Sex Differences In Response Research Articles

Sex differences regulate immune responses in experimental autoimmune encephalomyelitis and multiple sclerosis.

MS is an autoimmune disease of the CNS that afflicts over 2.5 million people worldwide. There are striking sex differences in the susceptibility to and progression of this disease in humans. Females are twice as likely to develop MS than males, whereas disease progression and disability is more rapid in males compared with females; however, the latter is still controversial. There is growing evidence, mainly from animal models, that innate and adaptive immune responses are different in males and females, and that this can influence the outcome of a range of diseases including infection, cancer, and autoimmunity. Since MS is an immune-mediated disease, sex differences in pathogenic immune responses may account for some of the differences in susceptibility to and progression seen in men versus women. Indeed, data from the mouse model of MS, EAE, have already provided some evidence that female mice have earlier disease onset associated with stronger Th17 responses. This review will discuss the possible immunological basis of sex differences in susceptibility and disease outcome in EAE and MS and how a better understanding of sex differences in the responses to disease-modifying therapies may lead to improved patient treatment.

Sex differences in the expression of the endocannabinoid system within V1M cortex and PAG of Sprague Dawley rats

BackgroundSeveral chronic pain disorders, such as migraine and fibromyalgia, have an increased prevalence in the female population. The underlying mechanisms of this sex-biased prevalence have yet to be thoroughly documented, but could be related to endogenous differences in neuromodulators in pain networks, including the endocannabinoid system. The cellular endocannabinoid system comprises the endogenous lipid signals 2-AG (2-arachidonoylglycerol) and AEA (anandamide); the enzymes that synthesize and degrade them; and the cannabinoid receptors. The relative prevalence of different components of the endocannabinoid system in specific brain regions may alter responses to endogenous and exogenous ligands.MethodsBrain tissue from naïve male and estrous staged female Sprague Dawley rats was harvested from V1M cortex, periaqueductal gray, trigeminal nerve, and trigeminal nucleus caudalis. Tissue was analyzed for relative levels of endocannabinoid enzymes, ligands, and receptors via mass spectrometry, unlabeled quantitative proteomic analysis, and immunohistochemistry.ResultsMass spectrometry revealed significant differences in 2-AG and AEA concentrations between males and females, as well as between female estrous cycle stages. Specifically, 2-AG concentration was lower within female PAG as compared to male PAG (*p = 0.0077); female 2-AG concentration within the PAG did not demonstrate estrous stage dependence. Immunohistochemistry followed by proteomics confirmed the prevalence of 2-AG-endocannabinoid system enzymes in the female PAG.ConclusionsOur results suggest that sex differences exist in the endocannabinoid system in two CNS regions relevant to cortical spreading depression (V1M cortex) and descending modulatory networks in pain/anxiety (PAG). These basal differences in endogenous endocannabinoid mechanisms may facilitate the development of chronic pain conditions and may also underlie sex differences in response to therapeutic intervention.

Disease activity in women with ankylosing spondylitis remains higher under Tumour Necrosis Factor inhibitor treatment than in men: a five-year observational study

Objective To assess sex differences in response, level of disease activity, and drug survival in tumour necrosis factor inhibitor (TNFi)-naïve ankylosing spondylitis (AS) patients. Method Consecutive AS patients, fulfilling the modified New York criteria, were included in a prospective cohort study at initiation of the first TNFi and followed until this medication was stopped (drug survival). Disease activity scores [AS Disease Activity Score using C-reactive protein (ASDAS-CRP), Bath AS Disease Activity Index (BASDAI), and CRP] were measured at 3, 6, and 12 months, and every subsequent year, up to 5 years. The response was defined by the ASDAS-CRP response criteria (clinically important improvement: ASDAS-CRP decrease ≥ 1.1). Analyses included regression methods for repeated measurements and survival analyses. Results Overall, 356 patients were included (34% women, mean ± sd age 46 ± 12 years), with a median disease duration of 12 (interquartile range 6;20) years. Women were less likely than men to achieve a clinically important response after 6 months of TNFi treatment (47% vs 64%; relative risk 1.4, 95% confidence interval (CI) 1.1;1.9, p = 0.02], despite a lack of sex differences in mean ASDAS-CRP levels over 5 year follow-up. Adjusted models for BASDAI over 5 years showed that women had a 0.6 point higher BASDAI score than men (β = 0.6 0.1;1.1 <0.02). Numerically, more women than men discontinued treatment over a period of 5 years (hazard ratio = 1.5, 95% CI 0.9;2.5, p = 0.15). Conclusion Female AS patients show a lower response to TNFi and a higher disease activity compared to men.

