Search Results (20)

Methamphetamine (METH) is a known proinflammatory agent; however, the impacts of inflammasomes on its neurotoxic effects are not fully understood. In the present study, we assessed the impact of prolonged METH administration on the hippocampal inflammasome profile in male and female mice and determined alterations of the inflammasome profile in response to METH. In addition to inflammasome activation, METH induced both systemic and hippocampal-specific inflammatory responses, leading to cognitive impairment, reduced hippocampal cell proliferation, and altered proteomic profiles. Importantly, the responses to METH exposure exhibited important sexual dimorphism. Treatment with inflammasome inhibitor MCC950 attenuated METH-induced inflammatory events; however, we also observed several off-target effects of this inhibitor affecting mouse anxiety-like behavior and cognitive function. Overall, our results indicate the preventive potential of MCC950 in METH-related neurotoxicity, while underscoring its limitations due to distinct sex-dependent differences in response to both METH and MCC950 and highlighting significant sexual dimorphism. Full article

Sex steroid hormones play a pivotal role in maintaining systemic homeostasis throughout life. Their age-related decline is closely associated with the onset of frailty, including sarcopenia and dementia. Here, this article provides a narrative review of the existing literature about the multifaceted roles of sex steroid hormones, particularly estrogens and androgens, in aging and age-related diseases. Sex steroid action is mediated by nuclear receptors such as estrogen receptor alpha (ERα) and androgen receptor (AR). Transcriptional activation through these receptors is orchestrated by epigenetic mechanisms, including histone modifications and chromatin remodeling. Beyond their reproductive functions, sex hormones also influence systemic physiology, metabolism, immune responses, and neuroplasticity. Clinical studies on hormone-deprivation therapies for prostate and breast cancers, as well as animal models, have revealed the key contributions of AR and ER activity to muscle integrity, bone density, and cognitive function. The sexual dimorphism in cognitive decline, especially in postmenopausal women, suggests the therapeutic potential of hormone supplementation and receptor-targeted strategies. Thus, AR- and ER-associated genes are considered promising targets for preventing frailty, sarcopenia, osteoporosis, and dementia. This review summarizes the current knowledge on sex hormone signaling in aging, with an emphasis on translational implications and future research directions. Full article

The global obesity pandemic has unveiled adipose tissue as a pivotal, active modulator of neurological health, intricately linking metabolic dysfunction to chronic pain and cognitive decline. This review synthesizes current evidence to propose a unified “neuro-metabo-inflammatory” model of the adipose-central nervous system (CNS) axis. We articulate a framework where, in pathological states such as obesity, dysfunctional adipose tissue releases a milieu of factors—including adipokines, lipids, and extracellular vesicles—that propagate peripheral and central neuroinflammation, disrupt blood–brain barrier integrity, and impair synaptic plasticity. These processes converge to drive pain sensitization and cognitive deficits. Critically, we evaluate the clinical evidence linking visceral adiposity to multisite chronic pain and accelerated cognitive impairment, while highlighting sexually dimorphic pathways. The review moves beyond cataloging findings to prioritize the most robust mechanisms, assess evidence quality, and identify key translational gaps. We conclude by discussing emerging therapeutic strategies targeting this axis and proposing precise directions for future research to disentangle the complex temporal and spatial dynamics of adipose–CNS communication. Full article

