Male Rodents Research Articles

Mesenchymal Stem Cell Therapy for Huntington Disease: A Meta-Analysis.

Mesenchymal stem cell (MSC) therapy has been explored in Huntington disease (HD) as a potential therapeutic approach; however, a complete synthesis of these results is lacking. We conducted a meta-analysis to evaluate the effects of MSCs on HD. Eligible studies published before November 2022 were screened from Embase, PubMed, Web of Science, Medline, and Cochrane in accordance with PRISMA guidelines. ClinicalTrial.gov and the World Health Organization International Clinical Trials Registry Platform were also searched for registered clinical trials. The outcomes in rodent studies evaluated included morphological changes (striatal volume and ventricular volume), motor function (rotarod test, wire hang test, grip strength test, limb-clasping test, apomorphine-induced rotation test, and neuromuscular electromyography activity), cognition (Morris water maze test), and body weight. The initial search returned 362 records, of which 15 studies incorporating 346 HD rodents were eligible for meta-analysis. Larger striatal and smaller ventricular volumes were observed in MSC-treated animals compared to controls. MSCs transplanted before the occurrence of motor dysfunction rescued the motor incoordination of HD. Among different MSC sources, bone marrow mesenchymal stem cells were the most investigated cells and were effective in improving motor coordination. MSC therapy improved muscle strength, neuromuscular electromyography activity, cortex-related motor function, and striatum-related motor function, while cognition was not changed. The body weight of male HD rodents increased after MSC transplantation, while that of females was not affected. Meta-analysis showed a positive effect of MSCs on HD rodents overall, as reflected in morphological changes, motor coordination, muscle strength, neuromuscular electromyography activity, cortex-related motor function, and striatum-related motor function, while cognition was not changed by MSC therapy.

Immunocytoprotection after reperfusion with Kv1.3 inhibitors has an extended treatment window for ischemic stroke.

Introduction: Mechanical thrombectomy has improved treatment options and outcomes for acute ischemic stroke with large artery occlusion. However, as the time window of endovascular thrombectomy is extended there is an increasing need to develop immunocytoprotective therapies that can reduce inflammation in the penumbra and prevent reperfusion injury. We previously demonstrated, that by reducing neuroinflammation, KV1.3 inhibitors can improve outcomes not only in young male rodents but also in female and aged animals. To further explore the therapeutic potential of KV1.3 inhibitors for stroke therapy, we here directly compared a peptidic and a small molecule KV1.3 blocker and asked whether KV1.3 inhibition would still be beneficial when started at 72 hours after reperfusion. Methods: Transient middle cerebral artery occlusion (tMCAO, 90-min) was induced in male Wistar rats and neurological deficit assessed daily. On day-8 infarction was determined by T2-weighted MRI and inflammatory marker expression in the brain by quantitative PCR. Potential interactions with tissue plasminogen activator (tPA) were evaluated in-vitro with a chromogenic assay. Results: In a direct comparison with administration started at 2 hours after reperfusion, the small molecule PAP-1 significantly improved outcomes on day-8, while the peptide ShK-223 failed to reduce infarction and neurological deficits despite reducing inflammatory marker expression. PAP-1 still provided benefits when started 72 hours after reperfusion. PAP-1 does not reduce the proteolytic activity of tPA. Discussion: Our studies suggest that KV1.3 inhibition for immunocytoprotection after ischemic stroke has a wide therapeutic window for salvaging the inflammatory penumbra and requires brain-penetrant small molecules.

Glucagon-Like Peptide-1 Is Involved in the Thermic Effects of Dietary Proteins in Male Rodents.

