates to DHEA reactivity more than cortisol.

Whereas the majority of mammalian species are uni-parental with the mother solely provisioning care for young conspecifics, fathering behaviors can emerge under certain circumstances. For example, a great deal of individual variation in response to young pups has been reported in multiple inbred strains of laboratory male mice. Further, sexual experience and subsequent cohabitation with a female conspecific can induce caregiving responses in otherwise indifferent, fearful or aggressive males. Thus, a highly conserved parental neural circuit is likely present in both sexes, however the extent to which infants are capable of accessing this circuit may vary. In support of this idea, fearful or indifferent responses toward pups in female mice are linked to greater immediate early gene (IEG) expression in a fear/defensive circuit involving the anterior hypothalamus than in an approach/attraction circuit involving the ventral tegmental area. However, experience with infants, particularly in combination with histone deacetylase inhibitor (HDACi) treatment, can reverse this pattern of neuronal activation and behavior. Thus, HDACi treatment may increase the transcription of primed/poised genes that play a role in the activation and selection of a maternal approach circuit in response to pup stimuli. Here, we asked whether HDACi treatment would impact behavioral response selection and associated IEG expression changes in virgin male mice that are capable of ignoring, attacking or caring for pups. Our results indicate that systemic HDACi treatment induces spontaneous caregiving behavior in non-aggressive male mice and alters the pattern of pup-induced IEG expression across a fear/defensive neural circuit.

A roadblock to successful treatment for anxiety and depression is the high proportion of individuals that do not respond to existing treatments. Different underlying neurobiological mechanisms may drive similar symptoms, so a more personalized approach to treatment could be more successful. There is increasing evidence that sex is an important biological variable modulating efficacy of antidepressants and anxiolytics. We review evidence for sex-specific effects of traditional monoamine based antidepressants and newer pharmaceuticals targeting kappa opioid receptors (KOR), oxytocin receptors (OTR), and N-methyl-D-aspartate receptors (ketamine). In some cases, similar behavioral effects are observed in both sexes while in other cases strong sex-specific effects are observed. Most intriguing are cases such as ketamine which has similar behavioral effects in males and females, perhaps through sex-specific neurobiological mechanisms. These results show how essential it is to include both males and females in both clinical and preclinical evaluations of novel antidepressants and anxiolytics.

BackgroundThe neuropeptide oxytocin (OT) is a key regulator of social and emotional behaviors. The effects of OT are context dependent, and it has been proposed that OT increases the salience of both positive and negative social cues. Here we tested whether the bed nucleus of the stria terminalis (BNST) mediates anxiogenic effects of OT.MethodsFirst, we studied the effects of systemic administration of an OT receptor (OTR) antagonist L-368,899 on social behavior in male and female California mice exposed to social defeat. We examined the effect of L-368,899 on G protein activation and used early growth response factor 1 immunohistochemistry to identify potential sites of OTR action. Finally, we examined the effects of L-368,899 infused in the BNST on behavior.ResultsA single dose of systemic L-368,899 increased social approach in stressed female mice and decreased social approach in male mice naïve to defeat. L-368,899 prevented OT activation of G proteins and did not activate G proteins in the absence of OT. Intranasal OT, which reduces social approach in female mice but not male mice, increased early growth response factor 1 immunoreactivity in the nucleus accumbens core and anteromedial BNST in female mice but not in male mice. Stressed female mice that received an infusion of L-368,899 into the anteromedial BNST but not the nucleus accumbens core increased social approach and decreased social vigilance responses.ConclusionsOur results suggest that OTR activation in anteromedial BNST induces a vigilance response in which individuals avoid, yet attend to, unfamiliar social contexts. Our results suggest that OTR antagonists may have unappreciated therapeutic potential for stress-induced psychiatric disorders.

Across invertebrates and vertebrates, steroids are potent signaling molecules that affect nearly every cell in the organism, including cells of the nervous system. Historically, researchers have focused on the genomic (or "nuclear-initiated") effects of steroids. However, all classes of steroids also have rapid non-genomic (or "membrane-initiated") effects, although there is far less basic knowledge of these non-genomic effects. In particular, steroids synthesized in the brain ("neurosteroids") have genomic and non-genomic effects on behavior. Here, we review evidence that estradiol has rapid effects on aggression, an important social behavior, and on intracellular signaling cascades in relevant regions of the brain. In particular, we focus on studies of song sparrows (Melospiza melodia) and Peromyscus mice, in which estradiol has rapid behavioral effects under short photoperiods only. Furthermore, in captive Peromyscus, estrogenic compounds (THF-diols) in corncob bedding profoundly alter the rapid effects of estradiol. Environmental factors in the laboratory, such as photoperiod, diet, and bedding, are critical variables to consider in experimental design. These studies are consistent with the hypothesis that locally-produced steroids are more likely than systemic steroids to act via non-genomic mechanisms. Furthermore, these studies illustrate the dynamic balance between genomic and non-genomic signaling for estradiol, which is likely to be relevant for other steroids, behaviors, and species.

Male parental care is an important social behavior for several mammalian species. Psychosocial stress is usually found to inhibit maternal behavior, but effects on paternal behavior have been less consistent. We tested the effects of social defeat stress on pair bond formation and paternal behavior in the monogamous California mouse (Peromyscus californicus). Social defeat reduced time spent in a chamber with a stranger female during a partner preference test conducted 24 h after pairing, but increased latency to the first litter. In 10 minute partner preference tests conducted after the birth of pups, both control and stressed males exhibited selective aggression towards stranger females. Unlike prairie voles, side by side contact was not observed in either partner preference test. Stressed male California mice engaged in more paternal behavior than controls and had reduced anxiety-like responses in the open-field test. Defeat stress enhanced prodynorphin and KOR expression in the medial preoptic area (MPOA) but not PVN. Increased KOR signaling has been linked to increased selective aggression in prairie voles. Together the results show that defeat stress enhances behaviors related to parental care and pair bonding in male California mice.

© 2016 A contribution to a special issue on Hormones and Human Competition. The relationship between androgenic hormones, like testosterone (T), and aggression is extensively studied in human populations. Yet, while this work has illuminated a variety of principals regarding the behavioral and phenotypic effects of T, it is also hindered by inherent limitations of performing research on people. In these instances, animal research can be used to gain further insight into the complex mechanisms by which T influences aggression. Here, we explore recent studies on T and aggression in numerous vertebrate species, although we focus primarily on males and on a New World rodent called the California mouse (Peromyscus californicus). This species is highly territorial and monogamous, resembling the modern human social disposition. We review (i) how baseline and dynamic T levels predict and/or impact aggressive behavior and disposition; (ii) how factors related to social and physical context influence T and aggression; (iii) the reinforcing or “rewarding” aspects of aggressive behavior; and (iv) the function of T on aggression before and during a combative encounter. Included are areas that may need further research. We argue that animal studies investigating these topics fill in gaps to help paint a more complete picture of how androgenic steroids drive the output of aggressive behavior in all animals, including humans.