Corticosteroid-Binding Globulin (SERPINA6) Consolidates Sexual Dimorphism of Adult Rat Liver.

Produced by the liver, corticosteroid-binding globulin (CBG) regulates the plasma distribution and actions of glucocorticoids. A sex difference in pituitary growth hormone secretion patterns established during puberty in rats results in increased hepatic CBG production and 2-fold higher plasma corticosterone levels in females. Glucocorticoids control hepatic development and metabolic activities, and we have therefore examined how disrupting the SerpinA6 gene encoding CBG influences plasma corticosterone dynamics, as well as liver gene expression in male and female rats before and after puberty. Comparisons of corticosterone plasma clearance and hepatic uptake in adult rats, with or without CBG, indicated that CBG limits corticosterone clearance by reducing its hepatic uptake. Hepatic transcriptomic profiling revealed minor sex differences (207 differentially expressed genes) and minimal effect of CBG deficiency in 30-day-old rats before puberty. While liver transcriptomes in 60-day-old males lacking CBG remained essentially unchanged, 2710 genes were differentially expressed in wild-type female vs male livers at this age. Importantly, ∼10% of these genes lost their sexually dimorphic expression in adult females lacking CBG, including those related to cholesterol biosynthesis, inflammation, and lipid and amino acid catabolism. Another 203 genes were altered by the loss of CBG specifically in adult females, including those related to xenobiotic metabolism, circadian rhythm, and gluconeogenesis. Our findings reveal that CBG consolidates the sexual dimorphism of the rat liver initiated by sex differences in growth hormone secretion patterns and provide insight into how CBG deficiencies are linked to glucocorticoid-dependent diseases.

Corticosteroid-binding Globulin (SERPINA6) Establishes Postpubertal Sex Differences in Rat Adrenal Development.

Encoded by SerpinA6, plasma corticosteroid-binding globulin (CBG) transports glucocorticoids and regulates their access to cells. We determined how CBG influences plasma corticosterone and adrenal development in rats during the pubertal to adult transition using CRISPR/cas9 to disrupt SerpinA6 gene expression. In the absence of CBG, total plasma corticosterone levels were ∼80% lower in adult rats of both sexes, with a greater absolute reduction in females than in males. Notably, free corticosterone and adrenocorticotropic hormone were comparable between all groups. Between 30 and 90 days of age, wild-type female rats showed increases in adrenal weight and the size of the corticosterone-producing region, the zona fasciculata (zf), in tandem with increases in plasma CBG and corticosterone concentrations, whereas no such changes were observed in males. This sex difference was lost in rats without CBG, such that adrenal growth and zf expansion were similar between sexes. The sex-specific effects of CBG on adrenal morphology were accompanied by remarkable changes in gene expression: ∼40% of the adrenal transcriptome was altered in females lacking CBG, whereas almost no effect was seen in males. Over half of the adrenal genes that normally exhibit sexually dimorphic expression after puberty were similarly expressed in males and females without CBG, including those responsible for cholesterol biosynthesis and mobilization, steroidogenesis, and growth. Rat adrenal SerpinA6 transcript levels were very low or undetectable. Thus, sex differences in adrenal growth, morphology and gene expression profiles that emerge during puberty in rats are dependent on concomitant increases in plasma CBG produced by the liver.

Sex Differences in Serotonin 5-HT 1A Receptor Responses to Repeated Restraint Stress in Adult Male and Female Rats.

