Underlying Sex Differences Research Articles

Sex differences in the medial prefrontal cortical glutamate system

BackgroundDysregulation in the prefrontal cortex underlies a variety of psychiatric illnesses, including substance use disorder, depression, and anxiety. Despite the established sex differences in prevalence and presentation of these illnesses, the neural mechanisms driving these differences are largely unexplored. Here, we investigate potential sex differences in glutamatergic transmission within the medial prefrontal cortex (mPFC). The goal of these experiments was to determine if there are baseline sex differences in transmission within this region that may underlie sex differences in diseases that involve dysregulation in the prefrontal cortex.MethodsAdult male and female C57Bl/6J mice were used for all experiments. Mice were killed and bilateral tissue samples were taken from the medial prefrontal cortex for western blotting. Both synaptosomal and total GluA1 and GluA2 levels were measured. In a second set of experiments, mice were killed and ex vivo slice electrophysiology was performed on prepared tissue from the medial prefrontal cortex. Spontaneous excitatory postsynaptic currents and rectification indices were measured.ResultsFemales exhibit higher levels of synaptosomal GluA1 and GluA2 in the mPFC compared to males. Despite similar trends, no statistically significant differences are seen in total levels of GluA1 and GluA2. Females also exhibit both a higher amplitude and higher frequency of spontaneous excitatory postsynaptic currents and greater inward rectification in the mPFC compared to males.ConclusionsOverall, we conclude that there are sex differences in glutamatergic transmission in the mPFC. Our data suggest that females have higher levels of glutamatergic transmission in this region. This provides evidence that the development of sex-specific pharmacotherapies for various psychiatric diseases is important to create more effective treatments.

Sex-specific alterations in corticotropin-releasing factor regulation of coerulear-cortical network activity

The locus coeruleus (LC)-norepinephrine system is a stress responsive system that regulates arousal and cognitive functions through extensive projections, including to the prefrontal cortex. LC-cortical circuits are activated by stressors, and this activation is thought to contribute to stress-induced impairments in executive function. Because corticotropin-releasing factor (CRF) is a mediator of stress-induced LC activation, we examined the effects of CRF administered into the LC of male and female rats on network activity of two functionally distinct regions of the PFC, the medial PFC (mPFC) and the orbitofrontal cortex (OFC). Network activity, measured as local field potentials, was recorded in awake animals before and after intra-LC infusion of aCSF or CRF (2 or 20 ng). CRF had qualitatively distinct effects on network activity in males and females with respect to dose, region and timecourse. CRF (20 ng) produced a prominent theta oscillation (7–9 Hz) selectively in female rats shortly after LC infusion and 20 min later. In contrast, in male rats, CRF (2 and 20 ng) decreased the amplitude of power in the 4–6 Hz range in the mPFC 10 min after injection. Lastly, CRF (20 ng) increased mPFC-OFC coherence in females and decreased mPFC-OFC coherence in males. In sum, these results show sex differences in CRF modulation of the LC-norepinephrine system that regulates prefrontal cortical networks, which may underlie sex differences in cognitive and behavioral responses to stress.

Estrogen-mediated mechanisms in hypertension and other cardiovascular diseases.

Cardiovascular disease (CVD) is the leading cause of death globally for men and women. Premenopausal women have a lower incidence of hypertension and other cardiovascular events than men of the same age, but diminished sex differences after menopause implicates 17-beta-estradiol (E2) as a protective agent. The cardioprotective effects of E2 are mediated by nuclear estrogen receptors (ERα and ERβ) and a G protein-coupled estrogen receptor (GPER). This review summarizes both established as well as emerging estrogen-mediated mechanisms that underlie sex differences in the vasculature during hypertension and CVD. In addition, remaining knowledge gaps inherent in the association of sex differences and E2 are identified, which may guide future clinical trials and experimental studies in this field.

Sex, lean body mass, and cardiac performance.

Lower lean body mass associated with reduced cardiovascular reserve at rest and peak exercise in women but not men may underlie sex differences in heart failure with preserved ejection fraction (Diaz-Canestro etal.).

