Effects of Sub-Chronic MPTP Exposure on Behavioral and Cognitive Performance and the Microbiome of Wild-Type and mGlu8 Knockout Female and Male Mice

Aside from abnormal angiogenesis, dual endothelin-1/VEGF signal peptide-activated receptor deficiency ( DEspR−/−) results in aberrant neuroepithelium and neural tube differentiation, thus elucidating DEspR's role in neurogenesis. With the emerging importance of neurogenesis in adulthood, we tested the hypothesis that nonembryonic-lethal DEspR haploinsufficiency ( DEspR+/−) perturbs neuronal homeostasis, thereby facilitating aging-associated neurodegeneration. Here we show that, in male mice only, DEspR-haploinsufficiency impaired hippocampus-dependent visuospatial and associative learning and induced noninflammatory spongiform changes, neuronal vacuolation, and loss in the hippocampus, cerebral cortex, and subcortical regions, consistent with autophagic cell death. In contrast, DEspR+/− females exhibited better cognitive performance than wild-type females and showed absence of neuropathological changes. Signaling pathway analysis revealed DEspR-mediated phosphorylation of activators of autophagy inhibitor mammalian target of rapamycin (mTOR) and dephosphorylation of known autophagy inducers. Altogether, the data demonstrate DEspR-mediated diametrical, sex-specific modulation of cognitive performance and autophagy, highlight cerebral neuronal vulnerability to autophagic dysregulation, and causally link DEspR haploinsufficiency with increased neuronal autophagy, spongiosis, and cognitive decline in mice.

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Progesterone's Effects on Cognitive Performance of Male Mice Are Independent of Progestin Receptors but Relate to Increases in GABAA Activity in the Hippocampus and Cortex

Frontiers in Endocrinology ◽

10.3389/fendo.2020.552805 ◽

2021 ◽

Vol 11 ◽

Author(s):

Cheryl A. Frye ◽

Vincent F. Lembo ◽

Alicia A. Walf

Keyword(s):

Object Recognition ◽

Cognitive Performance ◽

Adult Male ◽

Water Maze ◽

Recognition Task ◽

Male Mice ◽

Wild Type ◽

Maze Task ◽

Progestin Receptors ◽

Muscimol Binding

Progestogens' (e.g., progesterone and its neuroactive metabolite, allopregnanolone), cognitive effects and mechanisms among males are not well-understood. We hypothesized if progestogen's effects on cognitive performance are through its metabolite allopregnanolone, and not actions via binding to traditional progestin receptors (PRs), then progesterone administration would enhance performance in tasks mediated by the hippocampus and cortex, coincident with increasing allopregnanolone concentrations, brain derived neurotrophic factor (BDNF) and/or muscimol binding of PR knock out (PRKO) and wild-type PR replete mice. Experiment 1: Progesterone (4 mg/kg, subcutaneously (SC; n = 12/grp), or oil vehicle control, was administered to gonadally-intact adult male mice PRKO mice and their wild-type counterparts and cognitive behaviors in object recognition, T-maze and water maze was examined. Progesterone, compared to vehicle, when administered post-training increased time investigating novel objects by the PRKO and wild-type mice in the object recognition task. In the T-maze task, progesterone administration to wild-type and PRKO mice had significantly greater number of spontaneous alternations compared to their vehicle-administered counterparts. In the water maze task, PRKO mice administered vehicle spent significantly fewer seconds in the quadrant associated with the escape platform on testing compared to all other groups. Experiment 2: Progesterone administered to wild-type and PRKO mice increased plasma progesterone and allopregnanolone levels (n = 5/group). PRKO mice had higher allopregnanolone levels in plasma and hippocampus, but not cortex, when administered progesterone and compared to wild-type mice. Experiment 3: Assessment of PR binding revealed progesterone administered wild-type mice had significantly greater levels of PRs in the hippocampus and cortex, compared to all other groups (n = 5/group). Wild-type mice administered progesterone, but not vehicle, had increased BDNF levels in the hippocampus, but not the cortex, compared to PRKOs. Wild-type as well as PRKO mice administered progesterone experienced significant increases in maximal GABAA agonist, muscimol, binding in hippocampus and cortex, compared to their vehicle-administered counterparts. Thus, adult male mice can be responsive to progesterone for cognitive performance, and such effects may be independent of PRs trophic actions of BDNF levels in the hippocampus and/or increases in GABAA activity in the hippocampus and cortex.

