Epigenetic mechanisms underlying sex differences in the brain and behavior.

Sex differences are found across brain regions, behaviors, and brain diseases. Sexual differentiation of the brain is initiated prenatally but it continues throughout life, as a result of the interaction of three major factors: gonadal hormones, sex chromosomes, and the environment. These factors are thought to act, in part, via epigenetic mechanisms which control chromatin and transcriptional states in brain cells. In this review, we discuss evidence that epigenetic mechanisms underlie sex-specific neurobehavioral changes during critical organizational periods, across the estrous cycle, and in response to diverse environments throughout life. We further identify future directions for the field that will provide novel mechanistic insights into brain sex differences, inform brain disease treatments and women's brain health in particular, and apply to people across genders.

Postmortem tissue biomarkers of menopausal transition.

The menopausal transition (MT) is associated with an increased risk for many disorders including neurological and mental disorders. Brain imaging studies in living humans show changes in brain metabolism and structure that may contribute to the MT-associated brain disease risk. Although deficits in ovarian hormones have been implicated, cellular and molecular studies of the brain undergoing MT are currently lacking, mostly due to a difficulty in studying MT in postmortem human brain. To enable this research, we explored 39 candidate biomarkers for menopausal status in 42 pre-, peri-, and post-menopausal subjects across three postmortem tissues: blood, the hypothalamus, and pituitary gland. We identified thirteen significant and seven strongest menopausal biomarkers across the three tissues. Using these biomarkers, we generated multi-tissue and tissue-specific composite measures that allow the postmortem identification of the menopausal status across different age ranges, including the "perimenopausal", 45-55-year-old group. Our findings enable the study of cellular and molecular mechanisms underlying increased neuropsychiatric risk during the MT, opening the path for hormone status-informed, precision medicine approach in women's mental health.

Chronic intranasal oxytocin reverses stress-induced social avoidance in female prairie voles.

Social anxiety disorder (SAD) is a prevalent mental illness in both men and women, but current treatment approaches with selective serotonin reuptake inhibitors (SSRI) have limited success. The neuropeptide oxytocin (OXT) has become a therapeutic target due to its prosocial and anxiolytic effects. Nevertheless, no research has focused on the impact of chronic OXT treatment in animal models of SAD. Social defeat stress is an animal model of social conflict that reliably induces a social avoidance phenotype, reflecting symptoms observed in individuals suffering from SAD. Here, we used the socially monogamous prairie vole, which exhibits aggressive behavior in both sexes, to examine the effects of OXT and SSRI treatment following social defeat stress in males and females. Defeated voles became avoidant in unfamiliar social situations as early as one day after defeat experience, and this phenotype persisted for at least eight weeks. OXT receptor (OXTR) binding in mesocorticolimbic and paralimbic regions was reduced in defeated females during the eight-week recovery period. In males, serotonin 1A receptor binding was decreased in the basolateral amygdala and dorsal raphe nucleus starting at one week and four weeks post-defeat, respectively. Chronic intranasal treatment with OXT had a negative effect on sociability and mesolimbic OXTR binding in non-defeated females. However, chronic intranasal OXT promoted social engagement and increased mesolimbic OXTR binding in defeated females but not males. SSRI treatment led to only modest effects. This study identifies a sex-specific and stress-dependent function of intranasal OXT on mesolimbic OXTR and social behaviors.

Regulation of defeat-induced social avoidance by medial amygdala DRD1 in male and female prairie voles.

Social interaction with unfamiliar individuals is necessary for species-preserving behaviors such as finding mates and establishing social groups. However, social conflict is a potential negative outcome to interaction with a stranger that can be distressing enough to cause an individual to later avoid interactions with other unfamiliar conspecifics. Unfortunately, stress research using a prominent model of social conflict, social defeat stress, has largely omitted female subjects. This has left a void in the literature regarding social strain on female stress biology and adequate comparison of the effect of sex in stress pathways. The prairie vole (Microtus ochrogaster) exhibits aggressive behavior in both sexes, making voles an attractive candidate to model social defeat in both sexes. This study sought to establish a model of social defeat stress in both male and female prairie voles, characterize behavioral changes in response to this stressor, and investigate the role of dopamine signaling in the response to social defeat stress. Defeated male and female prairie voles displayed social avoidance as well as an increase in the level of dopamine receptor D1 (DRD1) in the medial amygdala (MeA). Pharmacological manipulation of DRD1 signaling in the MeA revealed that increased DRD1 signaling is sufficient to induce a social avoidant state, and could be a necessary component in the defeat-induced social avoidance response. These findings provide the prairie vole as a model of social defeat in both sexes, and implicate the MeA in avoidance of unfamiliar conspecifics after a distressing social encounter.

Inducing Partner Preference in Mice by Chemogenetic Stimulation of CA2 Hippocampal Subfield.

Social recognition is fundamental for social decision making and the establishment of long-lasting affiliative behaviors in behaviorally complex social groups. It is a critical step in establishing a selective preference for a social partner or group member. C57BL/6J lab mice do not form monogamous relationships, and typically do not show prolonged social preferences for familiar mice. The CA2 hippocampal subfield plays a crucial role in social memory and optogenetic stimulation of inputs to the dorsal CA2 field during a short memory acquisition period can enhance and extend social memories in mice. Here, we show that partner preference in mice can be induced by chemogenetic selective stimulation of the monosynaptic projections from the hypothalamic paraventricular nucleus (PVN) to the CA2 during the cohabitation period. Specifically, male mice spend more time in social contact, grooming and huddling with the partner compared to a novel female. Preference was not induced by prolonging the cohabitation period and allowing more time for social interactions and males to sire pups with the familiar female. These results suggest that PVN-to-CA2 projections are part of an evolutionarily conserved neural circuitry underlying the formation of social preference and may promote behavioral changes with appropriate stimulation.

Vasopressinergic Neurocircuitry Regulating Social Attachment in a Monogamous Species.

The prairie vole (Microtus ochrogaster) is a socially monogamous rodent species that forms a lasting connection between mates, known as a pair bond. The pair bond is primarily characterized by three distinct behaviors: partner preference, selective aggression, and biparental care of the young. The presence of these behaviors in the prairie vole and their absence in closely related non-monogamous species makes the prairie vole an important model of social relationships and facilitates the study of the neurobiological mechanisms of social affiliation and attachment. The nona-peptide arginine-vasopressin (AVP) is an important neuromodulator of social behavior and has been implicated in the regulation of the pair bond-related behaviors of the prairie vole, through activation of the AVP receptor subtype 1a (AVPR1a). Modulation of AVPR1a activity in different regions of the prairie vole brain impacts pair bond behavior, suggesting a role of AVP in neurocircuitry responsible for the regulation of social attachment. This review will discuss findings that have suggested the role of AVP in regulation of the pair bond-related behaviors of the prairie vole and the specific brain regions through which AVP acts to impact these unique behaviors.