In-depth investigations of the molecular basis underlying sex differences among middle-aged and elderly schizophrenia populations.

Sex can influence almost all aspects of schizophrenia. However, the molecular mechanisms underlying sex differences in schizophrenia remain poorly understood. In this project, the dataset GSE107638 containing neuronal RNA-seq data and age/sex information of individuals with or without schizophrenia were retrieved. Schizophrenia samples were divided into young male (M-1), young female (F-1), middle-aged and elderly male (M-2) and middle-aged and elderly female (F-2) groups. Next, green/yellow/turquoise modules related to the M-2 trait and turquoise module correlated with the F-2 trait were identified by weighted correlation network analysis (WGCNA) analysis (soft thresholding power: 13; min module size: 200). Crucial genes in the M-2 green, M-2 turquoise and F-2 turquoise modules were identified by WGCNA, gene significance/module membership, and protein-protein interaction (PPI) analysis. Moreover, 2067 and 934 differentially expressed genes (|log2 fold-change| ≥0.58 and P-value < 0.05) in M-2 and F-2 schizophrenia subgroups versus same-age and same-sex counterparts were identified, respectively. Additionally, 82 core genes in the M-2 turquoise module and 4 hub genes in the F-2 turquoise module were differentially expressed in M-2 and F-2 schizophrenia subgroups versus their counterparts, respectively. Among the 82 hub genes, 15 genes were found to be correlated with neuronal development by the Kyoto Encyclopedia of Genes and Genomes enrichment analysis. Also, 2 potential PPI networks related to neuronal development were identified. Taken together, multiple potential hub genes and 2 potential neurobiological networks related to schizophrenia sex differences and disease progression were identified among middle-aged and elderly schizophrenia populations.

Emotion processing differences mediate the link between sex and autistic traits in young adulthood.

The male preponderance in autism diagnoses is widely reported, yet the psychological mechanisms (e.g., emotion processing) underlying this sex difference are poorly understood. Contributing to this gap in knowledge, most research has not been designed to investigate the intermediary (i.e., mediating) role of psychological processes in the relationship between sex and autism. Compounding this issue, concerns that autism measures are not reliably measuring the same constructs in males and females, and bias against females in clinical samples, make it difficult to investigate the psychological mechanisms underlying sex differences in autism. Over two cross-sectional studies, 1656 young adults from the general population reported their sex (as assigned at birth) and completed questionnaires indexing their emotion processing differences, as well as a measure of autistic traits suggested to tap into the same psychometric construct in males and females. Emotion processing differences mediated the relationship between sex and autistic traits, whereby being male was associated with more emotion processing differences, which were subsequently linked with greater levels of autistic traits. There remained a direct effect of sex on autistic traits after accounting for emotion processing differences. Emotion processing differences are a potential psychological mechanism underpinning higher prevalence of autism in males, which may serve a compensatory function in females; for example, females may seek out emotion-inducing experiences to help compensate for social-emotional difficulties. These findings inform our understanding of autism-related sex differences and have potential implications for clinical practice, where the need for sex-specific support and diagnostic processes is increasingly being recognised.

Glycogen phosphorylase isoform regulation of glucose and energy sensor expression in male versus female rat hypothalamic astrocyte primary cultures