Protein intake potently increases body temperature and energy expenditure, but the underlying mechanism thereof remains incompletely understood. Simultaneously, protein intake potently stimulates glucagon-like peptide-1 (GLP-1) secretion. Here, we examined the involvement of GLP-1 in the thermic effects of dietary proteins in rodents by measuring rectal temperature and energy expenditure and modulating GLP-1 signaling. Rectal temperature of rats or mice fasted for 4 or 5 hours were measured using a thermocouple thermometer before and after an oral administration of nutrients. Oxygen consumption after oral protein administration was also measured in rats. Rectal temperature measurements in rats confirmed an increase in core body temperature after refeeding, and the thermic effect of the oral administration of protein was greater than that of a representative carbohydrate or lipid. Among the five dietary proteins examined (casein, whey, rice, egg, and soy), soy protein had the highest thermic effect. The thermic effect of soy protein was also demonstrated by increased oxygen consumption. Studies using a nonselective β-adrenergic receptor antagonist and thermal camera suggested that brown adipose tissue did not contribute to soy protein-induced increase in rectal temperature. Furthermore, the thermic effect of soy protein was completely abolished by antagonism and knockout of the GLP-1 receptor, yet potentiated via augmentation of intact GLP-1 levels through inhibition of dipeptidyl peptidase-4 activity. These results indicate that GLP-1 signaling is essential for the thermic effects of dietary proteins in rats and mice, and extend the metabolic actions of GLP-1 ensuing from nutrient ingestion to encompass the thermic response to ingested protein.

Potential biological contributers to the sex difference in multiple sclerosis progression.

Multiple sclerosis (MS) is an immune-mediated disease that targets the myelin sheath of central nervous system (CNS) neurons leading to axon injury, neuronal death, and neurological progression. Though women are more highly susceptible to developing MS, men that develop this disease exhibit greater cognitive impairment and accumulate disability more rapidly than women. Magnetic resonance imaging and pathology studies have revealed that the greater neurological progression seen in males correlates with chronic immune activation and increased iron accumulation at the rims of chronic white matter lesions as well as more intensive whole brain and grey matter atrophy and axon loss. Studies in humans and in animal models of MS suggest that male aged microglia do not have a higher propensity for inflammation, but may become more re-active at the rim of white matter lesions as a result of the presence of pro-inflammatory T cells, greater astrocyte activation or iron release from oligodendrocytes in the males. There is also evidence that remyelination is more efficient in aged female than aged male rodents and that male neurons are more susceptible to oxidative and nitrosative stress. Both sex chromosome complement and sex hormones contribute to these sex differences in biology.

Ascorbic acid reduces insulin resistance and pancreatic steatosis by regulating adipocyte hypertrophy in obese ovariectomized mice.

Ascorbic acid has been suggested to regulate obesity in obese male rodents.Moreover, increased adipocyte size has been associated with metabolic disease. Thus, we investigated the effects of ascorbic acid on adipocyte hypertrophy and insulin resistance in high-fat diet (HFD)-induced obese ovariectomized (OVX) C57BL/6J mice, an animal model of obese postmenopausal women. Administration of ascorbic acid (5%w/w in diet for 18 weeks) reduced the size of visceral adipocytes without changes in body weight and adipose tissue mass in HFD-fed obese OVX mice compared with obese OVX mice that did not receive ascorbic acid. Ascorbic acid inhibited adipose tissue inflammation, as shown by the decreased number of crown-like structures and CD68-positive macrophages in visceral adipose tissues. Ascorbic acid-treated mice exhibited improved hyperglycemia, hyperinsulinemia, and glucose and insulin tolerance compared with nontreated obese mice. Pancreatic islet size and insulin-positive β-cell area in ascorbic acid-treated obese OVX mice decreased to the levels observed in low-fat diet-fed lean mice. Ascorbic acid also suppressed pancreatic triglyceride accumulation in obese mice. These results suggest that ascorbic acid may reduce insulin resistance and pancreatic steatosis partly by suppressing visceral adipocyte hypertrophy and adipose tissue inflammation in obese OVX mice.

The therapeutic potential of glucagon-like peptide-1 for persons with addictions based on findings from preclinical and clinical studies.

