Sexually dimorphic and time-dependent influence of active avoidance learning by vilazodone in C57BL/6J mice.

Sexually Dimorphic Patterns of Episomal rAAV Genome Persistence in the Adult Mouse Liver and Correlation With Hepatocellular Proliferation

Long-term potentiation (LTP) is widely accepted as the best studied model for neurophysiological mechanisms that could underlie learning and memory formation. Despite a number of studies indicating that β-adrenoceptors in the hippocampal dentate gyrus (DG) is involved in the modulation of learning and memory as well as LTP, few studies have used glutamate release as a visual indicator in awake animals to explore the role of β-adrenoceptors in learning-dependent LTP. Therefore, in the present study, the effects of propranolol (an antagonist of β-adrenoceptor) and isoproterenol (an agonist of β-adrenoceptor) on extracellular concentrations of glutamate and amplitudes of field excitatory postsynaptic potential were measured in the DG region during active avoidance learning in freely moving conscious rats. In the control group, the glutamate level in the DG was significantly increased during the acquisition of active avoidance behavior and returned to basal level following extinction training. In propranolol group, antagonism of β-adrenoceptors in the DG significantly reduced the change in glutamate level, and the acquisition of the active avoidance behavior was significantly inhibited. In contrast, the change in glutamate level was significantly enhanced by isoproterenol, and the acquisition of the active avoidance behavior was significantly accelerated. Furthermore, in all groups, the changes in glutamate level were accompanied by corresponding changes in field excitatory postsynaptic potential amplitude and active avoidance behavior. Our results suggest that activation of β-adrenoceptors in the hippocampal DG facilitates active avoidance learning by modulations of glutamate level and synaptic efficiency in rats.

The aim of our study was to measure globotriaosylceramide (Gb(3)) and lyso-Gb(3) levels by tandem mass spectrometry in the urine and kidney in Fabry (gla knockout) mice and wild-type controls. We found that urine Gb(3) of male and female Fabry mice was higher than wild-type mice of the same sex but also significantly higher in male mice compared with females of the same genotype. In kidney tissue, sex and genotype-dependent differences in Gb(3) levels paralleled those in the urine. Isoforms C16, C22:1, and C24OHA were particularly higher in males compared with females in both wild-type and Fabry mice. Similarly, kidney lyso-Gb(3) concentrations were significantly higher in 12-month-old male Fabry mice than in their homozygous female counterparts. However, lyso-Gb(3) was undetectable in wild-type mice of both sexes. α-Galactosidase A activity and mRNA levels in kidney were significantly lower in male wild-type mice compared with female mice. This study shows the sex differences in kidney and urine Gb(3) and kidney lyso-Gb(3) levels in both wild-type and Fabry mice, and it suggests that these male-female differences should be taken into consideration when using murine models for Fabry disease.

Effects of calcitonin, parathyroid hormone and its related fragments on acquisition of active avoidance behavior

Nitric oxide facilitates active avoidance learning via enhancement of glutamate levels in the hippocampal dentate gyrus

A Role for the Androgen Receptor in Collagen Content of the Skin

Myostatin signaling governs neonatal longitudinal muscle growth and neuromuscular contractures in a sex-dependent manner, identifying a potential avenue for contracture treatment and underscoring the need to consider sex as a biological variable in the pathophysiology of acquired neuromuscular disorders.

Myostatin signaling governs neonatal longitudinal muscle growth and neuromuscular contractures in a sex-dependent manner, identifying a potential avenue for contracture treatment and underscoring the need to consider sex as a biological variable in the pathophysiology of acquired neuromuscular disorders.