Astrocyte glycogen constitutes the primary energy fuel reserve in the brain. Current research investigated the novel premise that glycogen turnover governs astrocyte responsiveness to critical metabolic and neurotransmitter (norepinephrine) regulatory signals in a sex-dimorphic manner. Here, rat hypothalamic astrocyte glycogen phosphorylase (GP) gene expression was silenced by short-interfering RNA (siRNA) to investigate how glycogen metabolism controlled by GP-brain type (GPbb) or GP-muscle type (GPmm) activity affects glucose [glucose transporter-2 (GLUT2)] and energy [5′-AMP-activated protein kinase (AMPK)] sensor and adrenergic receptor (AR) proteins in each sex. Results show that in the presence of glucose, glycogen turnover is regulated by GPbb in the male or by GPmm in the female, yet in the absence of glucose, glycogen breakdown is controlled by GPbb in each sex. GLUT2 expression is governed by GPmm-mediated glycogen breakdown in glucose-supplied astrocytes of each sex, but glycogenolysis controls glucoprivic GLUT2 up-regulation in male only. GPbb-mediated glycogen disassembly causes divergent changes in total AMPK versus phosphoAMPK profiles in male. During glucoprivation, glycogenolysis up-regulates AMPK content in male astrocytes by GPbb- and GPmm-dependent mechanisms, whereas GPbb-mediated glycogen breakdown inhibits phosphoAMPK expression in female. GPbb and GPmm activity governs alpha2-AR and beta1-AR protein levels in male, but has no effect on these profiles in the female. Outcomes provide novel evidence for sex-specific glycogen regulation of glucose- and energy-sensory protein expression in hypothalamic astrocytes, and identify GP isoforms that mediate such control in each sex. Results also show that glycogen regulation of hypothalamic astrocyte receptivity to norepinephrine is male-specific. Further studies are needed to characterize the molecular mechanisms that underlie sex differences in glycogen control of astrocyte protein expression.

X chromosome agents of sexual differentiation.

Understanding sex differences in physiology and disease requires the identification of the molecular agents that cause phenotypic sex differences. Two groups of such agents are genes located on the sex chromosomes, and gonadal hormones. The former have coherent linkage to chromosomes that form differently in the two sexes under the influence of genomic forces that are not related to reproductive function, whereas the latter have a direct or indirect relationship to reproduction. Evidence published in the past 5 years supports the identification of several agents of sexual differentiation encoded by the X chromosome in mice, including Kdm5c, Kdm6a, Ogt and Xist. These X chromosome agents have wide pleiotropic effects, potentially influencing sex differences in many different tissues, a characteristic shared with the gonadal hormones. The identification of X chromosome agents of sexual differentiation will facilitate understanding of complex intersecting gene pathways underlying sex differences in disease.

Illuminating the Mechanisms Underlying Sex Differences in Cardiovascular Disease.

Sex is a key risk factor for many types of cardiovascular disease. It is imperative to understand the mechanisms underlying sex differences to devise optimal preventive and therapeutic approaches for all individuals. Both biological sex (determined by sex chromosomes and gonadal hormones) and gender (social and cultural behaviors associated with femininity or masculinity) influence differences between men and women in disease susceptibility and pathology. Here, we focus on the application of experimental mouse models that elucidate the influence of 2 components of biological sex-sex chromosome complement (XX or XY) and gonad type (ovaries or testes). These models have revealed that in addition to well-known effects of gonadal hormones, sex chromosome complement influences cardiovascular risk factors, such as plasma cholesterol levels and adiposity, as well as the development of atherosclerosis and pulmonary hypertension. One mechanism by which sex chromosome dosage influences cardiometabolic traits is through sex-biased expression of X chromosome genes that escape X inactivation. These include chromatin-modifying enzymes that regulate gene expression throughout the genome. The identification of factors that determine sex-biased gene expression and cardiometabolic traits will expand our mechanistic understanding of cardiovascular disease processes and provide insight into sex differences that remain throughout the lifespan as gonadal hormone levels alter with age.

Regulation of sex differences in risk-based decision making by gonadal hormones: Insights from rodent models

Men and women differ in their ability to evaluate options that vary in their rewards and the risks that are associated with these outcomes. Most studies have shown that women are more risk averse than men and that gonadal hormones significantly contribute to this sex difference. Gonadal hormones can influence risk-based decision making (i.e., risk taking) by modulating the neurobiological substrates underlying this cognitive process. Indeed, estradiol, progesterone and testosterone modulate activity in the prefrontal cortex, amygdala and nucleus accumbens associated with reward and risk-related information. The use of animal models of decision making has advanced our understanding of the intersection between the behavioral, neural and hormonal mechanisms underlying sex differences in risk taking. This review will outline the current state of this literature, identify the current gaps in knowledge and suggest the neurobiological mechanisms by which hormones regulate risky decision making. Collectively, this knowledge can be used to understand the potential consequences of significant hormonal changes, whether endogenously or exogenously induced, on risk-based decision making as well as the neuroendocrinological basis of neuropsychiatric diseases that are characterized by impaired risk taking, such as substance use disorder and schizophrenia.

