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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.

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.

Autism spectrum disorder (ASD) is a neurodevelopmental disease associated with various gene mutations. Recent genetic and clinical studies report that mutations of the epigenetic gene ASH1L are highly associated with human ASD and intellectual disability (ID). However, the causality and underlying molecular mechanisms linking ASH1L mutations to genesis of ASD/ID remain undetermined. Here we show loss of ASH1L in the developing mouse brain is sufficient to cause multiple developmental defects, core autistic-like behaviors, and impaired cognitive memory. Gene expression analyses uncover critical roles of ASH1L in regulating gene expression during neural cell development. Thus, our study establishes an ASD/ID mouse model revealing the critical function of an epigenetic factor ASH1L in normal brain development, a causality between Ash1L mutations and ASD/ID-like behaviors in mice, and potential molecular mechanisms linking Ash1L mutations to brain functional abnormalities.Yuen Gao et al. characterize deficits in brain morphology, behavior, and gene expression following genetic ablation of the histone methyltransferase, ASH1L, during brain development in mice. Their results provide new insight into links between ASH1L activity and neurodevelopmental disorders.

The neuropeptides oxytocin (OT) and vasopressin (AVP) are key regulators of social and emotional behaviors. Accumulating evidence suggesting a role of OT, AVP, and their receptors in the pathophysiology of psychiatric disorders has sparked interest in these systems as therapeutic targets. Nonetheless, the specific neural circuits mediating context and sex specific behavioral effects of OT and AVP are not fully understood. Using the California mouse model of social defeat, we previously found that social defeat stress increases the reactivity of OT neurons in the medioventral bed nucleus of the stria terminalis (BNSTmv) and paraventricular nucleus in female but not male California mice. We also found that intranasal administration of OT has no effect on male social interaction, but reduces this behavior in females, mirroring the effect of social defeat stress. Here we conducted a series of experiments aimed at identifying receptor populations involved in sex specific effects of stress on social interaction behavior and specific sites of action. First we studied the effects of sex and social defeat stress on AVP receptor V1a (V1aR) binding in the forebrain. In females but not males, V1aR binding in the BNSTmv was negatively correlated to social interaction behavior. We hypothesized that activation of this receptor population was mediating stress-induced social deficits, but Infusions of V1aR antagonist in to the BNSTmv had anxiogenic effects in both males and females. Next, we studied the effects of systemic administration of an OT receptor antagonist (OTA) on social behavior in control and stressed males and females. We found that one dose of OTA reverses the effects of stress on female social behavior, but has the opposite effects in males. To identify potential sites of action, we used immediate early gene immunohistochemistry in mice that received intranasal OT or control infusions. We found that stress increases EGR-1 immunoreactivity in the dorsolateral nucleus accumbens core and anteromedial BNST in females but not males. Based on these results, we performed site-specific injections of OTA in stressed females. A single dose of OTA within the anteromedial BNST rapidly reversed stress-induced social avoidance in females. Together, these results support the hypothesis that stress-induced hyperactivity of OT neurons contributes to some stress-induced changes in female social behavior by activating OT receptors, and that OTR antagonists may have unappreciated therapeutic potential for stress-induced psychiatric disorders.

Polybrominated diphenyl ethers (PBDEs) are synthetic flame retardants once widely used in furniture, electronics, and other consumer products. Although phased out in the early 2000s, their chemical persistence, recycling into new materials, and leaching from waste sites have led to ongoing environmental contamination and widespread human exposure, especially through diet and indoor dust. This is particularly concerning for developing individuals, who not only accumulate the highest levels via placental transfer, breastfeeding, and behavioral factors, but are also especially vulnerable to long-term effects. Despite well-documented impacts of developmental PBDE exposure on neurobehavioral, endocrine, and metabolic systems, the effects on the immune system remain comparatively underexplored. To begin addressing this gap, we focused on mast cells, innate immune cells well-positioned to contribute to the multisystemic effects of developmental exposures. Mast cells are long-lived, tissue-resident cells enriched at barrier surfaces and perivascular sites throughout the body, including the brain. Their widespread distribution, extensive receptor repertoire, and unique ability to store and rapidly release bioactive mediators from cytoplasmic granules position them as key modulators of immune, endocrine, and nervous system function. Using oral exposure to two doses of a PBDE mixture throughout pregnancy and lactation in mice, we show that maternal exposure to ~87 ug/kg/day, aligned with the lower end of doses known to affect metabolic and neurobehavioral outcomes in preclinical models and within 10-fold of levels measured in human serum and placenta, leads to persistent dysfunction in mast cell mediator release in adult male and female offspring. This was evidenced by blunted anaphylaxis-associated hypothermia and plasma histamine release in vivo. These deficits were not due to changes in tissue-resident mast cell numbers, but rather to an impaired capacity to sustain histamine release over time. Studies in bone marrow-derived mast cells (BMMCs) revealed that histamine synthesis was intact, but granule maturation and stimulus-induced calcium mobilization were disrupted, in association with downregulation of genes such as IGF2R, ITGA4, ITGB6, and NGFR. Given that the bone marrow is the primary postnatal source of mast cells, these findings suggest that PBDEs induce lasting reprogramming at the level of hematopoietic progenitors. This may have broad implications not only for mast cell function across tissues, but also for other immune cell lineages that arise from the same progenitor pool. In sum, this study provides the first evidence that developmental exposure to PBDEs induces long-lasting impairments in mast cell functions, suggesting a previously unrecognized mechanism by which early-life exposure to environmental toxicants could contribute to persistent physiological and behavioral dysfunctions.