Sex Differences in Response to Deception Across Mate-Value Traits of Attractiveness, Job Status, and Altruism in Online Dating.

Sex differences in mate preferences are well established. It is also well understood that humans often seek to manipulate their standing on important mate-value traits. Yet, there is a paucity of work examining potential sex differences in response to deception along these important dimensions. In Study 1, a sample of 280 undergraduates (123 females) responded to a hypothetical online dating scenario asking participants to rank how upset they would be if deceived about a date's attractiveness, occupation, or volunteerism. Women ranked occupation deception as more upsetting than men did, and men ranked attractiveness deception as more upsetting than women did. Given potential measurement differences between forced-choice and continuous response options, Study 2 randomly assigned 364 undergraduates (188 females) to one of the deceptions conditions and asked them to report their level of upset and willingness to go on the date using a continuous response scale. Women were more likely than men to cancel the date if the deception involved volunteerism or occupation. There was no significant sex difference in the attractiveness condition. Neither mate value nor sociosexuality moderated the sex difference in the levels of upset due to the deception. Together, these findings demonstrate that women and men exhibit differences in the degree to which they become upset by opposite sex deceptions in online dating, regardless of self-perceived mate value and sociosexuality, in alignment with evolved sex differences in mate preferences.

Abstract P254: Sex Differences In Angiotensin Ii-induced Hypertension In Mice With Proximal Tubule-specific Deletion Of Mitochondrial Protein Sirtuin 3 In The Kidney

The development of Angiotensin II (Ang II)-induced hypertension is associated with mitochondrial dysfunction and kidney injury. Sirtuin 3 (SIRT3), a key mitochondrial protein, plays an important role in maintaining mitochondrial homeostasis. However, it remains unknown whether deletion of SIRT3 in the proximal tubules will alter the pressor and renal responses to Ang II in sex-different manners. In the present study, adult male, and female wild-type (WT) and mutant mice with proximal tubule-specific knockout of SIRT3, PT- Sirt3 -/- , were infused with or without a slow pressor dose of Ang II via an osmotic minipump (0.5 mg/kg/day, i.p.), supplemented with a 2% NaCI diet or losartan, 20 mg/kg/day, for 2 weeks. Systolic (SBP), diastolic (DBP), and mean arterial blood (MAP) pressure were determined using the tail-cuff method, whereas 24 hr. urinary sodium and potassium excretion were determined using a metabolic cage. Serum and urine creatinine were measured using colorimetric assays, whereas glomerular and tubulointerstitial injury was evaluated by Masson’s Trichrome staining. Basal SBP levels were lower in PT- Sirt3 -/- than in WT mice (SBP-WT: 112 ± 2 vs. SBP-PT- Sirt3 -/- : 93 ± 2 mmHg, P &lt;0,01). The magnitude of Ang II-induced hypertension was similar between WT and PT- Sirt3 -/- mice with or without losartan treatment. Serum creatinine levels and urinary creatinine excretion were higher in PT- Sirt3 -/- mice than in WT mice ( P &lt;0.05), but without significant sex differences in response to Ang II infusion or losartan treatment. Differences were found only in female WT and PT- Sirt3 -/- mice with lower 24 hr. urine and urinary creatinine excretion in response to Ang II infusion or losartan. Losartan significantly increased 24 hr. urinary potassium and chloride excretion in Ang II-infused male and female PT- Sirt3 -/- mice ( P &lt;0.01). Finally, Ang II-infused PT- Sirt3 -/- mice showed significant renal cortical tubulointerstitial fibrotic responses ( P &lt;0.05), but not glomerular fibrotic responses. We conclude that basal blood pressure is lower in male and female PT- Sirt3 -/- mice and that Ang II induces similar hypertensive and renal fibrotic responses in male and female PT- Sirt3 -/- mice without significant sex differences.

The Effect of Fatigue on Single-Leg Postural Sway and Its Transient Characteristics in Healthy Young Adults.