Although the multifaceted mechanisms underlying alcohol use disorder (AUD) have been partially defined, the neurobiological complexity of this disorder is yet to be unraveled. One of the systems that have gained attention in recent times is the gut-brain axis. Although numerous peptides participate in this axis, glucagon-like peptide-1 (GLP-1) plays a central role. GLP-1 is a crucial anorexigenic peptide, with potent abilities to reduce food intake and body weight. The physiological complexity of GLP-1 entails glucose homeostasis, gastrointestinal motility, and the release of insulin and glucagon. As reviewed in this study, acute or repeated treatment with GLP-1 receptor (GLP-1R) agonists decreases alcohol consumption in rodents. Moreover, the abilities of alcohol to promote hyperlocomotion, dopamine release in the nucleus accumbens, and reward in the conditioned place preference paradigm are all suppressed by GLP-1R ligands. Moreover, activation of GLP-1R suppresses the motivation to consume alcohol, alcohol-seeking behaviors, and relapse drinking in male rodents. Similarly, abstinence symptoms experienced during alcohol withdrawal are attenuated by activation of the GLP-1 pathway. On a similar note, the activation of GLP-1 receptors within areas of the brain that are processing reward modulates these alcohol-related responses. Another area that is crucial for this ability is the nucleus of the solitary tract, which is where GLP-1 is produced and from which GLP-1-containing neurons project to areas of reward. These findings may have clinical relevance as AUD is associated with polymorphisms in GLP-1-related genes. Although a GLP-1R agonist does not alter alcohol intake in AUD patients, it reduces this consumption in a sub-population of obese AUD individuals. Given the uncertainty of this outcome, additional clinical studies of obese AUD patients should explore the effects of the GLP-1R agonists on alcohol intake and body weight. Furthermore, GLP-1 receptors modulate the behavioral and neurochemical responses to addictive drugs. Taken together, these preclinical and clinical findings imply that the GLP-1 pathway plays a role in the complex mechanisms regulating alcohol and drug consumption patterns, unveiling a novel aspect of addiction medicine.

Sex-differences in prostaglandin signaling: a semi-systematic review and characterization of PTGDS expression in human sensory neurons

There is increasing evidence of sex differences in underlying mechanisms causing pain in preclinical models, and in clinical populations. There are also important disconnects between clinical pain populations and the way preclinical pain studies are conducted. For instance, osteoarthritis pain more frequently affects women, but most preclinical studies have been conducted using males in animal models. The most widely used painkillers, nonsteroidal anti-inflammatory drugs (NSAIDs), act on the prostaglandin pathway by inhibiting cyclooxygenase (COX) enzymes. The purpose of this study was to analyze the preclinical and clinical literature on the role of prostaglandins and COX in inflammation and pain. We aimed to specifically identify studies that used both sexes and investigate whether any sex-differences in the action of prostaglandins and COX inhibition had been reported, either in clinical or preclinical studies. We conducted a PubMed search and identified 369 preclinical studies and 100 clinical studies that matched our inclusion/exclusion criteria. Our analysis shows that only 17% of preclinical studies on prostaglandins used both sexes and, out of those, only 19% analyzed or reported data separated by sex. In contrast, 79% of the clinical studies analyzed used both sexes. However, only 6% of those reported data separated by sex. Interestingly, 14 out of 15 preclinical studies and 5 out of 6 clinical studies that analyzed data separated by sex have identified sex-differences. This builds on the increasing evidence of sex-differences in prostaglandin signaling and the importance of sex as a biological variable in data analysis. The preclinical literature identifies a sex difference in prostaglandin D2 synthase (PTGDS) expression where it is higher in female than in male rodents in the nervous system. We experimentally validated that PTGDS expression is higher in female human dorsal root ganglia (DRG) neurons recovered from organ donors. Our semi-systematic literature review reveals a need for continued inclusivity of both male and female animals in prostaglandins studies and data analysis separated by sex in preclinical and clinical studies. Our finding of sex-differences in neuronal PTGDS expression in humans exemplifies the need for a more comprehensive understanding of how the prostaglandin system functions in the DRG in rodents and humans.

Female mice are protected from impaired parenchymal arteriolar TRPV4 function and impaired cognition in hypertension.