Traumatic brain injury (TBI) is a leading cause of death and disability, with broad heterogeneity in recovery outcomes particularly noted in pediatric patients. Children post-TBI are vulnerable to aberrant neurodevelopment, specifically in structural and functional neural networks as they correlate with cognitive, behavioral, and motor function outcomes. Consideration for sex as a biological variable which innately influences neuroanatomy, neurodevelopment, and functional organization may elucidate risk factors for negative outcomes in pediatric TBI. For example, TBI damage in sexually dimorphic neural structures and networks may explain deficits in social cognition, working memory, as well as internalizing and externalizing behaviors, which differentially impact the quality of life in male versus female TBI patients. However, characterization of sex in conjunction with developmental patterns in normal and injured pediatric populations is limited due to small sample sizes, the low representation of females, a lack of longitudinal data, and the utilization of analyses that are not sensitive enough to detect subtle differences in TBI pathologies and recovery between the sexes. This review aims to analyze and synthesize the existing evidence regarding the influence of sex on the developmental trajectories of neuroanatomical structures, white and gray matter compartments, and the network disruptions that align with sex-specific functional recovery outcomes following pediatric TBI. The delineation of these sex influences will facilitate better precision-based medicine approaches to improve patient outcomes. Full article

Background: We recently reported sex-dependent impairment in cognitive functions in male and female mice exposed for 24 h, 48 h or 15 days to 2G hypergravity (HG). Methods: In the present study, we investigated brain functional correlates by analyzing synaptic activity and plasticity in the CA1 area of the hippocampus in both genders of mice previously exposed to 2G for the same duration. This was assessed by electrophysiological extracellular recordings in ex vivo slice preparations. Results: Basal synaptic transmission and glutamate release were unchanged regardless of HG duration. However, plasticity was altered in a sex- and time-specific manner. In males, long-term potentiation (LTP) induced by strong high-frequency stimulation and NMDA receptor (NMDAr) activation was reduced by 26% after 24 h of exposure but recovered at later timepoints. This deficit was reversed by D-serine or glycine, suggesting decreased activation at the NMDAr co-agonist site. In females, LTP deficits (23%) were found only after 15 days following mild theta burst stimulation and were not reversed by D-serine. Long-term depression (LTD) was unaffected in both sexes. Conclusions: This study highlights, for the first time, sex-dependent divergence in the CA1 hippocampal plasticity timeline following 2G exposure. The synaptic changes depend on exposure duration and the stimulation protocol and could underlie the previously observed cognitive deficits. Full article

Background: Helminth infections are associated with cognitive deficits, especially in school-age children. Deworming treatment in heavily infected children improves their short- and long-term memory recall. In mice, intraperitoneal helminth infection with Taenia crassiceps (T. crassiceps) shows sexual dimorphism in terms of the parasite load, immune response, hormone levels, and behavioral changes. We have previously shown poorer short-term memory performance and changes in the concentrations of cytokines and neurotransmitters in the hippocampus, which were replicated in this study. The molecular changes in other brain structures, such as those related to reproduction, are unknown. Methods: Male and female Balb/cAnN mice were chronically infected with T. crassiceps larvae. We determined the peritoneal parasite load and established the presence of cytokines and neurotransmitters in the hippocampus, olfactory bulb, and hypothalamus. Results: The parasite load was higher in female than male infected mice, as expected. In the hippocampus, the neurotransmitters norepinephrine and serotonin increased in males but decreased in females. In contrast, in the olfactory bulb and hypothalamus, the neurotransmitters assessed showed no statistical differences. The cytokine profiles were different in each brain structure. The TNF-α levels in the olfactory bulb and the IL-4 levels in the hippocampus of infected mice were dimorphic; IFN-γ was augmented in both male and female infected animals, although the increase was higher in infected males. Conclusions: The brain responds to peripheral infection with cytokine levels that vary from structure to structure. This could be a partial explanation for the dimorphic behavioral alterations associated with infection, it also demonstrates the synergic interaction between the immune, the endocrine, and the nervous systems. Full article

Two-thirds of Americans with Alzheimer’s disease are women, indicating a profound variance between the sexes. Variances exist between the sexes in the age and intensity of the presentation, cognitive deficits, neuroinflammatory factors, structural and functional brain changes, as well as psychosocial and cultural circumstances. Herein, we summarize the existing evidence for sexual dimorphism and present the available evidence for these distinctions. Understanding these complexities is critical to developing personalized interventions for the prevention, care, and treatment of Alzheimer’s disease. Full article