Neuromuscular fatigue is known to impair balance ability, which is reflected in increased postural sway during quiet standing tasks. Recently, quantifying transient characteristics of postural sway has been suggested as an approach to obtain additional information regarding postural control. However, this approach is currently vastly unexplored. The purpose of this study was to investigate the effects of fatigue (induced by a repeated change of direction task) on postural sway and its transient characteristics during single-leg standing, including whole-trial estimates and indexes of transient behavior in young healthy active adults. The study involved 28 physically active students (14 females). Single-leg postural sway was recorded for 30s before and after a fatiguing protocol, which consisted of a repeated change of direction tasks. We calculated the traditional whole-trial estimates of postural sway [center-of-pressure (CoP) velocity and amplitude in anterior-posterior (AP) and medial-lateral (ML) directions] and corresponding transient behavior indexes, based on three 10-s intervals. Statistically significant sex×fatigue interaction with medium effect sizes was found for whole-trial CoP velocity in AP (p=0.028; η2=0.17) and ML directions (p=0.019; η2=0.19). Post-hoc test showed that both variables substantially decreased in female participants (p=0.041–0.045; d=0.54–0.56), but remained similar in males (p=0.194–0.294). There were small to medium statistically significant main effects of fatigue on transient index for CoP amplitude in both directions (p=0.042–0.049; η2=0.02–0.14). Notably, CoP AP amplitude increased in the first 10-s interval for males (before fatigue: 5.6±1.3mm; after fatigue: 6.3±1.6mm), while the CoP AP amplitude in the third interval remained similar after fatigue (before fatigue: 5.5±1.4mm; after fatigue: 5.1±1.2mm). In conclusion, the responses to fatigue in terms of postural sway were time interval specific, and there were certain sex-differences in responses to fatigue, which could be related to better ability to adapt balance strategies in females. Moreover, our results demonstrate that the indexes of transient behavior could perhaps detect smaller fatigue-induced changes in postural sway that are seen in whole-trial estimates.

Neuroimmune mechanisms of cognitive impairment in a mouse model of Gulf War illness

Gulf War Illness (GWI) is a chronic, multi-symptom disorder affecting approximately 30 percent of the nearly 700,000 Veterans of the 1991 Persian Gulf War. GWI-related chemical (GWIC) exposure promotes immune activation that correlates with cognitive impairment and other symptoms of GWI. However, the molecular mechanisms and signaling pathways linking GWIC to inflammation and neurological symptoms remain unclear. Here we show that acute exposure of murine macrophages to GWIC potentiates innate immune signaling and inflammatory cytokine production. Using an established mouse model of GWI, we report that neurobehavioral changes and neuroinflammation are attenuated in mice lacking the cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) and NOD-, LRR- or pyrin domain-containing protein 3 (NLRP3) innate immune pathways. In addition, we report sex differences in response to GWIC, with female mice showing more pronounced cognitive impairment and hippocampal astrocyte hypertrophy. In contrast, male mice display a GWIC-dependent upregulation of proinflammatory cytokines in the plasma that is not present in female mice. Our results indicate that STING and NLRP3 are key mediators of the cognitive impairment and inflammation observed in GWI and provide important new information on sex differences in this model.

Sex Differences in Respiratory Viral Pathogenesis and Treatments.

Biological sex affects the outcome of diverse respiratory viral infections. The pathogenesis of respiratory infections caused by viruses ranging from respiratory syncytial virus to influenza viruses and severe acute respiratory syndrome coronavirus 2 differs between the sexes across the life course. Generally, males are more susceptible to severe outcomes from respiratory viral infections at younger and older ages. During reproductive years (i.e., after puberty and prior to menopause), females are often at greater risk than males for severe outcomes. Pregnancy and biological sex affect the pathogenesis of respiratory viral infections. In addition to sex differences in the pathogenesis of disease, there are consistent sex differences in responses to treatments, with females often developing greater immune responses but experiencing more adverse reactions than males. Animal models provide mechanistic insights into the causes of sex differences in respiratory virus pathogenesis and treatment outcomes, where available.

Protective Effects of Eicosapentaenoic Acid on Adiposity and Amyloidogenic Features in the APPswePS1dE9 Alzheimer’s Mouse Model