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NPY Deficiency Prevents Postmenopausal Adiposity by Augmenting Estradiol-Mediated Browning

The Journals of Gerontology Series A ◽

10.1093/gerona/gly282 ◽

2018 ◽

Vol 75 (6) ◽

pp. 1042-1049

Author(s):

Seongjoon Park ◽

Erkhembayar Nayantai ◽

Toshimitsu Komatsu ◽

Hiroko Hayashi ◽

Ryoichi Mori ◽

...

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

Fat Metabolism ◽

Male Mice ◽

Wild Type ◽

Male And Female ◽

Female Mice ◽

Age Related ◽

Promising Target ◽

Intracellular Mechanism

Abstract The orexigenic hormone neuropeptide Y (NPY) plays a pivotal role in the peripheral regulation of fat metabolism. However, the mechanisms underlying the effects of sex on NPY function have not been extensively analyzed. In this study, we examined the effects of NPY deficiency on fat metabolism in male and female mice. Body weight was slightly decreased, whereas white adipose tissue (WAT) mass was significantly decreased as the thermogenic program was upregulated in NPY-/- female mice compared with that in wild-type mice; these factors were not altered in response to NPY deficiency in male mice. Moreover, lack of NPY resulted in an increase in luteinizing hormone (LH) expression in the pituitary gland, with concomitant activation of the estradiol-mediated thermogenic program in inguinal WAT, and alleviated age-related modification of adiposity in female mice. Taken together, these data revealed a novel intracellular mechanism of NPY in the regulation of fat metabolism and highlighted the sexual dimorphism of NPY as a promising target for drug development to reduce postmenopausal adiposity.

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Lower skeletal muscle mass in male transgenic mice with muscle-specific overexpression of myostatin

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00107.2003 ◽

2003 ◽

Vol 285 (4) ◽

pp. E876-E888 ◽

Cited By ~ 193

Author(s):

Suzanne Reisz-Porszasz ◽

Shalender Bhasin ◽

Jorge N. Artaza ◽

Ruoqing Shen ◽

Indrani Sinha-Hikim ◽

...

Keyword(s):

Skeletal Muscle ◽

Transgenic Mice ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Fluorescent Protein ◽

Male Mice ◽

Wild Type ◽

Specific Expression ◽

Muscle Weight ◽

Myostatin Gene

Mutations in the myostatin gene are associated with hypermuscularity, suggesting that myostatin inhibits skeletal muscle growth. We postulated that increased tissue-specific expression of myostatin protein in skeletal muscle would induce muscle loss. To investigate this hypothesis, we generated transgenic mice that overexpress myostatin protein selectively in the skeletal muscle, with or without ancillary expression in the heart, utilizing cDNA constructs in which a wild-type (MCK/Mst) or mutated muscle creatine kinase (MCK-3E/Mst) promoter was placed upstream of mouse myostatin cDNA. Transgenic mice harboring these MCK promoters linked to enhanced green fluorescent protein (EGFP) expressed the reporter protein only in skeletal and cardiac muscles (MCK) or in skeletal muscle alone (MCK-3E). Seven-week-old animals were genotyped by PCR of tail DNA or by Southern blot analysis of liver DNA. Myostatin mRNA and protein, measured by RT-PCR and Western blot, respectively, were significantly higher in gastrocnemius, quadriceps, and tibialis anterior of MCK/Mst-transgenic mice compared with wild-type mice. Male MCK/Mst-transgenic mice had 18–24% lower hind- and forelimb muscle weight and 18% reduction in quadriceps and gastrocnemius fiber cross-sectional area and myonuclear number (immunohistochemistry) than wild-type male mice. Male transgenic mice with mutated MCK-3E promoter showed similar effects on muscle mass. However, female transgenic mice with either type of MCK promoter did not differ from wild-type controls in either body weight or skeletal muscle mass. In conclusion, increased expression of myostatin in skeletal muscle is associated with lower muscle mass and decreased fiber size and myonuclear number, decreased cardiac muscle mass, and increased fat mass in male mice, consistent with its role as an inhibitor of skeletal muscle mass. The mechanism of gender specificity remains to be clarified.

