Loss of muscarinic M5 receptor function manifests disparate impairments in exploratory behavior in male and female mice despite common dopamine regulation

There are five cloned muscarinic acetylcholine receptors (M1-M5). Of these, the muscarinic type 5 receptor (M5) is the only one localized to dopamine neurons in the ventral tegmental area and substantia nigra. Unlike M1-M4, the M5 receptor has relatively restricted expression in the brain, making it an attractive therapeutic target. Here we performed an in-depth characterization of M5-dependent potentiation of dopamine transmission in the nucleus accumbens and accompanying exploratory behaviors in male and female mice. We show that M5 receptors potentiate dopamine transmission by acting directly on the terminals within the nucleus accumbens. Using the agonist oxotremorine, we revealed a unique concentration response curve and a sensitivity to repeated stressor exposure. We found that constitutive deletion of M5 receptors reduced exploration of the center of an open field while at the same time impairing normal habituation only in male mice. In addition, M5 deletion reduced exploration of salient stimuli, especially under conditions of high novelty, yet had no effect on hedonia. We conclude that M5 receptors are critical for both engaging with the environment and updating behavioral output in responses to the environment cues, specifically in male mice. A cardinal feature of mood and anxiety disorders is a withdrawal from the environment. These data indicate that boosting M5 receptor activity may be a useful therapeutic target for ameliorating these symptoms of depression and anxiety.

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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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Gender differences in the response of CD-1 mouse bone to parathyroid hormone: potential role of IGF-I

Journal of Endocrinology ◽

10.1677/joe.1.06351 ◽

2006 ◽

Vol 189 (2) ◽

pp. 279-287 ◽

Cited By ~ 20

Author(s):

Yongmei Wang ◽

Takeshi Sakata ◽

Hashem Z Elalieh ◽

Scott J Munson ◽

Andrew Burghardt ◽

...

Keyword(s):

Gender Differences ◽

Parathyroid Hormone ◽

Cortical Bone ◽

Mineral Apposition Rate ◽

Mrna Levels ◽

Male Mice ◽

Bone Formation Rate ◽

Male And Female ◽

Female Mice ◽

Igf I

Parathyroid hormone (PTH) exerts both catabolic and anabolic actions on bone. Studies on the skeletal effects of PTH have seldom considered the effects of gender. Our study was designed to determine whether the response of mouse bone to PTH differed according to sex. As a first step, we analyzed gender differences with respect to bone mass and structural properties of 4 month old PTH treated (80 μg/kg per day for 2 weeks) male and female CD-1 mice. PTH significantly increased fat free weight/body weight, periosteal bone formation rate, mineral apposition rate, and endosteal single labeling surface, while significantly decreasing medullary area in male mice compared with vehicle treated controls, but induced no significant changes in female mice. We then analyzed the gender differences in bone marrow stromal cells (BMSC) isolated from 4 month old male and female CD-1 mice following treatment with PTH (80 μg/kg per day for 2 weeks). PTH significantly increased the osteogenic colony number and the alkaline phosphatase (ALP) activity (ALP/cell) by day 14 in cultures of BMSCs from male and female mice. PTH also increased the mRNA level of receptor activator of nuclear factor κB ligand in the bone tissue (marrow removed) of both females and males. However, PTH increased the mRNA levels of IGF-I and IGF-IR only in the bones of male mice. Our results indicate that on balance a 2-weeks course of PTH is anabolic on cortical bone in this mouse strain. These effects are more evident in the male mouse. These differences between male and female mice may reflect the greater response to PTH of IGF-I and IGF-IR gene expression in males enhancing the anabolic effect on cortical bone.

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Reevaluation of Hepatocellular Neoplasms in CD-1 Mice from a 2-year Oral Carcinogenicity Study with Permethrin

Toxicologic Pathology ◽

10.1177/0192623318809304 ◽

2018 ◽

Vol 47 (1) ◽

pp. 11-17 ◽

Cited By ~ 3

Author(s):

Erin M. Quist ◽

Gary A. Boorman ◽

John M. Cullen ◽

Robert R. Maronpot ◽

Amera K. Remick ◽

...