ObjectivesAlzheimer’s disease (AD) is a degenerative brain disease characterized by atypical development of amyloid-beta (Aβ) plaques. We previously showed that eicosapentaenoic acid (EPA), found in fish oil exerted anti-obesity and anti-inflammatory effects in diet-induced obese (DIO) mice. Here we hypothesize that EPA will reduce both adiposity and neuroinflammation in an amyloidogenic Alzheimer’s DIO mouse model. MethodsTwo-month-old male and female APPswePS1E9 transgenic (TG) and non-TG littermates were randomly assigned to low fat (LF; 10% kcal fat), high fat (HF; 45% kcal fat), or HF supplemented with EPA (36 g/kg EPA) diets for eight months. Body weights were recorded weekly, blood and tissues were harvested at termination. Serum amyloid Aβ-40 (AD marker), leptin, adiponectin, and resistin (adiposity markers) levels were quantified by Multiplex assays (n = 6–7/group). Outcomes were analyzed in three-way ANOVA, modeling genotype interactions, sex, and diet, using GraphPad (Version 9.0.1). ResultsOn average, TG mice had higher Aβ-40 in serum (p < 0.05) compared to non-TG mice in both males and females; Aβ-40 concentration did not differ by sex. However, serum leptin and resistin were higher in males vs. females (p < 0.001). Adiponectin did not differ by sex (P = 0.1897) and no adipokine differed by genotype. Interestingly, in TG males, compared to HF, EPA decreased serum Aβ-40, leptin, and resistin (P = 0.0182, P = 0.0086, P = 0.0051 respectively). Moreover, in non-TG male mice, EPA increased serum adiponectin compared to HF (P = 0.0342) and no other interactions were significant. ConclusionsEPA reduced adiposity, resistin, and serum Aβ-40 in HF-fed TG male mice. Additional analyses in the brain and adipose tissues from these mice are ongoing. These findings warrant future studies in humans to determine whether consumption of high doses of fish oil, known to reduce hypertriglyceridemia, may benefit patients with AD and whether there are sex differences in response to fish oil. Funding SourcesNIH (NCCIH and NIA) grant #R15AT008879–01A1.

Remote Hemodynamic Monitoring Equally Reduces Heart Failure Hospitalizations in Women and Men in Clinical Practice: A Sex-Specific Analysis of the CardioMEMS Post-Approval Study.

Response to pharmacological and device-based therapy for heart failure (HF) may vary by sex. We examined sex differences in response to ambulatory hemodynamic monitoring in clinical practice using the CardioMEMS PAS (Post-Approval Study). The CardioMEMS PAS was a prospective, single-arm, multicenter, open-label study of 1200 adults with New York Heart Association class III HF and at least 1 HF hospitalization (HFH) within 12 months who underwent pulmonary artery pressure sensor implantation between 2014 and 2017. Changes in pulmonary artery pressure over time were stratified by ejection fraction <40% and sex. Clinical outcomes including HFH rate at 12 months, 1-year mortality, and quality of life were examined in women and men. Four hundred fifty-two women (38% of total) enrolled in the PAS were less likely to be White (78% versus 86%) and more likely to have nonischemic cardiomyopathy (44% versus 34%) and had significantly higher SBP (132 versus 124 mm Hg), mean ejection fraction (44% versus 36%), and pulmonary vascular resistance (3.2 versus 2.6 WU) than men (P<0.001 for all). There were similar reductions in pulmonary artery pressure from baseline to 12 months in both men and women for the whole cohort and for subgroups with HF with reduced ejection fraction and HF with preserved ejection fraction. Both sexes experienced significant decreases in HFH over 12 months (men: HR, 0.46 [95% CI, 0.40-0.52]; women: HR, 0.39 [95% CI, 0.33-0.46]). In adjusted models, there were no significant differences in change in HFH between men and women (interaction P=0.13) or all-cause mortality at 1 year (adjusted HR, 1.25 [95% CI, 0.88-1.77]). Women and men enrolled in the CardioMEMS PAS had similar reductions from baseline in pulmonary artery pressure over 1 year and experienced similar reductions in HFH. Hemodynamic monitoring provides similar benefit with regard to HF events in both women and men. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02279888.

Effects of the glucocorticoid receptor antagonist PT150 on stress-induced fentanyl seeking in male and female rats.

Opioid use disorder (OUD) is highly comorbid with stress-related disorders, and stress can serve as a trigger for reinstatement of drug seeking. Glucocorticoid receptor (GR) antagonists such as mifepristone (RU-486) may be effective against stress-induced drug seeking. In the current study, PT150 (formerly ORG-34517), a more selective GR antagonist, was tested using two models of stress-induced drug seeking, namely footshock and yohimbine. Adult male and female Sprague-Dawley rats were trained to self-administer fentanyl (2.5 μg/kg/infusion, i.v.) in a model of escalation. Rats then received 7 days of abstinence, followed by extinction; PT150 (0, 50 or 100 mg/kg in Nutella®; p.o.) treatment started on the first day of extinction training and continued daily until the end of the study. Following 14 days of extinction, rats were tested for reinstatement following footshock and yohimbine (0, 1, or 2 mg/kg; i.p.), tested in counterbalanced order; PT150 or placebo treatment occurred prior to each extinction and reinstatement session. Prior to initiation of PT150 treatment, females self-administered greater levels of fentanyl during 1-h sessions compared to males; however, when switched to 6-h sessions, males and females self-administered similar levels of fentanyl and showed a similar escalation of intake over time. PT150 had no effect on extinction of self-administration. While both footshock and yohimbine reinstated fentanyl seeking, only footshock-induced reinstatement was decreased by PT150 (50 and 100 mg/kg). The effect of PT150 on footshock-induced reinstatement was driven primarily by males. The glucocorticoid antagonist PT150 reduces shock-induced fentanyl seeking, suggesting it may be effective against stress-induced relapse, although the sex difference in response may need further exploration.