angiotensin II ◼ aortic aneurysm, abdominal ◼ protein-lysine 6-oxidase ◼ sex characteristics Editorial, see p 1901 A bdominal aortic aneurysm (AAA) formation involves a complex process of aortic medial destruction through degradation of extracellular matrix proteins, elastin, and collagen.AAA exhibits sexual dimorphism because male sex is a major risk factor of AAA in both mice and humans. 1 In mice, testosterone has been implicated as a major contributor to sexual dimorphism of angiotensin II (AngII)-induced AAAs. 2 However, the mechanism by which testosterone drives sexual dimorphism of AAA is unknown.During aortic development, lysyl oxidase (LOX) covalently cross-links elastin and collagen to create an insoluble extracellular matrix resistant to proteolytic degradation. 3We hypothesized that testosterone-mediated suppression of LOX activity is a critical contributor to increased susceptibility of male to AAA formation.Ethics and institutional review board approvals were provided by University of Kentucky (Protocol-2011-0907) and the Ehime University (Protocol-1603002), and informed consent was received from all participants.To test this hypothesis, we first evaluated LOX protein in human male and female, nonaneurysmal and aneurysmal, abdominal aortic sections.LOX protein was significantly more abundant in the aortic media in female nonaneurysmal and aneurysmal aortic sections than in male nonaneurysmal and aneurysmal aortic sections (Figure A).Consistent with observations in humans, abdominal aortas from female C57BL/6J mice showed significantly more LOX protein in the aortic media than from male mice (Figure B).To discern whether this sexual dimorphism was functionally relevant, we examined LOX activity by measuring breakdown of fluorescent-labeled LOX substrate in aortic tissues from male and female mice infused with either saline or AngII (1000 ng•kg -1 •min -1 ) for 7 days.Consistent with LOX protein abundance, LOX activity in female aortic tissue was ≈2.5-fold significantly higher than in male aortic tissue, and AngII infusion had no influence on LOX activity in either sex (Figure C).To explore whether sex hormones regulate aortic LOX activity, 8-week-old male and female mice were subjected to either castration (orchiectomy or ovariectomy) or sham operation.Four weeks after surgery, abdominal aortic LOX activity was measured.Orchiectomy of male mice not only significantly increased LOX activity, in comparison with sham controls, but to a level present in female mice.Ovariectomy had no influence on LOX activity in female mice in comparison with sham controls (Figure D).Furthermore, testosterone replacement by dihydrotestosterone pellet (16 µg/d subcutaneously) administration for 2 weeks significantly suppressed LOX activity in orchiectomized mice similar to sham controls (Figure E).These results suggest that androgens, not estrogens, regulate and suppress aortic LOX activity in mice.

The sex difference in depression has long been an unsolved issue. Women are twice as likely to suffer from depression as men. However, there were significant differences in the composition of gut microbiota between women and men. There is a lack of studies linking sex differences in depression to microbiota, and the specific mechanisms of this process have not been explained in detail. The main purpose of this study was to explore the gender differences in the intestinal tract of male and female depressed mice. In this study, chronic restraint stress (CRS) mouse models were used to simulate chronic stress, and behavioral tests were conducted, including the open field test (OFT), tail suspension test (TST) and forced swimming test (FST). Microbial diversity analysis and metabolomics were performed on collected mouse feces. The results showed that female mice were highly active and prone to anxious behavior before stress, and the levels of f-Rikenellaceae, f-Ruminococcaceae and 16α-hydroxyestrone were significantly different from those in male mice. After 21days (Days) of stress, female mice showed depression-like behavior, and the levels of f-Erysipelotrichaceae, 5α-pregnane-3,20-dione, and 2-hydroxyestradiol were significantly different from those in male mice. After 14days of stress withdrawal, the depression-like behavior continued to worsen in female mice, and the levels of 5α-pregnane-3,20-dione, estrone glucuronide and f-Erysipelotrichaceae were significantly different from those in male mice. In summary, female mice have stronger stress sensitivity and weaker resilience than male mice, which may be related to differences in bacterial diversity and estrogen metabolism disorders.