Hypertension is a leading modifiable risk factor for cerebral small vessel disease. Our laboratory has shown that endothelium-dependent dilation in cerebral parenchymal arterioles (PAs) is dependent on transient receptor potential vanilloid 4 (TRPV4) activation, and this pathway is impaired in hypertension. This impaired dilation is associated with cognitive deficits and neuroinflammation. Epidemiological evidence suggests that women with midlife hypertension have an increased dementia risk that does not exist in age-matched men, though the mechanisms responsible for this are unclear. This study aimed to determine the sex differences in young, hypertensive mice to serve as a foundation for future determination of sex differences at midlife. We tested the hypothesis that young hypertensive female mice would be protected from the impaired TRPV4-mediated PA dilation and cognitive dysfunction observed in male mice. Angiotensin II (ANG II)-filled osmotic minipumps (800 ng/kg/min, 4 wk) were implanted in 16- to 19-wk-old male C56BL/6 mice. Age-matched female mice received either 800 ng/kg/min or 1,200 ng/kg/min ANG II. Sham-operated mice served as controls. Systolic blood pressure was elevated in ANG II-treated male mice and in 1,200 ng ANG II-treated female mice versus sex-matched shams. PA dilation in response to the TRPV4 agonist GSK1016790A (10-9-10-5 M) was impaired in hypertensive male mice, which was associated with cognitive dysfunction and neuroinflammation, reproducing our previous findings. Hypertensive female mice exhibited normal TRPV4-mediated PA dilation and were cognitively intact. Female mice also showed fewer signs of neuroinflammation than male mice. Determining the sex differences in cerebrovascular health in hypertension is critical for developing effective therapeutic strategies for women.NEW & NOTEWORTHY Vascular dementia is a significant public health concern, and the effect of biological sex on dementia development is not well understood. TRPV4 channels are essential regulators of cerebral parenchymal arteriolar function and cognition. Hypertension impairs TRPV4-mediated dilation and memory in male rodents. Data presented here suggest female sex protects against impaired TRPV4 dilation and cognitive dysfunction during hypertension. These data advance our understanding of the influence of biological sex on cerebrovascular health in hypertension.

Female and male microglia are not different in the dentate gyrus of postnatal day 10 mice

Microglia, the resident immune cells of the brain, support normal brain function and the brain’s response to disease and injury. The hippocampal dentate gyrus (DG) is important for microglial study due to its central role in many behavioral and cognitive functions. Interestingly, microglia and related cells are distinct in female vs. male rodents, even in early life. Indeed, postnatal day (P)-dependent sex differences in number, density, and morphology of microglia have been reported in certain hippocampal subregions at specific ages. However, sex differences in the DG have not yet been assessed at P10, a translationally relevant time point as the rodent neuroanatomical eqivalent of human term gestation. To address this knowledge gap, Iba1+ cells in the DG (which are enriched in the Hilus and Molecular Layer) in female and male C57BL/6J mice were analyzed for their number (via stereology) and density (via stereology and via sampling). Next, Iba1+ cells were classified into morphology categories previously established in the literature. Finally, the percent of Iba1+ cells in each morphology category was multiplied by total cell number to generate a total number of Iba1+ cells in each category. Results show no sex difference in Iba1+ cell number, density, or morphology in the P10 Hilus or Molecular Layer. The lack of sex difference in Iba1+ cells in P10 DG using commonly-employed methodologies (sampling, stereology, morphology classification) provides a baseline from which to interpret microglia changes seen after injury.

Chronic Intake of a Marginally Low Copper Diet Impairs In Vitro Activities of Lymphocytes and Neutrophils from Male Rats despite Minimal Impact on Conventional Indicators of Copper Status

We investigated the impact of chronic intake of a diet marginally low in Cu on traditional indicators of Cu status and in vitro activities of splenic mononuclear cells and neutrophils. Pregnant Sprague-Dawley rats were fed diets containing either 2.8 (LCu) or 6.7 [adequate (ACu)]mg Cu/kg from midgestation through lactation. Weaned male and female offspring were fed the same diets as their dams until 6 months of age. Dietary Cu level did not alter growth, heart weight, the concentrations of Cu or the activities of cuproenzymes in serum and most tissues. In contrast, splenic mononuclear cells (MNC) from males, but not females, fed the LCu diet were less responsive to in vitro mitogenic activation and generated less interleukin-2 bioactivity than cultures prepared from males fed the ACu diet. Repletion with the ACu diet for 2 wk restored in vitro activities of splenic MNC to control levels. The phorbol myristate acetate-induced generation of superoxide anion by elicited neutrophils from male rodents fed the LCu diet was only 60% that of cells from the ACu diet group. Brain Cu in adult rats fed LCu diet was irreversibly decreased compared with those fed ACu diet. These data show that the in vitro activities of T lymphocytes and neutrophils isolated from adult male rats chronically fed a diet marginally low in Cu were significantly suppressed without marked alterations in the traditional indicators of Cu status.

