Biology of Sex Differences最新文献

Background: Brain-derived neurotrophic factor (BDNF) is highly expressed in the hypothalamus where it exerts regulatory functions over neurogenesis, reproduction, energy balance, and metabolism. Analyzing a hypothalamic single-nucleus transcriptomic, we identified Fezf1 ventromedial hypothalamic (VMH) neurons as an important source of BDNF. During development, Fezf1 neurons are involved in the organization of the olfactory bulb, and mutations on this gene are responsible for Kallmann syndrome; however, in adult life, little is known about the functions of Fezf1 neurons.

Methods: In this study, we aimed at providing advance in the characterization of Fezf1 neurons and exploring the role of Fezf1-BDNF in the regulation of the metabolic phenotype of mice. Hypothalamic immunofluorescence was employed to determine the distribution and projections of Fezf1 neurons. Mice with a Fezf1-specific knockout of BDNF were constructed and used in the determination of the metabolic phenotype.

Results: Using a Cre-Lox system to express mCherry specifically in Fezf1 neurons of the VMH, we identified projections to the dorsomedial hypothalamus and the zona incerta, regions involved in metabolic control and motor activity, respectively. The Fezf1-specific knockout of BDNF resulted in increased cold tolerance in males, and protection against diet-induced obesity due to a reduction in food intake and increased spontaneous ambulatory activity in females. This was accompanied by protection against glucose intolerance, and increased insulin sensitivity, in females.

Conclusions: Thus, the present work provides advance in the understanding of the biology of VMH Fezf1 neurons, revealing the details of its distribution and projections, and demonstrating that the expression of BDNF in these neurons is involved, according to a sexual dimorphic pattern, in the regulation of metabolic function. In addition, this is the first evidence that, in a specific hypothalamic cell population, BDNF may have a detrimental rather than positive role in the regulation of systemic metabolism.

Background: Abdominal aortic aneurysm (AAA) is an abnormal dilation of the abdominal aorta that carries up to a 90% mortality rate when ruptured. Although male patients experience AAA at a higher rate than females, female patients experience AAA rupture at a rate three- to four-fold higher that of their male counterparts. The current standard clinicians use for determining when to surgically intervene is maximum transverse diameter of the AAA perpendicular to the axis of flow. However, some aneurysms below these diameter thresholds rupture. Machine learning (ML) classification models have been previously shown to predict patient outcomes with more discriminability than the diameter criterion. However, these models do not consider sex-based differences. In this proof-of-concept study, we investigate how creating sex-specific ML models impacts patient outcome prediction as compared to a general model encompassing all patients (sex agnostic).

Methods: Computed tomography image sets were acquired from 537 patients (n = 159 female, n = 378 male) at the University of Pittsburgh Medical Center (UPMC) and Mayo Clinic Health Systems. Features used as input to the ML models were categorized as clinical, biomechanical, and morphological data. Prior to ML model training, patient data were randomly split for 20% holdout testing. ML models encompassing all patients (general model), only male patients (male-specific model), and only female patients (female-specific model) were trained and tested.

Results: A female-specific model and male-specific model both had a higher maximum area under the receiver-operating characteristic curve values than a general model for female patients and male patients, respectively. Equalizing the sample sizes of female and male patients in the model led to improved outcomes for female patients without decreasing performance for male patients.

Conclusion: ML classification models show promise in improving predictions of patient outcomes for AAA. The higher AAA prevalence rate for males leads to female patients being underrepresented in AAA datasets. In this proof-of-concept study, we demonstrated that sex-specific models outperformed a general model in predicting patient outcomes. Additionally, equalizing sample sizes within the dataset improved predictions for female patients without compromising overall performance of the model. As ML applications in medicine continue to grow, it is important to consider population representation within datasets to reduce model bias.

Background: Brain oscillations are critical for neural communication and are increasingly recognized as sensitive biomarkers of neuropsychiatric dysfunction. Specifically, the auditory steady-state response (ASSR) has been identified as a reliable assessment of cortical entrainment and is a potential biomarker for the diagnosis or even prognosis of schizophrenia. Despite the growing awareness of sex as a biological variable, sex differences in oscillatory dynamics remain underexplored.

Methods: Using electrophysiological recordings in mice, this study investigated sex differences in both spontaneous and evoked oscillatory brain activity under baseline conditions and following systemic NMDA receptor suppression via ketamine, a widely used pharmacological model of schizophrenia.

Results: Although spontaneous oscillations across a wide range of frequency bands did not differ significantly between sexes, male mice exhibited greater gamma-band entrainment at 40 Hz ASSRs than females did. The administration of a subanaesthetic dose of ketamine consistently disrupted both spontaneous and gamma-band entrainment during ASSRs but without sex-specific effects. All measured oscillatory parameters showed high test‒retest reliability, thus indicating the robustness of the findings.

Conclusions: Collectively, these results demonstrate sex-dependent differences in baseline cortical entrainment, highlighting the importance of including both sexes in preclinical research to fully elucidate the neurobiological mechanisms underlying brain oscillations and their implications in psychiatric disorders.