Sex differences in blushing and eye contact in mixed versus same-sex dyads

It is commonly assumed that women blush more strongly than men, but sex differences in blushing have been identified in only a few studies and what underlies these differences has not been explored. Hence, the aim of this study was to investigate factors that might underlie sex differences in blushing. To monitor blushing, changes in pulse amplitude in the forehead skin were measured in 40 male and 40 female participants during stressful laboratory tasks (serial subtractions and singing). A male or female experimenter interacted with participants during these tasks in a critical or friendly manner. In addition to blushing, the effect of these manipulations on gaze aversion (a nonverbal cue of embarrassment) was explored. Blushing was greater in women than men and was greater in participants tested by a male than female experimenter. However, neither the sex-composition of experimenter-participant dyads nor the interpersonal style of the experimenter modified blushing intensity, despite effects on eye contact. These findings suggest that sex-linked influences on autonomic reactivity rather than embarrassment moderate blushing during social interactions. These sex-linked influences may be important during cognitive-behavioural treatments for social anxiety associated with fear of blushing.

Sex differences in atrial electrical properties

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Swiss Heart Foundation Background Pronounced sex differences are known in the incidence and recurrence rates of atrial fibrillation (AF). In general, men carry a higher risk for AF - particularly at younger age - during which women are protected. Purpose In this project, we aimed to investigate electrophysiological properties of the atria that may underlie sex differences in AF development in the younger population. Methods First, we assessed sex differences in P-wave morphology (duration: PWD; area: PWA, amplitude) in 12-lead ECG in healthy volunteers (men 31.3±1.6 y, n=10; women 29.8±1.6 y, n=10) and wildtype (WT) rabbits (3-6 months, males n=12, females n=15). We investigated sex differences in atrial action potential (AP) in WT rabbits of both sexes using sharp electrode recording technique (males n=5, females n=6). To elucidate underlying mechanisms, sex differences on atrial inwardly rectifying potassium current IK1 at 37°C were evaluated using whole-cell patch-clamp technique in isolated atrial rabbit cardiomyocytes; to evaluate the long-term effect of sex hormones on IK1, we incubated the isolated cardiomyocytes for 24h with 3 or 10µM of 17β-estradiol (EST) or of dihydrotestosterone (DHT). Results Analyzing ECG parameters (figure 1), we observed a prolonged PWD and an increased PWA both in healthy men (p&amp;lt;0.0001) and in male rabbits (p&amp;lt;0.0001) as compared to healthy women or female rabbits, which may theoretically be due to a slower conduction velocity or longer AP duration in males. Intracellular AP recordings (figure 2A) showed a more negative atrial resting membrane potential (RMP, males -83.07±0.3mV vs. females -74.33±2.6mV, p&amp;lt;0.05) and a prolonged atrial AP duration (APD10, 18.20±3.6ms vs. 10.06±1.9ms, p=0.06; APD50, 36.60±6.6ms vs. 20.06±1.9ms, p&amp;lt;0.05; APD90, 91.00±10.3ms vs. 74.00±4.0ms, p=0.13) in males as compared to females. As highlighted in figure 2B, male atrial cardiomoycytes had smaller IK1 current densities, which could be due to high DHT concentration; in line with these findings (figure 2C) 24h DHT incubation of atrial cardiomyocytes from females reduced IK1, mimicking the sex differences observed. Conclusions Sex impacts on atrial electrophysiology, resulting in sex differences in P-wave morphology, AP parameters and ionic current densities. Delayed (early) repolarization in males may be causatively linked to the observed changes in P-wave morphology. The reduction of IK1 observed in males may be due to testosterone, since this reduction was observed even in female cardiomyocytes when incubated with DHT.