Sex differences in chronic pain-induced mental disorders: Mechanisms of cerebral circuitry.

Mental disorders such as anxiety and depression induced by chronic pain are common in clinical practice, and there are significant sex differences in their epidemiology. However, the circuit mechanism of this difference has not been fully studied, as preclinical studies have traditionally excluded female rodents. Recently, this oversight has begun to be resolved and studies including male and female rodents are revealing sex differences in the neurobiological processes behind mental disorder features. This paper reviews the structural functions involved in the injury perception circuit and advanced emotional cortex circuit. In addition, we also summarize the latest breakthroughs and insights into sex differences in neuromodulation through endogenous dopamine, 5-hydroxytryptamine, GABAergic inhibition, norepinephrine, and peptide pathways like oxytocin, as well as their receptors. By comparing sex differences, we hope to identify new therapeutic targets to offer safer and more effective treatments.

Indomethacin restores loss of hippocampal neurogenesis and cholinergic innervation and reduces innate immune expression and reversal learning deficits in adult male and female rats following adolescent ethanol exposure.

Adolescent intermittent ethanol (AIE) exposure causes long-term changes in the brain and behavior of adult male rodents, including persistent induction of innate immune pathways, reductions in hippocampal neurogenic and forebrain cholinergic neuronal markers, and reversal learning deficits. The current study tests the hypothesis that proinflammatory induction mediates AIE-induced (1) loss of adult neurogenesis (i.e., doublecortin (DCX) expressing immature neurons), (2) reductions in forebrain and hippocampal cholinergic markers, and (3) reversal learning deficits. Male and female rats underwent AIE (5.0g/kg/day ethanol or water, i.g., 2 day-on/2 day-off from postnatal day (PND) 25-54), followed by a 2-week regimen of the anti-inflammatory compound indomethacin (4.0g/kg/day, PND 56-69) or vehicle, after which one cohort was euthanized for immunohistochemical markers (PND 70) and the second underwent the Morris water maze to assess reversal learning. AIE reduced adult (PND 70) DCX+ immunoreactivity (IR) and increased hippocampal expression of the innate immune signal's high-mobility group box protein 1 (HMGB1 + IR) and cyclooxygenase-2 (COX-2+ IR) in adult male and female rats. AIE also reduced choline acetyltransferase (ChAT+IR) in the basal forebrain and co-labeling of hippocampal vesicular acetylcholine transporter (VAChT+) cholinergic terminals on DCX + IR neurons. Indomethacin treatment after AIE restored molecular endpoints to control levels and rescued AIE-induced reversal learning deficits in the Morris water maze in both sexes. Of note, indomethacin produced several adverse effects selectively in control conditions, highlighting the uniquely beneficial effect of indomethacin in AIE rats. These data suggest that in males and females, (1) AIE persistent neuroimmune induction mediates both the loss of adult hippocampal DCX and loss of basal forebrain cholinergic neurons and their innervation to hippocampal targets, and (2) anti-inflammatory indomethacin treatment following AIE that restores these persistent molecular pathologies also restores spatial reversal learning deficits.

Learning pain in context: Response-conditioned placebo analgesia and nocebo hyperalgesia in male rats with chronic neuropathic pain

BackgroundAnimal models of placebo analgesia and nocebo hyperalgesia have great potential to assist in the development of novel treatments for chronic pain that exploit or inhibit these phenomena. This study sought to elicit both conditioned placebo analgesia and conditioned nocebo hyperalgesia in rats with chronic neuropathic pain using non-pharmacological, contextual conditioning approaches, similar to those most often used in humans. MethodsSciatic nerve-injured male Sprague-Dawley rats (n = 80), and sham controls (n = 16), underwent a conditioning procedure in which three different thermal stimulus intensities (4 °C, 20 °C or 30 °C) were paired with contextual cues. Injured hind paw withdrawal behaviours were used to determine pain sensitivity, and either conditioned analgesia or conditioned hyperalgesia was evoked by re-exposing the rats to the same context with either an increased or decreased thermal stimulus, respectively. ResultsStronger conditioned analgesia and conditioned hyperalgesia were seen when rats were conditioned in a more complex environment, highlighting the importance of context in these processes. Rats that did not undergo conditioning procedures showed fewer hind paw withdrawals, indicating a learned component to these pain behaviours. ConclusionsOur data call attention to context and learning as two critical factors in the development of placebo and nocebo effects in male rodents with a neuropathic injury. Additionally, the response-conditioning model we present in this study affords better comparisons between human and animal studies, in particular for those seeking to identify commonalities in the neurobiological mechanisms of placebo and nocebo responses.