Preeclampsia (PE) is a multisystem disorder characterized by elevated blood pressure in the mother, typically occurring after 20 weeks of gestation and posing risks to both maternal and fetal health. PE causes placental changes that can affect the fetus, particularly neurodevelopment. Its key pathophysiological mechanisms encompass hypoxia, vascular and angiogenic dysregulation, inflammation, neuronal and glial alterations, and disruptions in neuronal signaling. Animal models indicate that PE is correlated with neurodevelopmental alterations and cognitive dysfunctions in offspring and in humans, an association between PE and conditions such as cerebral palsy, autism spectrum disorder, attention deficit hyperactivity disorder, and sexual dimorphism has been observed. Considering the relevance for mothers and children, we conducted a narrative literature review to describe the relationships between the pathophysiological mechanisms behind neurodevelopmental alterations in the offspring of PE mothers, along with their potential consequences. Furthermore, we emphasize aspects pertinent to the prevention/treatment of PE in pregnant mothers and alterations observed in their offspring. The present narrative review offers a current, complete, and exhaustive analysis of (i) the pathophysiological mechanisms that can affect neurodevelopment in the children of PE mothers, (ii) the relationship between PE and neurological alterations in offspring, and (iii) the prevention/treatment of PE. Full article

Alzheimer’s disease (AD) exhibits sex-linked variations, with women having a higher prevalence, and little is known about the sexual dimorphism in progressing from Mild Cognitive Impairment (MCI) to AD. The main aim of our study was to shed light on the sex-specific conversion-to-AD risk factors using Random Survival Forests (RSF), a Machine Learning survival approach, and Shapley Additive Explanations (SHAP) on dementia biomarkers in stable (sMCI) and progressive (pMCI) patients. With this purpose, we built two separate models for male (M-RSF) and female (F-RSF) cohorts to assess whether global explanations differ between the sexes. Similarly, SHAP local explanations were obtained to investigate changes across sexes in feature contributions to individual risk predictions. The M-RSF achieved higher performance on the test set (0.87) than the F-RSF (0.79), and global explanations of male and female models had limited similarity (<71.1%). Common influential variables across the sexes included brain glucose metabolism and CSF biomarkers. Conversely, the M-RSF had a notable contribution from hippocampus, which had a lower impact on the F-RSF, while verbal memory and executive function were key contributors only in F-RSF. Our findings confirmed that females had a higher risk of progressing to dementia; moreover, we highlighted distinct sex-driven patterns of variable importance, uncovering different feature contribution risks across sexes that decrease/increase the conversion-to-AD risk. Full article

Maternal obesity and gestational diabetes predispose the next generation to metabolic disturbances. Moreover, the lactation phase also stands as a critical phase for metabolic programming. Nevertheless, the precise mechanisms originating these changes remain unclear. Here, we investigate the consequences of a maternal lipid-rich diet during gestation and lactation and its impact on metabolism and behavior in the offspring. Two experimental groups of Wistar female rats were used: a control group (NC) that was fed a standard diet during the gestation and lactation periods and an overnutrition group that was fed a high-fat diet (HF, 60% lipid-rich) during the same phases. The offspring were analyzed at postnatal days 21 and 28 and at 2 months old (PD21, PD28, and PD60) for their metabolic profiles (weight, fasting glycemia insulin sensitivity, and glucose tolerance) and euthanized for brain collection to evaluate metabolism and inflammation in the hypothalamus, hippocampus, and prefrontal cortex using Western blot markers of synaptic dynamics. At 2 months old, behavioral tests for anxiety, stress, cognition, and food habits were conducted. We observed that the female offspring born from HF mothers exhibited increased weight gain and decreased glucose tolerance that attenuated with age. In the offspring males, weight gain increased at P21 and worsened with age, while glucose tolerance remained unchanged. The offspring of the HF mothers exhibited elevated levels of anxiety and stress during behavioral tests, displaying decreased predisposition for curiosity compared to the NC group. In addition, the offspring from mothers with HF showed increased food consumption and a lower tendency towards food-related aggression. We conclude that exposure to an HF diet during pregnancy and lactation induces dysmetabolism in the offspring and is accompanied by heightened stress and anxiety. There was sexual dimorphism in the metabolic traits but not behavioral phenotypes. Full article