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Androgen Receptor-Dependent and Independent Atheroprotection by Testosterone in Male Mice

Endocrinology ◽

10.1210/en.2010-0663 ◽

2010 ◽

Vol 151 (11) ◽

pp. 5428-5437 ◽

Cited By ~ 58

Author(s):

Johan Bourghardt ◽

Anna S. K. Wilhelmson ◽

Camilla Alexanderson ◽

Karel De Gendt ◽

Guido Verhoeven ◽

...

Keyword(s):

Androgen Receptor ◽

Apolipoprotein E ◽

High Fat Diet ◽

Atherosclerotic Lesion ◽

Male Mice ◽

Wild Type ◽

High Fat ◽

Lesion Area ◽

Major Pathway

The atheroprotective effect of testosterone is thought to require aromatization of testosterone to estradiol, but no study has adequately addressed the role of the androgen receptor (AR), the major pathway for the physiological effects of testosterone. We used AR knockout (ARKO) mice on apolipoprotein E-deficient background to study the role of the AR in testosterone atheroprotection in male mice. Because ARKO mice are testosterone deficient, we sham operated or orchiectomized (Orx) the mice before puberty, and Orx mice were supplemented with placebo or a physiological testosterone dose. From 8 to 16 wk of age, the mice consumed a high-fat diet. In the aortic root, ARKO mice showed increased atherosclerotic lesion area (+80%, P < 0.05). Compared with placebo, testosterone reduced lesion area both in Orx wild-type (WT) mice (by 50%, P < 0.001) and ARKO mice (by 24%, P < 0.05). However, lesion area was larger in testosterone-supplemented ARKO compared with testosterone-supplemented WT mice (+57%, P < 0.05). In WT mice, testosterone reduced the presence of a necrotic core in the plaque (80% among placebo-treated vs. 12% among testosterone-treated mice; P < 0.05), whereas there was no significant effect in ARKO mice (P = 0.20). In conclusion, ARKO mice on apolipoprotein E-deficient background display accelerated atherosclerosis. Testosterone treatment reduced atherosclerosis in both WT and ARKO mice. However, the effect on lesion area and complexity was more pronounced in WT than in ARKO mice, and lesion area was larger in ARKO mice even after testosterone supplementation. These results are consistent with an AR-dependent as well as an AR-independent component of testosterone atheroprotection in male mice.

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Dietary Intake of 17α-Ethinylestradiol Promotes HCC Progression in Humanized Male Mice Expressing Sex Hormone-Binding Globulin

International Journal of Molecular Sciences ◽

10.3390/ijms222212557 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12557

Author(s):

Sang R. Lee ◽

Su Hee Jeong ◽

Jun H. Heo ◽

Seong Lae Jo ◽

Je-Won Ko ◽

...

Keyword(s):