Skeletal muscle atrophy occurs under a variety of conditions and can result from alterations in both protein synthesis and protein degradation. The muscle-specific E3 ubiquitin ligases, MuRF1 and MAFbx, are excellent markers of muscle atrophy and increase under divergent atrophy-inducing conditions such as denervation and glucocorticoid treatment. While deletion of MuRF1 or MAFbx has been reported to spare muscle mass following 14 days of denervation, their role in other atrophy-inducing conditions is unclear. The goal of this study was to determine whether deletion of MuRF1 or MAFbx attenuates muscle atrophy after 2 weeks of treatment with the synthetic glucocorticoid dexamethasone (DEX). The response of the triceps surae (TS) and tibialis anterior (TA) muscles to 14 days of DEX treatment (3 mg kg(-1) day(-1)) was examined in 4 month-old male and female wild type (WT) and MuRF1 or MAFbx knock out (KO) mice. Following 14 days of DEX treatment, muscle wet weight was significantly decreased in the TS and TA of WT mice. Comparison of WT and KO mice following DEX treatment revealed significant sparing of mass in both sexes of the MuRF1 KO mice, but no muscle sparing in MAFbx KO mice. Further analysis of the MuRF1 KO mice showed significant sparing of fibre cross-sectional area and tension output in the gastrocnemius (GA) after DEX treatment. Muscle sparing in the MuRF1 KO mice was related to maintenance of protein synthesis, with no observed increases in protein degradation in either WT or MuRF1 KO mice. These results demonstrate that MuRF1 and MAFbx do not function similarly under all atrophy models, and that the primary role of MuRF1 may extend beyond controlling protein degradation via the ubiquitin proteasome system.

Absence seizures in man are behaviourally manifested as arrest and mild jerks mainly of facial muscles, associated in the electroencephalogram with synchronous spike and wave discharges. Gamma-hydroxybutyrolactone (GHBL) administration is currently used as an experimental model of absence seizures in rats and mice. The aim of the present study was to examine the effects of three potent gamma-aminobutyric acid (GABA)B receptor antagonists CGP55845A, CGP62349 and CGP71982 (0.01 mg/kg) on the development of GHBL-induced absence epilepsy and in learning paradigms of active and passive avoidance tests in GHBL-treated mice and rats. After 4 weeks of development of the absence syndrome, active and passive avoidance tests with negative reinforcement were performed. In both animal species, the absence syndrome was observed after 3 weeks of treatment in the saline group. The GABAB receptor antagonists CGP55845A and CGP62349 appeared to suppress the development of the absence syndrome to a greater degree in mice than in rats. CGP71982 suppressed it later than the other two antagonists (fifth week). In an active avoidance test in GHBL-treated mice, the GABAB antagonists had different effects - CGP62349 improved learning and memory retention to a greater extent than CGP55845A, whilst CGP71982 had no influence on it. In a passive avoidance test in GHBL-treated mice, the GABAB antagonists also had different effects - CGP71982 improved both learning and memory retrieval, whereas CGP55845A and CGP62349 had no effect. In the active avoidance test in GHBL-treated rats, the GABAB antagonist CGP55845A improved learning, whereas the other two, CGP62349 and CGP71982, had no effect. In the passive avoidance test the GHBL-treated rats showed an improvement in short memory retrieval. CGP55845A and CGP71982 improved this further, whilst CGP62349 had no effect. GHBL appeared to influence mice and rats in a different manner - rats learned the active avoidance task better than the GHBL-treated mice. The present study confirms previous data that GABAB antagonists suppress absence behaviour.

BackgroundGroup 2 innate lymphoid cells (ILC2s) are the most dominant ILCs in heart tissue, and sex-related differences exist in mouse lung ILC2 phenotypes and functions; however, it is still unclear whether there are sex differences in heart ILC2s.ResultsCompared with age-matched wild-type (WT) male mice, 8-week-old but not 3-week-old WT female mice harbored an obviously greater percentage and number of heart ILC2s in homeostasis. However, the percentage of killer-cell lectin-like receptor G1 (Klrg1)− ILC2s was higher, but the Klrg1+ ILC2s were lower in female mice than in male mice in both heart tissues of 3- and 8-week-old mice. Eight-week-old Rag2−/− mice also showed sex differences similar to those of age-matched WT mice. Regarding surface marker expression, compared to age-matched male mice, WT female mice showed higher expression of CD90.2 and Ki67 and lower expression of Klrg1 and Sca-1 in heart total ILC2s. There was no sex difference in IL-4 and IL-5 secretion by male and female mouse heart ILC2s. Increased IL-33 mRNA levels within the heart tissues were also found in female mice compared with male mice. By reanalyzing published single-cell RNA sequencing data, we found 2 differentially expressed genes between female and male mouse heart ILC2s. Gene set variation analysis revealed that the glycine, serine and threonine metabolism pathway was upregulated in female heart ILC2s. Subcluster analysis revealed that one cluster of heart ILC2s with relatively lower expression of Semaphorin 4a and thioredoxin interacting protein but higher expression of hypoxia-inducible lipid droplet-associated.ConclusionsThese results revealed greater numbers of ILC2s, higher expression of CD90.2, reduced Klrg1 and Sca-1 expression in the hearts of female mice than in male mice and no sex difference in IL-4 and IL-5 production in male and female mouse heart ILC2s. These sex differences in heart ILC2s might be due to the heterogeneity of IL-33 within the heart tissue.