Sex-dimorphic gene effects on survival outcomes in people with coronary artery disease

BackgroundIschemic coronary heart disease (IHD) is the leading cause of death worldwide. Genetic variation is presumed to be a major factor underlying sex differences for IHD events, including mortality. The purpose of this study was to identify sex-specific candidate genes associated with all-cause mortality among people diagnosed with coronary artery disease (CAD). MethodsWe performed a sex-stratified, exploratory genome-wide association (GWAS) screen using existing data from CAD-diagnosed males (n = 510) and females (n = 174) who reported European ancestry from the Duke Catheterization Genetics biorepository. Extant genotype data for 785,945 autosomal SNPs generated with the Human Omni1-Quad BeadChip (Illumina, CA, USA) were analyzed using an additive inheritance model. We estimated instantaneous risk of all-cause mortality by genotype groups across the 11-year follow-up using Cox multivariate regression, covarying for age and genomic ancestry. ResultsThe top GWAS hits associated with all-cause mortality among people with CAD included 8 SNPs among males and 15 among females (p = 1 × 10−6 or 10−7), adjusted for covariates. Cross-sex comparisons revealed distinct candidate genes. Biologically relevant candidates included rs9932462 (EMP2/TEKT5) and rs2835913 (KCNJ6) among males and rs7217169 (RAP1GAP2), rs8021816 (PRKD1), rs8133010 (PDE9A), and rs12145981 (LPGAT1) among females. ConclusionsWe report 20 sex-specific candidate genes having suggestive association with all-cause mortality among CAD-diagnosed subjects. Findings demonstrate proof of principle for identifying sex-associated genetic factors that may help explain differential mortality risk in people with CAD. Replication and meta-analyses in larger studies with more diverse samples will strengthen future work in this area.

Innate immune mechanisms underlying sex differences in COVID-19

Abstract COVID-19 exhibits a sex-bias with males showing signs of more severe disease and hospitalizations compared to females. The mechanisms are not clear but differential immune responses, particularly the initial innate immune response, between sexes may be playing a role. The early innate immune responses to SARS-CoV2 have not been studied because of the gap in timing between the patient getting infected, showing symptoms, and getting the treatment. The primary objective of the present study was to compare the response of DCs and monocytes from males and females to SARS-CoV2 24h after infection. To investigated this, PBMCs from healthy young individuals were stimulated in vitro with the virus. Our results indicate that DCs and monocytes from females displayed increased activation compared to males. In addition, females secreted significantly higher levels of IFN-α and IL-29 early while the secretion of IFN-α was delayed and prolonged in males. Further investigations revealed that the secretion of CXCL-10, a chemokine associated with lung complications, was higher in males than females. The PBMCs from females also displayed increased induction of CTLs. Bulk RNA-seq analysis indicates that IFN related pathways may be upregulated in females at baseline. Altogether, our results suggest that decreased activation of pDCs, mDCs and monocytes, the delayed and prolonged IFN-α secretion along with increased CXCL-10 secretion may be responsible for the severity of COVID-19 in males. The study is supported by grants R00RG2352 and R01RG3735 to AA from University of California office of the President (UCOP).

Sex hormones more than sex chromosomal complement predict sex differences in influenza vaccine-induced immunity and protection in mice

Abstract Following influenza vaccination, adult female mice have greater quantity and quality of antiviral antibodies than males, which is a correlate of protection against live influenza virus challenge. Whether sex steroid hormone concentrations, sex chromosome complement, or both underlie greater immunity and protection following vaccination has not been determined. To dissect the relative contribution of steroid hormones and chromosome complement, we used the Four Core Genotype (FCG) mouse model on a C57BL/6 background to evaluate how gonadal sex (i.e., testes or ovaries) and sex chromosome complement (i.e., XX or XY) can independently or together contribute to sex differences in influenza immunity. Adult FCG mice were vaccinated intramuscularly with inactivated mouse-adapted A/California/04/09 (ma2009 H1N1). Blood samples were collected at several time points post vaccination to measure total IgG and neutralizing antibodies. All mice were challenged intranasally with live ma2009 H1N1 drift variant virus and used to either measure lung virus replication kinetics or disease pathogenesis. Gonadal females (i.e., XXF and XYF), regardless of chromosome complement, produced greater antibody responses and had less pulmonary virus replication than gonadal males (i.e., XYM and XXM). Gonadal sex and sex chromosomal complement intersected to impact disease severity following challenge, in which among gonadal females, XX females experienced less morbidity than XY females. In contrast, there was no effect of chromosome complement among gonadal males. Our data suggests that sex steroid hormones more than sex chromosome complement underlie sex differences in influenza vaccine-induced immunity and protection. Financial support provided by NIH/OWRH/NIA U54AG062333