The Role of Superoxide in Sex Differences in Angiotensin II‐induced Hypertensive and Natriuretic Responses in Mice with Proximal Tubule‐Specific Deletion of Mitochondrial Protein Sirtuin 3 in The Kidney

Sirtuin 3 (SIRT3), aNAD-dependent deacetylase, is a major mitochondrial protein in the matrix that is encoded by the SIRT3 gene. The key functions of SIRT3 in the mitochondria include anti-oxidative, anti-aging, anti-inflammation, and blood pressure-regulating effects by decreasing reactive oxygen species/superoxide production. However, the role of SIRT3 via superoxide in the proximal tubules (PT) of the kidney in angiotensin II-induced hypertensive or natriuretic responses remains poorly understood. To test our hypothesis, five groups of adult male and female wild-type (WT) and PT-SIRT3-/- mice were treated without (Control) or with Ang II (~0.65 mg/kg/day, i.p.) treated with 2% NaCl diet or tempol, a membrane-permeable radical scavenger and superoxide dismutase-mimetic (50 mg/kg/day, p.o.) for 2 weeks. Under basal conditions, systolic (SBP), diastolic (DBP) and mean arterial pressure (MAP) were significantly lower in adult male and female PT-SIRT3-/- mice than male and female wild-type mice (~13 ± 3 mmHg, P<0.01). Although there were no sex differences in male and female WT mice, SBP and MAP were significantly lower in female than male PT-SIRT3-/- mice (P<0.01). Urinary excretion of electrolytes including sodium (Na+), potassium (K+), chloride (Cl-), and lithium (Li+) were also significantly lower in female PT-SIRT3-/- mice (P<0.01). In response to Ang II infusion and 2% high salt treatment, SBP was increased similarly to 136 ± 7 mmHg in male and 135 ± 7 mmHg in female PT-SIRT3-/- mice (P<0.01). Urinary Na+, K+, Cl-, and Li+ excretion were all significantly increased in male and female PT-SIRT3-/- mice without significant sex differences in these responses to Ang II-induced hypertension. There were also no sex differences found in response to Ang II infusion alone. Tempol treatment alone had no significant effects on blood pressure and urinary electrolyte excretory responses compared with their basal levels. Interestingly, however, tempol treatment of Ang II-infused and 2% NaCl-fed male and female PT-SIRT3-/- mice revealed significant sex differences in these responses (P<0.01). SBP and MAP increased further in male (P<0.01), but not in female PT-SIRT3-/- mice (n.s.), whereas the natriuretic response was significantly greater in female PT-SIRT3-/- mice (P<0.01). Taken together, we concluded that SIRT3 in the mitochondria of the proximal tubules plays an important role in the development of ANG II-dependent hypertension, and that superoxide may be implicated in sex differences in Ang II-induced hypertensive and natriuretic responses in PT-SIRT3-/- mice.

Examining Sex Differences in Response to NMDAR Antagonist MK‐801 on Sleep Architecture and Brain Function Using Electroencephalography in Rats