Sex differences in the antidepressant-like response and molecular events induced by the imidazoline-2 receptor agonist CR4056 in rats

In searching for novel targets to design antidepressants, among the characterized imidazoline receptors (IR), I2 receptors are an innovative therapeutical approach since they are dysregulated in major depressive disorder and by classical antidepressant treatments. In fact, several I2 agonists have been characterized for their antidepressant-like potential, but the results in terms of efficacy were mixed and exclusively reported in male rodents. Since there are well-known sex differences in antidepressant-like efficacy, this study characterized the potential effects induced by two I2 drugs, CR4056 (i.e., most promising drug already in phase II clinical trial for its analgesic properties) and B06 (a compound from a new family of bicyclic α-iminophosphonates) under the stress of the forced-swim test in male and female rats exposed to early-life stress. Moreover, some hippocampal neuroplasticity markers related to the potential effects observed were also evaluated (i.e., FADD, p-ERK/ERK, mBDNF, cell proliferation: Ki-67 + cells). The main results replicated the only prior study reporting the efficacy of CR4056 in male rats, while providing new data on its efficacy in females, which was clearly dependent on prior early-life stress exposure. Moreover, B06 showed no antidepressant-like effects in male or female rats. Finally, CR4056 increased FADD content and decreased cell proliferation in hippocampus, without affecting p-ERK/t-ERK ratio and/or mBDNF content. Interestingly, these effects were exclusively observed in female rats, and independently of early-life conditions, suggesting some distinctive molecular underpinnings participating in the therapeutic response of CR4056 for both sexes. In conjunction, these results present CR4056 with an antidepressant-like potential, especially in female rats exposed to stress early in life, together with some neuronal correlates described in the context of these behavioral changes in females.

Protective effects of melatonin against physical injuries to testicular tissue: A systematic review and meta-analysis of animal models.

Modern societies face infertility as a global challenge. There are certain environmental conditions and disorders that damage testicular tissue and may cause male infertility. Melatonin, as a potential antioxidant, may protect testicular tissue. Therefore, we conducted this systematic review and meta-analysis to evaluate the effects of melatonin in animal models against physical, heat, and ischemic damage to the testicular tissue. PubMed, Scopus, and Web of Science were systematically searched to identify animal trials evaluating the protective effect of melatonin therapy on rodent testicular tissue when it is exposed to physical, thermal, ischemic, or hypobaric oxygen stress. Random-effect modeling was used to estimate the standardized mean difference and 95% confidence intervals based on the pooled data. Additionally, the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool was used to assess the risk of bias. The study protocol was prospectively registered in PROSPERO (CRD42022354599). A total of 41 studies were eligible for review out of 10039 records. Studies employed direct heat, cryptorchidism, varicocele, torsion-detorsion, testicular vascular occlusion, hypobaric hypoxia, ischemia-reperfusion, stress by excessive or restraint activity, spinal cord injury, and trauma to induce stress in the subjects. The histopathological characteristics of testicular tissue were generally improved in rodents by melatonin therapy. Based on the pooled data, sperm count, morphology, forward motility, viability, Johnsen's biopsy score, testicular tissue glutathione peroxidase, and superoxide dismutase levels were higher in the melatonin treatment rodent arms. In contrast, the malondialdehyde level in testicular tissue was lower in the treatment rodent arms. The included studies suffered from a high risk of bias in most of the SYRCLE domains. This study concludes that melatonin therapy was associated with improved testicular histopathological characteristics, reproductive hormonal panel, and tissue markers of oxidative stress in male rodents with physical, ischemic, and thermal testicular injuries. In this regard, melatonin deserves scientific investigations as a potential protective drug against rodent male infertility. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022354599.

Methimazole-induced gestational hypothyroidism affects the offspring development and differently impairs the conditioned fear in male and female adulthood rodents.