P6. Sex-Specific Cholinergic Regulation of Dopamine Release Mechanisms in the Nucleus Accumbens (NAc) Underlying Reward Learning

Addiction is characterized by dysfunction in reward-seeking behavior, yet male subjects have been overwhelmingly utilized even though women are the most susceptible population. The neural control of reward is dependent on tonic/phasic dopamine release mechanisms in the NAc that are heavily modulated by cholinergic interneurons (ChATs) signaling through nicotinic acetylcholine receptors (nAChRs). Biological sex impacts the prevalence and prognosis of addiction, yet the mechanisms that underlie sex differences in reward learning are largely unknown.

Developmental sex differences in the peri-pubertal pattern of hypothalamic reproductive gene expression, including Kiss1 and Tac2, may contribute to sex differences in puberty onset

The mechanisms regulating puberty still remain elusive, as do the underlying causes for sex differences in puberty onset (girls before boys) and pubertal disorders. Neuroendocrine puberty onset is signified by increased pulsatile GnRH secretion, yet how and when various upstream reproductive neural circuits change developmentally to govern this process is poorly understood. We previously reported day-by-day peri-pubertal increases (Kiss1, Tac2) or decreases (Rfrp) in hypothalamic gene expression of female mice, with several brain mRNA changes preceding external pubertal markers. However, similar pubertal measures in males were not previously reported. Here, to identify possible neural sex differences underlying sex differences in puberty onset, we analyzed peri-pubertal males and directly compared them with female littermates. Kiss1 expression in male mice increased over the peri-pubertal period in both the AVPV and ARC nuclei but with lower levels than in females at several ages. Likewise, Tac2 expression in the male ARC increased between juvenile and older peri-pubertal stages but with levels lower than females at most ages. By contrast, both DMN Rfrp expressionand Rfrp neuronal activation strongly decreased in males between juvenile and peri-pubertal stages, but with similar levels as females. Neither ARC KNDy neuronal activation nor Kiss1r expression in GnRH neurons differed between males and females or changed with age. These findings delineate several peri-pubertal changes in neural populations in developing males, with notable sex differences in kisspeptin and NKB neuron developmental patterns. Whether these peri-pubertal hypothalamic sex differences underlie sex differences in puberty onset deserves future investigation.

Estradiol-dependent and independent effects of FGF21 in obese female mice.

The f ibroblast growth factor 21 (FGF21) synthesized in the liver, acting as a hormone, increases insulin sensitivity and energy expenditure. FGF21 administration has potent benef icial effects on obesity and diabetes in humans, cynomolgus monkey, and rodents. The therapeutic effects of FGF21 have been studied mainly in males. They are not always manifested in females, and they are accompanied by sex-specif ic activation of gene expression in tissues. We have suggested that one of the causes of sexual dimorphism in response to FGF21 is the effect of estradiol (E2). Currently, it is not known how estradiol modif ies the pharmacological effects of FGF21. The objec tive of this study was to study the inf luence of FGF21 on metabolic characteristics, food intake, and the expression of carbohydrate and fat metabolism genes in the liver, adipose tissue, and hypothalamus in female mice with alimentary obesity and low (ovariectomy) or high (ovariectomy + E2) blood estradiol level. In ovariectomized (OVX) females, the development of obesity was induced by the consumption of a high sweet-fat diet (standard chow, lard, and cookies) for 8 weeks. We investigated the effects of FGF21 on body weight, blood levels, food preferences and gene expression in tissues when FGF21 was administered separately or in combination with E2 for 13 days. In OVX obese females, FGF21, regardless of E2-treatment, did not affect body weight, and adipose tissue weight, or glucose tolerance but increased the consumption of standard chow, reduced blood glucose levels, and suppressed its own expression in the liver (Fgf21), as well as the expression of the G6pc and Acacα genes. This study is the f irst to show the modif ication of FGF21 effects by estradiol: inhibition of FGF21-inf luence on the expression of Irs2 and Pklr in the liver and potentiation of the FGF21-stimulated expression of Lepr and Klb in the hypothalamus. In addition, when administered together with estradiol, FGF21 exerted an inhibitory effect on the expression of Cpt1α in subcutaneous white adipose tissue (scWAT), whereas no stimulating FGF21 effects on the expression of Insr and Acacβ in scWAT or inhibitory FGF21 effect on the plasma insulin level were observed. The results suggest that the absence of FGF21 effects on body and adipose tissue weights in OVX obese females and its benef icial effect on food intake and blood glucose levels are not associated with the action of estradiol. However, estradiol affects the transcriptional effects of FGF21 in the liver, white adipose tissue, and hypothalamus, which may underlie sex differences in the FGF21 effect on the expression of metabolic genes and, possibly, in pharmacological FGF21 effects