Background: Maternal nutrient restriction (MNR) can increase maternal androgen concentrations during pregnancy and cause placental dysfunction leading to reduced fetal growth, especially in males. Placental androgen metabolism, as well as differential expression and subcellular localisation of androgen receptor (AR) variants, modulates androgen signalling, which may benefit placental function; however, the impact of MNR on these adaptations remains undefined. We characterised the impact of MNR and fetal sex on placental androgen signalling in a non-human primate model of pregnancy.

Methods: Pregnant baboons (Papio spp.) were randomly assigned to control diet (Ctrl; offspring female n = 5, male n = 6) or MNR diet (70% of global Ctrl; offspring female n = 5, male n = 5) at 0.16 gestation (term = ~ 180 days). Fetuses were delivered by Caesarean section at 0.9 gestation and placenta collected. Molecular measures of sex steroid signalling and placental function were quantified using established LC-MS/MS assays, Western blot, and qRT-PCR. Data were analysed using two-way ANOVA (factors: diet, sex) with Tukey's multiple comparison test.

Results: CYP17A1, SRD5A1, and PGF expression was higher, whereas HSD3B1, CYP19A1, and ANGPT2 was lower in male compared to female placentae, independent of diet. KDR expression and CYP19A1 activity increased in MNR versus Ctrl in females only. Cytoplasmic expression of the antagonistic AR variant, AR-45, was higher in males, whereas MNR increased cytoplasmic and nuclear AR-45 expression independent of sex.

Conclusions: Differences in placental steroidogenic and angiogenic genes, as well as androgen metabolism and signalling, may explain sex-specific placental responses to MNR. Better understanding of molecular regulators of androgen signalling may lead to novel, targetable therapeutics that improve placental function in complicated pregnancies associated with increased androgen concentrations.

Background: Sex differences are crucial to understanding neuropsychiatric disorders, yet they are often overlooked in the development of therapies. Transcranial alternating current stimulation (tACS) shows promise for cognitive enhancement, but its sex-specific effects are largely unknown.

Methods: In this study, the effects of 10 Hz and 40 Hz tACS on spatial cognition were examined in male and female mice using three tests: the Y-maze to evaluate spatial recognition memory, the Barnes maze to evaluate spatial learning and memory related to punishment, and the reversal Barnes maze to evaluate reversal learning. General behaviors, such as anxiety, exploration, and locomotion, were evaluated using the elevated plus maze and open field tests.

Results: The results showed that 40 Hz tACS improved spatial recognition memory in males, while 10 Hz and 40 Hz tACS enhanced spatial learning in females. Males learned faster, while females performed better initially in the spatial learning process. In addition, no significant effects of tACS were observed in reversal learning, spatial memory, anxiety, or exploration. Interestingly, males exhibited reduced locomotion compared to females across tasks, and tACS potentially exacerbated this difference.

Conclusions: This animal study suggests that tACS may influence spatial cognition differently in males and females. Our findings highlight the importance of considering the interaction between sex and stimulation frequency when optimizing tACS intervention parameters.

The association between exposure to particulates in polluted air and cognitive impairment is an emerging and significant health concern, particularly among younger populations. Although exposure to particulate matter ≤ 2.5 μm (PM_2.5) is linked with a lower estimated risk for dementia compared to traditional risk factors such as APOEɛ4 gene variants, the widespread and long-term population exposure to PM_2.5 pose substantial implications for public health. This review explores the sex differences in cognitive function induced by PM_2.5, which are age-dependent and distinct from the sex bias observed in Alzheimer's disease. In addition to biological sex and sex hormones, we also discuss the role of epigenetic regulation as a mechanism underlying sex-specific cognitive vulnerabilities to environmental toxins, particularly PM_2.5. Understanding these differences is important for developing targeted interventions and public health strategies to mitigate the cognitive impacts of PM_2.5 exposure.

Background: To examine the impact of gender and its interaction with the side of surgery on cognition, affectivity, and quality of life (QOL) in drug-resistant epilepsy, as well as postsurgical changes in these domains.

Methods: In this prospective cohort study, 86 adults with TLE (46 women and 40 men) underwent a neuropsychological evaluation before and one year after surgery, including attention, executive function, language, verbal and visual memory, anxiety, depression, and QOL outcomes.

Results: After surgery, 84.1% of patients were seizure-free. In the group with right-sided surgery, men had poorer executive functioning (p = 0.05) and memory than women (for all, p < 0.05), independently of the time point (i.e., before or after surgery). Men with right-side surgery showed poorer executive function than those with left-side surgery (for all, p < 0.04), and a postsurgical anxiety decrease (p < 0.001). Women with right-side surgery had a better memory than those with left-side surgery, independently of the time point (for all, p < 0.001). Both genders showed postsurgical QOL improvements modulated by surgery side (p = 0.037). Regardless of the surgery side, women had poorer semantic fluency (p = 0.03) and QOL (p = 0.05) than men and postsurgical semantic fluency declines (p = 0.024), whereas men had postsurgical executive function declines (p = 0.05).

Conclusions: These findings underscore the importance of accounting for both gender and the side of surgery in understanding cognitive, affective, and QOL outcomes in patients with TLE, and could be useful for designing targeted neuropsychological interventions.