Keyword(s):

Chronic Toxicity ◽

Expert Panel ◽

Biological Significance ◽

Male Mice ◽

Male And Female ◽

Female Mice ◽

Carcinogenicity Study ◽

Dose Dependent Increase ◽

Dose Dependent ◽

The Continuum

A 24-month oral carcinogenicity study of permethrin was conducted by feeding male and female CD-1 mice diets containing concentrations of 0, 20, 500, and 2,000 ppm of permethrin (males) or 0, 20, 2,500, and 5,000 ppm of permethrin (females). After approximately two years on study, surviving mice were sacrificed for the evaluation of chronic toxicity and/or carcinogenicity. An expert panel of pathologists was convened as a Pathology Working Group (PWG) to review coded liver histology sections from male and female mice and to classify all liver neoplasms according to current nomenclature and diagnostic criteria guidelines. The PWG results indicate that permethrin induced a significant dose-dependent increase in the incidence of hepatocellular neoplasms in treated female mice ( p < .01) as well as a nonstatistically significant increase in the incidence of hepatocellular tumors in treated male mice. Given the continuum of the diagnoses of adenoma and carcinoma, and the difficulty in distinguishing some of the lesions, it is appropriate to consider only the combined incidences of hepatocellular tumors (adenoma and/or carcinoma) for biological significance and risk assessment.

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Ovarian hormones mediate the prophylactic efficacy of (R,S)-ketamine and (2R,6R)-hydroxynorketamine in female mice

10.1101/712752 ◽

2019 ◽

Author(s):

Briana K. Chen ◽

Christina T. LaGamma ◽

Xiaoming Xu ◽

Shi-Xian Deng ◽

Rebecca A. Brachman ◽

...

Keyword(s):

Learned Helplessness ◽

Hormone Replacement ◽

Ovarian Hormones ◽

Contextual Fear Conditioning ◽

Male Mice ◽

Prophylactic Efficacy ◽

Male And Female ◽

Female Mice ◽

Learned Fear ◽

Necessary And Sufficient

ABSTRACTBACKGROUNDFemales are more likely than males to develop major depressive disorder (MDD) after exposure to stress. We previously reported that the administration of (R,S)-ketamine before stress can prevent stress-induced depressive-like behavior in male mice but have yet to assess efficacy in female mice or for other compounds, such as the metabolites of (R,S)-ketamine.METHODSWe administered (R,S)-ketamine or its metabolites (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) and (2S,6S)-HNK at various doses 1 week before one of a number of stressors, including contextual fear conditioning (CFC), learned helplessness (LH), and chronic immobilization stress (CIS), in male and female 129S6/SvEv mice. To examine the interaction between ovarian hormones and stress resilience, female mice also underwent ovariectomy surgery (OVX) and a hormone replacement protocol prior to drug administration.RESULTS(R,S)-ketamine and (2S,6S)-HNK, but not (2R,6R)-HNK, attenuated learned fear in male mice. (R,S)-ketamine and (2R,6R)-HNK, but not (2S,6S)-HNK, significantly reduced stress-induced depressive-like behavior in male and female mice. (R,S)-ketamine and (2R,6R)-HNK) were prophylactically effective at a lower dose (10 mg/kg and 0.025 mg/kg, respectively) in female mice than in male mice (30 mg/kg and 0.075 mg/kg, respectively). Moreover, ovarian-derived hormones were necessary and sufficient for prophylaxis in female mice.CONCLUSIONSOur results suggest that prophylactics against stress-induced depressive-like behavior can be developed in a sex-specific manner and that ovarian hormones mediate prophylactic efficacy in females. To our knowledge, this is the first demonstration of the prophylactic efficacy of the metabolites of (R,S)-ketamine in male and female mice.

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Adolescent intermittent ethanol exposure induces sex-dependent divergent changes in ethanol drinking and motor activity in adulthood in C57BL/6J mice

10.1101/2020.04.28.066472 ◽

2020 ◽

Cited By ~ 1

Author(s):

Antoniette M. Maldonado-Devincci ◽

Joseph G. Makdisi ◽

Andrea M. Hill ◽

Renee C. Waters ◽

Nzia I. Hall ◽

...