BACKGROUND: Male and female rats were exposed to repeated restraint to determine how changes in serotonin (5-hydroxytryptamine; 5-HT) 1A receptors associate with stress hypothalamic-pituitary-adrenal (HPA) axis habituation. METHODS: In response to 2-hour episodes of restraint, repeated daily for 5 consecutive days, males and females displayed reliable declines in HPA output, indicated by diminished adrenocorticotropin and corticosterone secretory responses. Using the 5-HT 1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) as a pharmacological challenge for inducing hypothermia and elevations in plasma corticosterone, males displayed sensitized hypothermal responses after repeated restraint, whereas corticosterone responses to 8-OH-DPAT were enhanced in both sexes following single or repeated exposure. RESULTS: Only males showed elevations in 5-HT 1A receptor G-protein coupling responses in the dorsal raphe after repeated restraint, whereas only females showed an increase in 5-HT 1A receptor responses in the hippocampus following single or repeated exposure. G-protein coupling responses within both regions correlated positively with 5-HT 1A receptor binding capacity. Thus, despite expressing similar capacities for stress HPA axis habituation, males and females emerged from repeated restraint to show region-specific changes in 5-HT 1A receptor function that may be explained, at least in part, by changes in receptor availability. CONCLUSIONS: Based on the hypothermal and corticosteroid responses to 8-OH-DPAT, the present data suggest that stress habituation is met by an increase in the sensitivity of presynaptic 5-HT 1A receptors in males and by an increase in the sensitivity of a population of postsynaptic receptors in both sexes.

Digital Health Interventions for Delivery of Mental Health Care: Systematic and Comprehensive Meta-Review.

BACKGROUND: The COVID-19 pandemic has shifted mental health care delivery to digital platforms, videoconferencing, and other mobile communications. However, existing reviews of digital health interventions are narrow in scope and focus on a limited number of mental health conditions. OBJECTIVE: To address this gap, we conducted a comprehensive systematic meta-review of the literature to assess the state of digital health interventions for the treatment of mental health conditions. METHODS: We searched MEDLINE for secondary literature published between 2010 and 2021 on the use, efficacy, and appropriateness of digital health interventions for the delivery of mental health care. RESULTS: Of the 3022 records identified, 466 proceeded to full-text review and 304 met the criteria for inclusion in this study. A majority (52%) of research involved the treatment of substance use disorders, 29% focused on mood, anxiety, and traumatic stress disorders, and >5% for each remaining mental health conditions. Synchronous and asynchronous communication, computerized therapy, and cognitive training appear to be effective but require further examination in understudied mental health conditions. Similarly, virtual reality, mobile apps, social media platforms, and web-based forums are novel technologies that have the potential to improve mental health but require higher quality evidence. CONCLUSIONS: Digital health interventions offer promise in the treatment of mental health conditions. In the context of the COVID-19 pandemic, digital health interventions provide a safer alternative to face-to-face treatment. However, further research on the applications of digital interventions in understudied mental health conditions is needed. Additionally, evidence is needed on the effectiveness and appropriateness of digital health tools for patients who are marginalized and may lack access to digital health interventions.

Cellular and serotonergic correlates of habituated neuroendocrine responses in male and female rats.

Male and females appear equally capable of showing habituated hypothalamic-pituitary-adrenal (HPA) axis output responses to repeated exposures of the same challenge. Whether this reflects, within males and females, common mechanisms of decreased neuronal activity within stress responding, afferents to the paraventricular hypothalamic nucleus (PVH), the final common pathway to the HPA axis, has not been examined. Here we compared in adult male and female rats the extent to which declines in HPA axis responses to repeated restraint are met by habituated cellular (Fos) responses, in addition to changes in serotonin (5-hydroxytryptamine; 5-HT) expression and signaling, which normally stimulates the HPA axis. Thus, alterations in this component of HPA axis drive could provide an underlying basis for sex differences in adaptive responses. Males and females showed reliable declines in ACTH and corticosterone responses after 10 daily episodes of repeated restraint, recapitulated, in largest part, by similar regional patterns of Fos habituation, including within the PVH, several stress sensitive cell groups of the limbic forebrain, as well as within the raphe nucleus. Serotonin staining in the dorsal raphe and terminal profiles in the forebrain continued to reflect a higher pre-synaptic capacity for the 5-HT system in females. The sexual dimorphism encountered within the lateral septum and medial preoptic area of control animals was less distinguished in the repeat condition, however, whereas 5-HT varicosities in the PVH increased after repeated restraint only in females. Relative to their singly restrained counterparts, males displayed an increase in 5-HT 1 A receptor expression in the raphe nucleus after repeated restraint, whereas females showed a decrease in 5-HT 1 A mRNA levels in the hippocampus and in the zona incerta, representing the most proximal of cell groups expressing the 5-HT 1 A receptor in the vicinity of the PVH. In conclusion, similar regional profiles of cellular habituation in males and females suggest common CNS substrates of neuroendocrine adaptation. However, this process may be met by underlying sex differences in serotonergic control, given the respective roles for pre- and postsynaptic 5-HT 1 A receptors in mediating serotonin availability and signal transfer.