Accumulating evidence suggests glutamatergic hypofunction is one underlying factor in the pathology of schizophrenia. Administration of N-methyl-D-aspartate receptor (NMDAR) antagonists induces psychotomimetic-like symptoms in healthy humans and has emerged as a pharmacological model for symptoms of schizophrenia in animals. MK-801, an NMDAR antagonist, is frequently used to disrupt cognition and induce hyperlocomotion, modelling the cognitive and positive symptoms of schizophrenia, respectively. However, despite significant contributions of these models to surrounding literature, there are vast sex differences in the symptomology of schizophrenia in the human population that are underrepresented in animal models. Evidence suggests that prevalence and severity of negative and cognitive symptoms may be greater in males relative to females. Furthermore, sleep disturbances are underappreciated symptoms of schizophrenia, and sex differences in these have also been reported. Applying a translational biomarker approach that can be readily implemented in human subjects, present studies used polysomnography and quantitative electroencephalography (qEEG) measures to determine if NMDAR antagonists can reveal sex differences on sleep and brain function in animals similar to those reported in the human population. EEG surface electrodes and wireless transmitters were implanted in male and female Sprague-Dawley rats. EEG's were recorded for 24 hours in freely moving rats from their homecage. MK-801 (males: 0.056-0.56 mg/kg, sc; females: 0.03-0.3 mg/kg, sc) was administered 2 hours into the light cycle. Recordings were manually scored into wake, rapid eye movement (REM), and non-REM sleep, and qEEG spectral power was evaluated during waking epochs only. Activity counts were also simultaneously recorded. Consistent with previous literature, MK-801 induced hyperlocomotion, increased time awake, and decreased both NREM and REM sleep. Females were more sensitive than males to all of these measures, showing longer duration and magnitude of effects. Furthermore, MK-801 induced profound dose-dependent increases on both low and high gamma power in male rats. Interestingly, no comparable dose-dependent increases in gamma power were found in female rats across a full log unit dose range. Gamma power is highly sensitive to glutamate function, and abnormalities have been associated with cognitive impairment and psychotic symptoms in patients with schizophrenia. This is the first report, to our knowledge, of a blunted response to MK-801's effects in female rats compared to males despite increased sensitivity to all other reported measures. Ultimately, EEG revealed sex-related differences in NMDAR function which may correspond with prevalence/severity of symptoms of schizophrenia in humans. This may overall strengthen the validity of using NMDAR antagonism in preclinical model to experimentally induce schizophrenia-like symptoms.

Effect of Glucocorticoid Receptor Antagonism on Alcohol Self-Administration in Genetically-Selected Marchigian Sardinian Alcohol-Preferring and Non-Preferring Wistar Rats.

Alcoholism is a chronically relapsing disorder characterized by high alcohol intake and a negative emotional state during abstinence, which contributes to excessive drinking and susceptibility to relapse. Stress, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and alterations in glucocorticoid receptor (GR) function have been linked to transition from recreational consumption to alcohol use disorder (AUD). Here, we investigated the effect of pharmacological antagonisms of GR on alcohol self-administration (SA) using male and female Wistar and Marchigian Sardinian alcohol-preferring (msP) rats, a rodent line genetically selected for excessive alcohol drinking and highly sensitive to stress. Animals were trained to self-administer 10% (v/v) alcohol. Once a stable alcohol SA baseline was reached, we tested the effect of the GR antagonists mifepristone (0.0, 10, 30 and 60 mg/kg; i.p.) and CORT113176 (0.0, 10, 30 and 60 mg/kg) on alcohol SA. To evaluate whether the effects of the two compounds were specific for alcohol, the two drugs were tested on a similar saccharin SA regimen. Finally, basal blood corticosterone (CORT) levels before and after alcohol SA were determined. Systemic injection with mifepristone dose-dependently reduced alcohol SA in male and female Wistars but not in msPs. Administration of CORT113176 decreased alcohol SA in male and female Wistars as well as in female msPs but not in male msP rats. At the highest dose, mifepristone also reduced saccharin SA in male Wistars and female msPs, suggesting the occurrence of some nonspecific effects at 60 mg/kg of the drug. Similarly, the highest dose of CORT113176 (60 mg/kg) decreased saccharin intake in male Wistars. Analysis of CORT levels revealed that females of both rat lines had higher blood levels of CORT compared to males. Alcohol consumption reduced CORT in females but not in males. Overall, these findings indicate that selective blockade of GR selectively reduces alcohol SA, and genetically selected msP rats are less sensitive to this pharmacological manipulation compared to heterogeneous Wistars. Moreover, results suggest sex differences in response to GR antagonism and the ability of alcohol to regulate GR transmission.

Sex differences in insulin resistance, but not peripheral neuropathy, in a diet-induced prediabetes mouse model.