Keyword(s):

Open Field ◽

Ethanol Consumption ◽

Ethanol Exposure ◽

Male Mice ◽

Open Field Behavior ◽

Male And Female ◽

Female Mice ◽

Binge Ethanol Exposure ◽

Binge Ethanol

AbstractWith alcohol readily accessible to adolescents, its consumption leads to many adverse effects, including impaired learning, attention, and behavior. Adolescents report higher rates of binge drinking compared to adults. Adolescents are also more prone to substance use disorder during adulthood due to physiological changes during the adolescent developmental period. We used C57BL/6J male and female mice to investigate the long-lasting impact of binge ethanol exposure during adolescence on voluntary ethanol intake and open field behavior during later adolescence and in young adulthood. The present set of experiments were divided into four stages: (1) chronic intermittent vapor inhalation exposure, (2) abstinence, (3) voluntary ethanol intake, and (4) open field behavioral testing. During adolescence, male and female mice were exposed to air or ethanol using an intermittent vapor inhalation with repeated binge pattern ethanol exposure from postnatal day (PND) 28–42. Following this, mice underwent abstinence during late adolescence from PND 43–49 (Experiment 1) or PND 43–69 (Experiment 2). Beginning on PND 49–76 (Experiment 1) or PND 70–97 (Experiment 2), mice were assessed for intermittent voluntary ethanol consumption using a two-bottle drinking procedure over 28 days. Male mice that were exposed to ethanol during adolescence showed increased ethanol consumption during later adolescence (Experiment 1) and in emerging adulthood (Experiment 2), while the female mice showed decreased ethanol consumption. These data demonstrate a sexually divergent shift in ethanol consumption following binge ethanol exposure during adolescence and differences in open field behavior. These data highlight sex-dependent vulnerability to developing substance use disorders in adulthood.Significance StatementCurrently, it is vital to determine the sex-dependent impact of binge alcohol exposure during adolescence, given that until recently females have largely been ignored. Here we show that adolescent male mice that are exposed to binge ethanol during adolescence show long-term changes in behavior in adulthood. In contrast, female mice show a transient decrease in ethanol consumption in adulthood and decreased motor activity spent in the center zone of the open field test. Male mice appear to be more susceptible to the long-term changes in ethanol consumption following binge ethanol exposure during adolescence.

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Certain aspects of the host-parasite relationship of Nematospiroides dubius (Baylis). I. Resistance of male and female mice to experimental infections

Parasitology ◽

10.1017/s0031182000068578 ◽

1961 ◽

Vol 51 (1-2) ◽

pp. 173-179 ◽

Cited By ~ 60

Author(s):

Colin Dobson

Keyword(s):

Relative Length ◽

Industrial Research ◽

Male Mice ◽

Male And Female ◽

Female Mice ◽

Host Parasite Relationship ◽

Parasite Relationship ◽

Nematospiroides Dubius ◽

Host Parasite ◽

Relationship Of

1. It has been shown that there is a difference between the resistance of male and female mice to infection with Nematospiroides dubius.2. More parasites were harboured, during both the larval and adult parasitic phases, by male mice.3. These worms were found to occupy a similar relative length of the intestine between the stomach and the caecum in male and female mice infected for either 5 or 10 days.4. The relative length of the intestine infected on the fifth day was significantly greater than that infected on the tenth day.This investigation was carried out during the tenure of a Research Studentship from the Department of Scientific and Industrial Research. I should like to thank Professor I. Chester Jones, in whose department the work was done, for the facilities provided and Dr E. T. B. Francis for his helpful and critical supervision.

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Sex Differences in the Relation Between Frailty and Endothelial Dysfunction in Old Mice

The Journals of Gerontology Series A ◽

10.1093/gerona/glab317 ◽

2021 ◽

Author(s):

Jazmin A Cole ◽

Mackenzie N Kehmeier ◽

Bradley R Bedell ◽

Sahana Krishna Kumaran ◽

Grant D Henson ◽

...