Over recent decades, substantial research has focused on fish cognitive evolution to increase our understanding of the evolution of the enormous diversity of cognitive abilities that exists in fishes. One important but understudied aspect of cognitive evolution is sexual dimorphism in cognitive abilities. Sex-specific variation in brain region morphology has been proposed to be an important mechanism in this context. However, it is also common to find sex-specific variation in behavior and cognition without associated differences in brain morphology among the sexes. The telencephalon is the major cognitive center in the vertebrate brain and variation in telencephalon size has been associated with variation in cognition. Here, we utilize recently developed guppy artificial selection lines with ca. 10% differences in relative telencephalon size to investigate whether similar responses to selection of the size of this region may affect cognitive abilities differently in males and females. To that end, we compared two ecologically relevant aspects of cognition, detour learning and binary spatial discrimination. We tested the significance of the interaction between telencephalon size and sex, and we found no sex-specific effects of evolutionary increases in telencephalon size in the cognitive abilities tested. This study indicates that no clear cognitive sex-specific effects occur in response to rapid selection of telencephalon size. We suggest that future research on sexual dimorphism in cognitive abilities in fish could use various cognitive tests and examine telencephalic sub-regions to gain a more comprehensive understanding of their evolution. Full article

Repeated maternal separation (MS) is a useful experimental model in rodents for studying the long-term influence of early-life stress on brain neurophysiology. In our work, we assessed the effect of repeated MS (postnatal day (PND)1–21, 180 min/day) on the postnatal development of rat brain regions involved in memory using proton magnetic resonance spectroscopy (¹HMRS) for tissue volume and the level of amino acids such as glutamate, aspartate, glutamine, glycine and gamma-aminobutyric acid (GABA) in the hippocampus. We assessed whether these effects are sex dependent. We also use novel object recognition (NOR) task to examine the effect of MS on memory and the effect of ethanol on it. Finally, we attempted to ameliorate postnatal stress-induced memory deficits by using VU-29, a positive allosteric modulator (PAM) of the metabotropic glutamate type 5 (mGlu5) receptor. In males, we noted deficits in the levels of glutamate, glycine and glutamine and increases in GABA in the hippocampus. In addition, the values of perirhinal cortex, prefrontal cortex and insular cortex and CA3 were decreased in these animals. MS females, in contrast, demonstrated significant increase in glutamate levels and decrease in GABA levels in the hippocampus. Here, the CA1 values alone were increased. VU-29 administration ameliorated these cognitive deficits. Thus, MS stress disturbs amino acids levels mainly in the hippocampus of adult male rats, and enhancement of glutamate neurotransmission reversed recognition memory deficits in these animals. Full article