ABSTRACTPeripheral neuropathy (PN) is a common complication of prediabetes and diabetes and is an increasing problem worldwide. Existing PN treatments rely solely on glycemic control, which is effective in type 1 but not type 2 diabetes. Sex differences in response to anti-diabetic drugs further complicate the identification of effective PN therapies. Preclinical research has been primarily carried out in males, highlighting the need for increased sex consideration in PN models. We previously reported PN sex dimorphism in obese leptin-deficient ob/ob mice. This genetic model is inherently limited, however, owing to leptin's role in metabolism. Therefore, the current study goal was to examine PN and insulin resistance in male and female C57BL6/J mice fed a high-fat diet (HFD), an established murine model of human prediabetes lacking genetic mutations. HFD mice of both sexes underwent longitudinal phenotyping and exhibited expected metabolic and PN dysfunction compared to standard diet (SD)-fed animals. Hindpaw thermal latencies to heat were shorter in HFD females versus HFD males, as well as SD females versus males. Compared to HFD males, female HFD mice exhibited delayed insulin resistance, yet still developed the same trajectory of nerve conduction deficits and intraepidermal nerve fiber density loss. Subtle differences in adipokine levels were also noted by sex and obesity status. Collectively, our results indicate that although females retain early insulin sensitivity upon HFD challenge, this does not protect them from developing the same degree of PN as their male counterparts.This article has an associated First Person interview with the first author of the paper.

Inhibition of P110α and P110δ catalytic subunits of PI3 kinase reverses impaired arterial healing after injury in hypercholesterolemic male mice.

Endothelial cell (EC) migration is critical for healing arterial injuries, such as those that occur with angioplasty. Impaired re-endothelialization following arterial injury contributes to vessel thrombogenicity, intimal hyperplasia, and restenosis. Oxidized lipid products, including lysophosphatidylcholine (lysoPC), induce canonical transient receptor potential 6 (TRPC6) externalization leading to increased [Ca2+]i, activation of calpains, and alterations of the EC cytoskeletal structure that inhibit migration. The p110α and p110δ catalytic subunit isoforms of phosphatidylinositol 3-kinase (PI3K) regulate lysoPC-induced TRPC6 externalization in vitro. The goal of this study was to assess the in vivo relevance of those in vitro findings to arterial healing following a denuding injury in hypercholesterolemic mice treated with pharmacologic inhibitors of the p110α and p110δ isoforms of PI3K and a general PI3K inhibitor. Pharmacologic inhibition of the p110α or the p110δ isoform of PI3K partially preserves healing in hypercholesterolemic male mice, similar to a general PI3K inhibitor. Interestingly, the p110α, p110δ, and the general PI3K inhibitor do not improve arterial healing after injury in hypercholesterolemic female mice. These results indicate a potential new role for isoform-specific PI3K inhibitors in male patients following arterial injury/intervention. The results also identify significant sex differences in the response to PI3K inhibition in the cardiovascular system, where female sex generally has a cardioprotective effect. This study provides a foundation to investigate the mechanism for the sex differences in response to PI3K inhibition to develop a more generally applicable treatment option.

Gender Differences in the Dynamics of Attitudes towards the Prevention of Cardiovascular Diseases in Population Aged 25-64 Years from 1988 To 2017

The aim: To determine gender differences in the dynamics of attitudes towards the cardiovascular prevention in an open population of 25-64 years over a long-term period - 29 years in Russia / Siberia (Novosibirsk).&#x0D; Methods: Within the framework of the screening in 1988-89 under the WHO MONICA-psychosocial (MOPSY) program (n=1676, 49.5% males, mean age 44.1±0.4 years), MOPSY screening in 1994-95 (n=1527, 43% males, mean age 44.85 ± 0.4 years), in 2003-2005 under the international project HAPIEE (n=1650, 34,9% males, mean age 54,25±0,2 years), in 2013-2016 (n=975, 43,8% males, mean age 34,5±0,4 years) and 2016-2017 гг.( n=663, 41,3% years 51,95±0,32 years) within the framework of the budgetary theme No. АААА-А17-117112850280-2, random representative samples of men and women in one of districts in Novosibirsk were examined. Attitude towards preventive methods and health care utilization were assessed using the questionnaire "Knowledge and attitude towards own's health".&#x0D; Results: About 100% male and female population aged of 25-64 years considered it probable "to develop a serious illness within the next 5-10 years" in 1988. This proportion has not changed significantly by 2017. In 1988, men more often than women certainly believed that they would avoid serious illness if they took action on their own health. In subsequent years of observation these sex differences in responses were erased. Belief in the power of medicine to prevent all or most of the heart disease was present among young men in 2013 and 2017. In comparison with them, women are more balanced about the preventive possibilities of medicine.&#x0D; Despite the fact that 100% of men and women in the open population 25-64 years find "preventive health screening" useful, only 6.8% of males and 3% of females were regularly checked by a doctor in 1988. In 2016-2017, the frequency of regular health checks exceeded the 10% in middle-aged groups.&#x0D; An equal proportion of men and women - 67% sought medical help only in case of chest pain, and 11-12% would not go to a doctor even with intense pain; by 2017, their share had decreased to 6.5%.&#x0D; Conclusions: Among those who consider it likely to have a serious illness, only one of ten is regularly checked by a doctor. At the same time, men are more likely than women to shift responsibility for their health to the preventive capabilities of medicine.&#x0D; Keywords: awareness, cardiovascular prevention, sex differences, population, healthcare utilization