Gestational hypothyroidism is a prevalent disorder in pregnant women and also impairs fetal development with relevant outcomes. One of the outcomes of greatest interest has been rodent fear- and anxiety-like behavior. However, the relationship between maternal hypothyroidism and onset of conditioned fear-related responses in offspring remains controversial. Here, we used a well-validated methimazole-induced gestational hypothyroidism to investigate the behavioral consequences in offspring. Dams were treated with methimazole at 0.02% in drinking water up to gestational Day 9. Maternal body weights and maternal behavior were evaluated, and the puppies ware analyzed for weight gain and physical/behavioral development and assigned for the open field and fear conditioning test. Methimazole-induced gestational hypothyroidism induced loss in maternal and litter weight, increases in maternal behavior, and impairs in offspring developmental landmarks in both male and female rodents. Only male offspring enhanced responsiveness to conditioned fear-like behavior in adulthood.

Prolonged- and upgraded- oral AlCl3 induced toxicity on the femoral diaphysis cell composition in male rodents

Prolonged- and upgraded- oral AlCl3 induced toxicity on the femoral diaphysis cell composition in male rodents

Elucidating the sex differences in a translational mouse model of diabetic cardiomyopathy

Obesity is a major risk factor for type 2 diabetes (T2D) and related cardiovascular diseases including diabetic cardiomyopathy (DbCM), which is often asymptomatic during the early stages of T2D. Increased cardiovascular risk associated with diabetes is more prominent in women, but an understanding of the pathology of DbCM in females is lacking, as most of the reported mechanistic studies have been performed in male rodents.

Chromosomal and environmental contributions to sex differences in the vulnerability to neurological and neuropsychiatric disorders: Implications for therapeutic interventions.

Neurological and neuropsychiatric disorders affect men and women differently. Multiple sclerosis, Alzheimer's disease, anxiety disorders, depression, meningiomas and late-onset schizophrenia affect women more frequently than men. By contrast, Parkinson's disease, autism spectrum condition, attention-deficit hyperactivity disorder, Tourette's syndrome, amyotrophic lateral sclerosis and early-onset schizophrenia are more prevalent in men. Women have been historically under-recruited or excluded from clinical trials, and most basic research uses male rodent cells or animals as disease models, rarely studying both sexes and factoring sex as a potential source of variation, resulting in a poor understanding of the underlying biological reasons for sex and gender differences in the development of such diseases. Putative pathophysiological contributors include hormones and epigenetics regulators but additional biological and non-biological influences may be at play. We review here the evidence for the underpinning role of the sex chromosome complement, X chromosome inactivation, and environmental and epigenetic regulators in sex differences in the vulnerability to brain disease. We conclude that there is a pressing need for a better understanding of the genetic, epigenetic and environmental mechanisms sustaining sex differences in such diseases, which is critical for developing a precision medicine approach based on sex-tailored prevention and treatment.

Short-term high-fat diet alters the mouse brain magnetic resonance imaging parameters consistently with neuroinflammation on males and metabolic rearrangements on females. A pre-clinical study with an optimized selection of linear mixed-effects models.

High-fat diet (HFD) consumption is known to trigger an inflammatory response in the brain that prompts the dysregulation of energy balance, leads to insulin and leptin resistance, and ultimately obesity. Obesity, at the same, has been related to cerebral magnetic resonance imaging (MRI) alterations, but the onset of HFD-induced neuroinflammation, however, has been principally reported on male rodents and by ex vivo methods, with the effects on females and the origin of MRI changes remaining unassessed. We characterized the onset and evolution of obesity on male and female mice during standard or HFD administration by physiological markers and multiparametric MRI on four cerebral regions involved in appetite regulation and energy homeostasis. We investigated the effects of diet, time under diet, brain region and sex by identifying their significant contributions to sequential linear mixed-effects models, and obtained their regional neurochemical profiles by high-resolution magic angle spinning spectroscopy. Male mice developed an obese phenotype paralleled by fast increases in magnetization transfer ratio values, while females delayed the obesity progress and showed no MRI-signs of cerebral inflammation, but larger metabolic rearrangements on the neurochemical profile. Our study reveals early MRI-detectable changes compatible with the development of HFD-induced cerebral cytotoxic inflammation on males but suggest the existence of compensatory metabolic adaptations on females that preclude the corresponding detection of MRI alterations.