High Plasma ◽

Sex Hormone ◽

Sex Hormone Binding Globulin ◽

Hormone Action ◽

Male Mice ◽

Hormone Binding ◽

Wild Type ◽

Synthetic Estrogen ◽

Androgen Binding ◽

Old Mice

Hepatocellular carcinoma (HCC) is a male-oriented malignancy; its progression is affected by sex hormones. 17α-ethinylestradiol (EE2) is a synthetic estrogen widely used as an oral contraceptive; however, it is unknown whether EE2 regulates sex hormone action in HCC. We investigated whether EE2 influences HCC risk in male androgenic environments, using mice expressing human sex hormone-binding globulin (SHBG). Two-week-old male mice were injected with diethyl-nitrosamine (DEN, 25 mg/kg) and fed an EE2 diet for 10 weeks from 30 weeks of age. Development and characteristics of liver cancer were evaluated in 40-week-old mice via molecular and histological analyses. Although EE2 did not increase HCC progression in wild-type mice, SHBG mice exhibited remarkably higher HCC risk when fed EE2. The livers of EE2-treated SHBG mice exhibited substantially increased pro-inflammatory necrosis with high plasma levels of ALT and HMGB1, and intrahepatic injury and fibers. Additionally, increased androgen response and androgen-mediated proliferation in the livers of EE2-treated SHBG mice and EE2-exposed hepatocytes under SHBG conditions were observed. As a competitor of SHBG-androgen binding, EE2 could bind with SHBG and increase the bioavailability of androgen. Our results revealed that EE2 is a novel risk factor in androgen-dominant men, predisposing them to HCC risk.

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Testosterone production in mice lacking inducible nitric oxide synthase expression is sensitive to restraint stress

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00412.2006 ◽

2007 ◽

Vol 292 (2) ◽

pp. E615-E620 ◽

Cited By ~ 10

Author(s):

Ben A. Weissman ◽

Chantal M. Sottas ◽

Ping Zhou ◽

Costantino Iadecola ◽

Matthew P. Hardy

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Inducible Nitric Oxide Synthase ◽

Restraint Stress ◽

Immobilization Stress ◽

Male Mice ◽

Wild Type ◽

Basal Plasma ◽

Oxide Synthase ◽

Inducible Nitric Oxide

Immobilization stress (IMO) induces a rapid increase in glucocorticoid secretion [in rodents, corticosterone CORT)] and this is associated with decreased circulating testosterone (T) levels. Nitric oxide (NO), a reactive free radical and neurotransmitter, has been reported to be produced at higher rates in tissues such as brain during stress. The biosynthesis of T is also known to be dramatically suppressed by NO. Specifically, the inducible isoform of nitric oxide synthase (iNOS) was directly implicated in this suppression. To assess the respective roles of CORT and NO in stress-mediated inhibition of T production, adult wild-type (WT) and inducible nitric oxide synthase knockout (iNOS−/−) male mice were evaluated. Animals of each genotype were assigned to either basal control or 3-h IMO groups. Basal plasma and testicular T levels were equivalent in both genotypes, whereas testicular weights of mutant mice were significantly higher compared with WT animals. Exposure to 3-h IMO increased plasma CORT and decreased T concentrations in mice of both genotypes. Testicular T levels were also affected by stress in WT and mutant males, being sharply reduced in both genotypes. However, the concentrations of nitrite and nitrate, the stable metabolites of NO measured in testicular extracts, did not differ between control and stressed WT and iNOS−/− mice. These results support the hypothesis that CORT, but not NO, is a plausible candidate to mediate rapid stress-induced suppression of Leydig cell steroidogenesis.

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Effects of Six Sequential Charged Particle Beams on Behavioral and Cognitive Performance in B6D2F1 Female and Male Mice

Frontiers in Physiology ◽

10.3389/fphys.2020.00959 ◽

2020 ◽

Vol 11 ◽

Author(s):

Jacob Raber ◽

Andrea Fuentes Anaya ◽

Eileen Ruth S. Torres ◽

Joanne Lee ◽

Sydney Boutros ◽

...

Keyword(s):

Charged Particle ◽

Cognitive Performance ◽

Male Mice ◽

Particle Beams ◽

Charged Particle Beams

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17α-Estradiol Modulates IGF1 and Hepatic Gene Expression in a Sex-Specific Manner

The Journals of Gerontology Series A ◽

10.1093/gerona/glaa215 ◽

2020 ◽

Author(s):

Silvana Sidhom ◽

Augusto Schneider ◽

Yimin Fang ◽

Samuel McFadden ◽

Justin Darcy ◽

...