Disclosure: M.A. Venegas: None. N. Westray: None. J.S. Pendergast: None. The circadian system aligns 24-hour cycles of internal biological processes with the environmental light-dark cycle. Abrupt shifts in the timing of the light-dark cycle that occur during travel across time zones misalign internal circadian clocks with the environment and cause jet lag. The symptoms of jet lag subside when circadian clocks resynchronize to the new light-dark cycle. Female mice in proestrus resynchronize to shifted light-dark cycles faster than males. The objective of this study was to investigate the estrogen signaling mechanisms underlying this sex difference in jet lag in mice. We measured wheel-running activity rhythms in C57BL/6J male and female wild-type (WT) and ERα knockout (ERαKO) mice. Female WT mice had 2-fold greater daily activity than male mice. Disabling the function of ERα ablated the sex difference in daily activity; both male and female ERαKO mice had markedly reduced activity compared to WT mice. Next, we advanced the timing of the light-dark cycle by 6 hours to simulate eastward travel. Female WT mice resynchronized to the new light-dark cycle faster than WT males. This sex difference was abolished in ERαKO mice. The rate of resynchronization was slower in female ERaKO mice compared to WT females and was indistinguishable from males. We next investigated 2 putative mechanisms underlying the accelerated rate of resynchronization in WT females. First, mice with faster endogenous clocks resynchronize to new light-dark cycles faster. However, we found that the velocity of the endogenous clock (circadian period) did not differ between WT and ERαKO male and female mice. Second, mice with greater phase advances to light exposure in the late night also resynchronize faster. To determine the magnitude of phase advances, we housed mice in constant darkness and then exposed them to a 15-minute light pulse during the late subjective night. We found no differences in the magnitudes of phase shifts between WT and ERαKO male and female mice. Together these studies show that ERα regulates the rate of resynchronization to shifted light-dark cycles in female mice but does not do so by altering conventional circadian rhythm parameters. Uncovering the mechanisms underlying the sex difference in resynchronization to shifted light-dark cycles can be used to develop strategies to alleviate jet lag and shift work symptoms. Presentation: 6/3/2024

Pharmacokinetic interaction of sunitinib with diclofenac, paracetamol, mefenamic acid and ibuprofen was evaluated due to their P450 mediated metabolism and OATP1B1, OATP1B3, ABCB1, ABCG2 transporters overlapping features. Male and female mice were administered 6 sunitinib doses (60mg/kg) PO every 12h and 30min before the last dose were administered vehicle (control groups), 250mg/kg paracetamol, 30mg/kg diclofenac, 50mg/kg mefenamic acid or 30mg/kg ibuprofen (study groups), euthanized 6h post last administration and sunitinib plasma, liver, kidney, brain concentrations analyzed. Ibuprofen halved sunitinib plasma concentration in female mice (p<0.01) and showed 59% lower concentration than male mice (p<0.05). Diclofenac and paracetamol female mice showed 45 and 25% higher plasma concentrations than male mice which were 27% lower in mefenamic acid female mice. Paracetamol increased 2.2 (p<0.05) liver and 1.4-fold (p<0.05) kidney sunitinib concentrations in male mice that were lower in female mice (p<0.01, p<0.001, respectively). Ibuprofen increased 2.9-fold (p<0.01) liver concentration in male mice that were higher than in female mice (p<0.001). Female control mice had 35% higher sunitinib brain concentration than male mice but the concentration decreased 37, 33, 10 and 57% in the diclofenac, paracetamol, mefenamic acid and ibuprofen (p<0.001), respectively. Tissue-plasma concentrations correlations were nonsignificant in control, paracetamol, mefenamic acid and ibuprofen groups but was significant in the diclofenac group in male mice (liver, brain) and female mice (liver, kidney). These results portray gender-based sunitinib pharmacokinetic differences and NSAIDs selective effects on male or female mice, with potential clinical translatability.