Sub-chronic stress induces similar behavioral effects in male and female mice despite sex-specific molecular adaptations in the nucleus accumbens

Women are more likely than men to suffer from major depression and anxiety disorders, a fact that is thought to depend in part on sex differences in stress susceptibility. Consistent with this, several preclinical stress paradigms have been reported to exert differential effects in males vs. females. For example, several studies have reported that female rodents are susceptible to a subset of depression- and anxiety-like behaviors induced by six days of stress exposure while males remain largely resilient. The current study sought to evaluate the generalizability of this increased vulnerability of female mice to sub-chronic stressors by examining potential sex differences in response to a new five-day stress paradigm. In addition to measuring behavior, the current work also evaluated the effects of stress on the expression of several genes in the nucleus accumbens that have been suggested to underlie sex differences in behavioral responses to sub-chronic stress. The current results indicate that males and females exhibit mostly similar behavioral alterations after exposure to this new stress model, but several sex-specific molecular alterations were observed in the nucleus accumbens following stress. Overall, our data indicate that females do not exhibit a general increase in susceptibility to ‘depression-’ and ‘anxiety-like’ behaviors induced by sub-chronic stressors, and they could reflect an example of sexual convergence in which similar behavioral alterations occur in males and females despite sex-specific molecular changes.

Sex-specific role for serotonin 5-HT2A receptor in modulation of opioid-induced antinociception and reward in mice

Opioids are among the most effective analgesics and the mainstay of pain management. However, concerns about safety and abuse liability have challenged their widespread use by the medical community. Opioid-sparing therapies include drugs that in combination with opioids have the ability to enhance analgesia while decreasing opioid requirement as well as their side effects. Sex differences in antinociceptive responses to opioids have received increasing attention in recent years. However, the molecular mechanisms underlying sex differences related to opioid-sparing adjuncts remain largely unexplored. Using warm water tail-withdrawal as a mouse model of acute thermal nociception, our data suggest that adjunctive administration of the serotonin 5-HT2A receptor (5-HT2AR) antagonist volinanserin dose-dependently enhanced potency of the opioid analgesic oxycodone in male, but not female, mice. This antinociceptive-like response induced by oxycodone was also augmented in 5-HT2AR knockout (5-HT2AR−/−) male, but not female mice; an effect that was reversed by Cre-loxP-mediated selective expression of 5-HT2AR in dorsal root ganglion (DRG) neurons of 5-HT2AR−/− littermates. Pharmacological inhibition with volinanserin or genetic deletion in 5-HT2AR−/− animals potentiated the ability of oxycodone to reduce DRG excitability in male mice. Adjunctive volinanserin did not affect oxycodone-induced conditioned place preference (CPP), whereas it reduced oxycodone-induced locomotor sensitization in male and female mice. Together, these results suggest that adjunctive volinanserin augments opioid-induced antinociception, but not abuse-related behavior, through a sex-specific signaling crosstalk mechanism that requires 5-HT2AR expression in mouse DRG neurons. Ultimately, our results may pave the way for the clinical evaluation of volinanserin as a potential sex-specific opioid adjuvant.