Exposure to space galactic cosmic radiation is a principal consideration for deep space missions. While the effects of space irradiation on the nervous system are not fully known, studies in animal models have shown that exposure to ionizing radiation can cause neuronal damage and lead to downstream cognitive and behavioral deficits. Cognitive health implications put humans and missions at risk, and with the upcoming Artemis missions in which female crew will play a major role, advance critical analysis of the neurological and performance responses of male and female rodents to space radiation is vital. Here, we tested the hypothesis that simulated Galactic Cosmic Radiation (GCRSim) exposure disrupts species-typical behavior in mice, including burrowing, rearing, grooming, and nest-building that depend upon hippocampal and medial prefrontal cortex circuitry. Behavior comprises a remarkably well-integrated representation of the biology of the whole animal that informs overall neural and physiological status, revealing functional impairment. We conducted a systematic dose-response analysis of mature (6-month-old) male and female mice exposed to either 5, 15, or 50 cGy 5-ion GCRSim (H, Si, He, O, Fe) at the NASA Space Radiation Laboratory (NSRL). Behavioral performance was evaluated at 72 h (acute) and 91-days (delayed) postradiation exposure. Specifically, species-typical behavior patterns comprising burrowing, rearing, and grooming as well as nest building were analyzed. A Neuroscore test battery (spontaneous activity, proprioception, vibrissae touch, limb symmetry, lateral turning, forelimb outstretching, and climbing) was performed at the acute timepoint to investigate early sensorimotor deficits postirradiation exposure. Nest construction, a measure of neurological and organizational function in rodents, was evaluated using a five-stage Likert scale ‘Deacon’ score that ranged from 1 (a low score where the Nestlet is untouched) to 5 (a high score where the Nestlet is completely shredded and shaped into a nest). Differential acute responses were observed in females relative to males with respect to species-typical behavior following 15 cGy exposure while delayed responses were observed in female grooming following 50 cGy exposure. Significant sex differences were observed at both timepoints in nest building. No deficits in sensorimotor behavior were observed via the Neuroscore. This study revealed subtle, sexually dimorphic GCRSim exposure effects on mouse behavior. Our analysis provides a clearer understanding of GCR dose effects on species typical, sensorimotor and organizational behaviors at acute and delayed timeframes postirradiation, thereby setting the stage for the identification of underlying cellular and molecular events. Full article

Oxylipins are the oxidation products of polyunsaturated fatty acids and have been implicated in neurodegenerative disorders, including dementia. Soluble epoxide hydrolase (sEH) converts epoxy-fatty acids to their corresponding diols, is found in the brain, and its inhibition is a treatment target for dementia. In this study, male and female C57Bl/6J mice were treated with an sEH inhibitor (sEHI), trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), for 12 weeks to comprehensively study the effect of sEH inhibition on the brain oxylipin profile, and modulation by sex. Ultra-high-performance liquid chromatography–tandem mass spectrometry was used to measure the profile of 53 free oxylipins in the brain. More oxylipins were modified by the inhibitor in males than in females (19 versus 3, respectively) and favored a more neuroprotective profile. Most were downstream of lipoxygenase and cytochrome p450 in males, and cyclooxygenase and lipoxygenase in females. The inhibitor-associated oxylipin changes were unrelated to serum insulin, glucose, cholesterol, or female estrous cycle. The inhibitor affected behavior and cognitive function as measured by open field and Y-maze tests in males, but not females. These findings are novel and important to our understanding of sexual dimorphism in the brain’s response to sEHI and may help inform sex-specific treatment targets. Full article

The crosstalk between obesity, diabetes, steatohepatitis, and dementia creates a controversial scenario when also studied using animal models. In the present work, this crosstalk was investigated in male and female 3xTg-AD mice for Alzheimer’s disease (AD) at different ages/stages and compared to sex- and age-matched counterparts with normal aging. The relevance of the genetic background and classical intrinsic factors (AD genotype and sex) were determined using a retrospective analysis of population data and an experimental design. Age/stage of disease was considered a source of stochastic and non-stochastic factors. Data from two different colonies of 3xTg-AD mice with distinct genetic backgrounds were analyzed to verify the functional interplay between the studied factors. Data from asymptomatic/prodromal to early/advanced stages of the disease were screened. Then, all factors’ relationships were studied in an experimental design using the same set of animals. The population data unveiled that the genetic background and sex effects were confirmed with regards to the variable body weight, with changes during disease development and progress. Sexual dimorphism was found as an important factor in glucose metabolism. Statistically significant differences in glucose tolerance and behavioral assessment (exploration, anxiety, and cognition in a two-days open-field paradigm) were found when all the factors were analyzed. In summary, the present study shows that all the studied factors should always be considered when assessing the outcome of the research interventions in the field because they have a distinct functional interplay through the process of normal and AD-pathological aging and from a gendered perspective. Full article