Keyword(s):

Growth Hormone ◽

Insulin Sensitivity ◽

Growth Hormone Receptor ◽

Health Benefits ◽

Male Mice ◽

Wild Type ◽

Somatotropic Axis ◽

Gh Secretion ◽

17Β Estradiol ◽

Estradiol 17Β

Abstract Aging is the greatest risk factor for most chronic diseases. The somatotropic axis is one of the most conserved biological pathways that regulates aging across species. 17α-Estradiol (17α-E2), a diastereomer of 17β-estradiol (17β-E2), was recently found to elicit health benefits, including improved insulin sensitivity and extend longevity exclusively in male mice. Given that 17β-E2 is known to modulate somatotropic signaling in females through actions in the pituitary and liver, we hypothesized that 17α-E2 may be modulating the somatotropic axis in males, thereby contributing to health benefits. Herein, we demonstrate that 17α-E2 increases hepatic insulin-like growth factor 1 (IGF1) production in male mice without inducing any changes in pulsatile growth hormone (GH) secretion. Using growth hormone receptor knockout (GHRKO) mice, we subsequently determined that the induction of hepatic IGF1 by 17α-E2 is dependent upon GH signaling in male mice, and that 17α-E2 elicits no effects on IGF1 production in female mice. We also determined that 17α-E2 failed to feminize the hepatic transcriptional profile in normal (N) male mice, as evidenced by a clear divergence between the sexes, regardless of treatment. Conversely, significant overlap in transcriptional profiles was observed between sexes in GHRKO mice, and this was unaffected by 17α-E2 treatment. Based on these findings, we propose that 17α-E2 acts as a pleiotropic pathway modulator in male mice by uncoupling IGF1 production from insulin sensitivity. In summary, 17α-E2 treatment upregulates IGF1 production in wild-type (and N) male mice in what appears to be a GH-dependent fashion, while no effects in female IGF1 production are observed following 17α-E2 treatment.

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Localized Suppression of Inflammation at Sites of Helicobacter pylori Colonization

Infection and Immunity ◽

10.1128/iai.05602-11 ◽

2011 ◽

Vol 79 (10) ◽

pp. 4186-4192 ◽

Cited By ~ 16

Author(s):

Alison L. Every ◽

Garrett Z. Ng ◽

Caroline D. Skene ◽

Stacey N. Harbour ◽

Anna K. Walduck ◽

...

Keyword(s):

Helicobacter Pylori ◽

Potential Model ◽

Gastric Ph ◽

Male Mice ◽

Wild Type ◽

Content Type ◽

Female Mice ◽

Gastric Corpus ◽

Acid Secreting ◽

H Pylori

ABSTRACTWhile gastric adenocarcinoma is the most serious consequence ofHelicobacter pyloriinfection, not all infected persons develop this pathology. Individuals most at risk of this cancer are those in whom the bacteria colonize the acid-secreting region of the stomach and subsequently develop severe inflammation in the gastric corpus. It has been reported anecdotally that male mice become infected with greater numbers ofH. pyloribacteria than female mice. While investigating this phenomenon, we found that increasedH. pyloriinfection densities in male mice were not related to antibody production, and this phenomenon was not normalized by gonadectomy. However, the gastric pH in male 129/Sv mice was significantly elevated compared with that in female mice. Differences in colonization were evident within 1 day postinfection and significantly arose due to colonization of the gastric corpus region in male mice. This provided a potential model for comparing the effect of corpus colonization on the development of gastritis. This was explored using two models ofH. pylori-induced inflammation, namely, 2-month infections ofMuc1−/−mice and 6-month infections of wild-type 129/Sv mice. WhileH. pyloriinfection of female mice induced a severe, corpus-predominant atrophic gastritis, to our surprise, male mice developed minimal inflammation despite being colonized with significantly moreH. pyloribacteria than female controls. Thus, colonization of the gastric corpus in male mice was associated with a loss of inflammation in that region. The suppression of inflammation concomitant with infection of the gastric corpus in male mice demonstrates a powerful localized suppression of inflammation induced at sites ofH. pyloricolonization.

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