Loss of MeCP2 in adult 5-HT neurons induces 5-HT1A autoreceptors, with opposite sex-dependent anxiety and depression phenotypes.

The 5-HT1A autoreceptor mediates feedback inhibition of serotonin (5-HT) neurons, and is implicated in major depression. The human 5-HT1A gene (HTR1A) rs6295 risk allele prevents Deaf1 binding to HTR1A, resulting in increased 5-HT1A autoreceptor transcription. Since chronic stress alters HTR1A methylation and expression, we addressed whether recruitment of methyl-binding protein MeCP2 may alter Deaf1 regulation at the HTR1A locus. We show that MeCP2 enhances Deaf1 binding to its HTR1A site and co-immunoprecipitates with Deaf1 in cells and brain tissue. Chromatin immunoprecipitation assays showed Deaf1-dependent recruitment of MeCP2 to the mouse HTR1A promoter, and MeCP2 modulated human and mouse HTR1A gene transcription in a Deaf1-dependent fashion, enhancing Deaf1-induced repression at the Deaf1 site. To address the role of MeCP2 in HTR1A regulation in vivo, mice with conditional knockout of MeCP2 in adult 5-HT neurons (MeCP2 cKO) were generated. These mice exhibited increased 5-HT1A autoreceptor levels and function, consistent with MeCP2 enhancement of Deaf1 repression in 5-HT neurons. Interestingly, female MeCP2-cKO mice displayed reduced anxiety, while males showed increased anxiety and reduced depression-like behaviors. These data uncover a novel role for MeCP2 in 5-HT neurons to repress HTR1A expression and drive adult anxiety- and depression-like behaviors in a sex-specific manner.

Sex-dependent adaptive changes in serotonin-1A autoreceptor function and anxiety in Deaf1-deficient mice.

The C (-1019) G rs6295 promoter polymorphism of the serotonin-1A (5-HT1A) receptor gene is associated with major depression in several but not all studies, suggesting that compensatory mechanisms mediate resilience. The rs6295 risk allele prevents binding of the repressor Deaf1 increasing 5-HT1A receptor gene transcription, and the Deaf1-/- mouse model shows an increase in 5-HT1A autoreceptor expression. In this study, Deaf1-/- mice bred on a mixed C57BL6-BALB/c background were compared to wild-type littermates for 5-HT1A autoreceptor function and behavior in males and females. Despite a sustained increase in 5-HT1A autoreceptor binding levels, the amplitude of the 5-HT1A autoreceptor-mediated current in 5-HT neurons was unaltered in Deaf1-/- mice, suggesting compensatory changes in receptor function. Consistent with increased 5-HT1A autoreceptor function in vivo, hypothermia induced by the 5-HT1A agonist DPAT was augmented in early generation male but not female Deaf1-/- mice, but was reduced with succeeding generations. Loss of Deaf1 resulted in a mild anxiety phenotype that was sex-and test-dependent, with no change in depression-like behavior. Male Deaf1 knockout mice displayed anxiety-like behavior in the open field and light-dark tests, while female Deaf1-/- mice showed increased anxiety only in the elevated plus maze. These data show that altered 5-HT1A autoreceptor regulation in male Deaf1-/- mice can be compensated for by generational adaptation of receptor response that may help to normalize behavior. The sex dependence of Deaf1 function in mice is consistent with a greater role for 5-HT1A autoreceptors in sensitivity to depression in men.