Sex differences in response to environmental and social breeding cues in an amphibian

Abstract The relative influence of climatic and social factors on sex-specific variation in reproductive behaviour remains poorly understood. Here, we examine the influence of multiple climatic cues in combination with a social cue on the reproductive behaviours of males and females in a terrestrial breeding toadlet (Pseudophryne coriacea). Over a 115-day breeding season, arrival patterns of each sex, and male calling activity, were recorded daily, while climatic variables were logged continuously. Multivariate analysis showed that arrival of males at the breeding site, as well as male nightly calling activity, were most strongly influenced by a climatic variable (rainfall). By contrast, female arrival was strongly correlated with a social variable (male calling activity), with abiotic conditions having no influence, other than a moderate influence of lunar phase (lunar illumination). These results suggest that cues used for breeding are sex specific and provide new evidence that combinations of climatic and social cues can be integrated into breeding decisions.

The Effects of Human Milk Oligosaccharide Supplementation During Critical Periods of Development on the Mesolimbic Dopamine System

Human milk oligosaccharides (HMO)s are a key component in human milk and represent an important dietary modulator of infant gut microbiota composition and associated gut-brain axis development and homeostasis. The brain reward system, specifically the mesolimbic dopamine (DA) projections from the ventral tegmental area (VTA) to nucleus accumbens (NAc) is involved in the motivation and preference for food. The objective of the present study was to determine if HMO fortified diets given during the critical period of reward system development (p21) could affect the structure of the reward system. At weaning (p21), Sprague-Dawley rats were randomized to one of four fortified diet groups: Control, 3′sialyllactose (3′FL), 2′-fucosyllactose (2′FL), or a combination of 3′SL and 2′FL (3′SL + 2′FL). Messenger RNA (mRNA) expression was quantified for DA and appetite associated markers in the VTA and NAc and western blots measured the immediate early gene FosB and its isoform ΔFosB. Females fed the 3′SL + 2′FL fortified diet displayed a decrease in DAT expression in the VTA and an increase in leptin expression in the NAc. Females displayed an overall lower expression of NAc D2, VTA ghrelinR, and VTA leptin. In males, VTA DAT and FosB were negatively correlated with body weight and systemic leptin. Sex differences in the expression of DA markers underscore the need to investigate this phenomenon and understand the functional significance in preventing or treating obesity. This study highlights sex differences in response to HMO supplementation and the need for further investigations into the functional significance of nutritional interventions during DA system development.

Dopamine multilocus genetic profiles predict sex differences in reactivity of the human reward system.

Sex differences in the neural processing of decision-making are of high interest as they may have pronounced effects on reward- and addiction-related processes. In these, the neurotransmitter dopamine plays a central role by modulating the responsiveness of the reward circuitry. The present functional magnetic resonance imaging study aimed to explore sex and dopamine transmission interactions in decision-making. 172 subjects (111 women) performed a behavioral self-control task assessing reward-related activation during acceptance and rejection of conditioned rewards. Participants were genotyped for six key genetic polymorphisms in the dopamine system that have previously been associated with individual differences in reward sensitivity or dopaminergic transmission in the human striatum, such as rs7118900 (dopamine receptor D2 (DRD2) Taq1A), rs1554929 (DRD2 C957T), rs907094 (DARPP-32), rs12364283 (DRD2), rs6278 (DRD2), and rs107656 (DRD2). The selected polymorphisms were combined in a so-called multilocus genetic composite (MGC) score reflecting the additive effect of different alleles conferring relative increased dopamine transmission in every individual. We successfully demonstrated that reward-related activation in the ventral striatum and ventral tegmental area (VTA) was significantly modulated by biologically informed MGC profiles and sex. When comparing men and women with low MGC profiles that may indicate lower dopamine transmission, only women displayed a reduced down-regulation of activation in the mesolimbic system during reward rejection and additionally, a significant non-linear u-shape relationship between MGC score and VTA activation. Taken together, by integrating neuroimaging and genetics, the present findings contribute to a better understanding of the effects of sex differences on the human brain.