Mast cells are innate immune cells that regulate physiological processes by releasing pre-stored and newly synthesized mediators in response to allergens, infection, and other stimuli. Dysregulated mast cell activity can lead to multisystemic pathologies, but the underlying regulatory mechanisms remain poorly understood. We found that FOSB and ΔFOSB, transcription factors encoded by the gene, are robustly expressed in mast cells following IgE-antigen stimulation, suggesting a role in modulating stimulus-induced mast cell functions. Using phenotypic, gene binding, and gene expression analyses in wild-type and mast cell-specific knockout male mice, we demonstrate that FOSB/ΔFOSB modulates mast cell functions by limiting reactivity to allergen-like stimuli both and . These effects seem to be mediated, at least in part, by FOSB/ΔFOSB-driven enhanced expression of DUSP4, a dual-specificity phosphatase that attenuates MAPK signaling. These findings highlight FOSB/ΔFOSB as critical regulators of mast cell activity and potential targets for therapeutic intervention.

Oxytocin is a neuropeptide that can promote or inhibit affiliative social behaviors. Recent evidence suggests that these diverse effects are mediated by distinct oxytocin receptor-expressing neurons. An outstanding question is whether these behavioral effects are also driven by distinct or overlapping populations of oxytocin-producing neurons. The paraventricular nucleus (PVN) of the hypothalamus is a major source of oxytocin and sends projections to the mesolimbic dopamine system and extended amygdala. Previous work found that social defeat increased oxytocin neuron activity in the anterior PVN (aPVN) but not posterior PVN (pPVN). We reduced oxytocin synthesis with antisense morpholino oligonucleotides in either anterior or posterior PVN in California mice ( ), a strong model system for studying effects of social stress on brain function and behavior. Antisense morpholinos in aPVN had no effect on behavior in unstressed females but increased social approach and reduced social vigilance in females exposed to social defeat stress. In pPVN, antisense morpholinos reduced social approach in unstressed male and female California mice. We then used mice to compare electrophysiological profiles of oxytocin in aPVN and pPVN with a population of oxytocin neurons in the bed nucleus of the stria terminalis (BNST). Oxytocin neurons in aPVN and BNST had higher post-synaptic events and responded more strongly to current injections than oxytocin neurons in pPVN, though they had similar excitatory and inhibitory input balance at the observed resting membrane potential. These findings shed light onto functional and physiological heterogeneity of PVN oxytocin neurons. Our results suggest that context dependent effects of oxytocin are mediated by different populations of oxytocin neurons.

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.

Abstract 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. Competing Interest Statement The authors have declared no competing interest.

Exposure to early life adversity (ELA) in the form of physical and/or psychological abuse or neglect increases the risk of developing psychiatric and inflammatory disorders later in life. It has been hypothesized that exposure to ELA results in persistent, low grade inflammation that leads to increased disease susceptibility by amplifying the crosstalk between stress-processing brain networks and the immune system, but the mechanisms remain largely unexplored. The meninges, a layer of three overlapping membranes that surround the central nervous system (CNS)- duramater, arachnoid, and piamater – possess unique features that allow them to play a key role in coordinating immune trafficking between the brain and the peripheral immune system. These include a network of lymphatic vessels that carry cerebrospinal fluid from the brain to the deep cervical lymph nodes, fenestrated blood vessels that allow the passage of molecules from blood to the CNS, and a rich population of resident mast cells, master regulators of the immune system. Using a mouse model of ELA consisting of neonatal maternal separation plus early weaning (NMSEW), we sought to explore the effects of ELA on duramater mast cell histology and expression of inflammatory markers in male and female C57Bl/6 mice. We found that mast cell number, activation level, and relative expression of pseudopodia differ across duramater regions, and that NMSEW exerts region-specific effects on mast cells in males and females. Using gene expression analyses, we next found that NMSEW increases the expression of inflammatory markers in the duramater of females but not males, and that this is prevented by pharmacological inhibition of mast cells with ketotifen. Together, our results show that ELA drives sex-specific, long-lasting effects on the duramater mast cell population and immune-related gene expression, suggesting that the long-lasting effects of ELA on disease susceptibility could be partly mediated by meningeal function.