Keyword(s):

Sex Differences ◽

Endothelial Function ◽

Vascular Function ◽

Mesenteric Artery ◽

Frailty Index ◽

Mesenteric Arteries ◽

Male Mice ◽

Male And Female ◽

Female Mice ◽

Age Related

Abstract Vascular endothelial function declines with age on average, but there is high variability in the magnitude of this decline within populations. Measurements of frailty, known as frailty index (FI), can be used as surrogates for biological age, but it is unknown if frailty relates to the age-related decline in vascular function. To examine this relation, we studied young (4-9 months) and old (23-32 months) C57BL6 mice of both sexes. We found that FI was greater in old compared with young mice, but did not differ between old male and female mice. Middle cerebral artery (MCA) and mesenteric artery endothelium-dependent dilation (EDD) also did not differ between old male and female mice; however, there were sex differences in the relations between FI and EDD. For the MCA, FI was inversely related to EDD among old female mice, but not old male mice. In contrast, for the mesenteric artery, FI was inversely related to EDD among old male mice, but not old female mice. A higher FI was related to a greater improvement in EDD with the superoxide scavenger TEMPOL in the MCAs for old female mice and in the mesenteric arteries for old male mice. FI related to mesenteric artery gene expression negatively for extracellular superoxide dismutase (Sod3) and positively for interleukin-1β (Il1b). In summary, we found that the relation between frailty and endothelial function is dependent on sex and the artery examined. Arterial oxidative stress and pro-inflammatory signaling are potential mediators of the relations of frailty and endothelial function.

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The Effect of Polyphenolic Composition BP-C3 on the Efficacy and Hematological Toxicity of Cyclophosphamide in the Chemotherapy of Mice Bearing Soft Tissue Sarcomas Induced by Benzo[a]pyrene

Integrative Cancer Therapies ◽

10.1177/1534735419833778 ◽

2019 ◽

Vol 18 ◽

pp. 153473541983377 ◽

Cited By ~ 1

Author(s):

Andrey V. Panchenko ◽

Elena I. Fedoros ◽

Sergey E. Pigarev ◽

Mikhail A. Maydin ◽

Ekaterina A. Gubareva ◽

...

Keyword(s):

Soft Tissue ◽

Antitumor Activity ◽

Soft Tissue Sarcomas ◽

Hematological Toxicity ◽

Tumor Growth Inhibition ◽

Male Mice ◽

Blood Cell Count ◽

Male And Female ◽

Female Mice ◽

Polyphenolic Composition

This study aimed to evaluate the effect of lignin-derived polyphenolic composition BP-C3 on the efficacy and hematological toxicity of cyclophosphamide (CPA). Male and female Swiss-H derived mice bearing benzo[a]pyrene-induced soft tissue sarcomas were treated with CPA 300 mg/kg, BP-C3 75 mg/kg, or a combination. Tumor growth inhibition in male mice treated with CPA, BP-C3, or a combination of CPA and BP-C3 was significant and corresponded to 78%, 45%, and 82%, respectively, on day 21 after CPA administration on day 0. In female mice, tumor growth inhibition was 58%, −11%, and 35% when treated with CPA, BP-C3, or a combination of CPA and BP-C3, respectively. CPA administration resulted in significant hematological toxicity evidenced by a decreased white blood cell count on day 4 (2.43 ± 1.77 × 109/L in male mice and 1.19 ± 0.71 × 109/L in female mice) and anemia development on day 7 (6.55 ± 1.74 × 1012/L in male mice and 5.89 ± 2.24 × 1012/L in female mice). The red blood cell count measured on day 7 in animals treated with the combination of BP-C3 and CPA constituted 7.12 ± 1.17 × 1012/L and 7.36 ± 2.07 × 1012/L for male and female mice, respectively. The results of our study demonstrate the antitumor activity of BP-C3 in male mice bearing soft tissue sarcomas. Neither the antitumor activity nor the hematological toxicity of CPA were significantly influenced by BP-C3. A less pronounced effect of CPA on RBC count is demonstrated when this agent is given jointly with BP-C3.

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Sex differences in renal and metabolic responses to a high-fructose diet in mice

AJP Renal Physiology ◽

10.1152/ajprenal.00403.2014 ◽

2015 ◽

Vol 308 (5) ◽

pp. F400-F410 ◽

Cited By ~ 17

Author(s):

Nikhil Sharma ◽

Lijun Li ◽

C. M. Ecelbarger

Keyword(s):

Sex Differences ◽

Glucose Transporter ◽

Collecting Duct ◽

Urine Volume ◽

Thick Ascending Limb ◽

Male Mice ◽

Male And Female ◽

Female Mice ◽

High Fructose Diet ◽

High Fructose

High fructose intake has been associated with increased incidences of renal disease and hypertension, among other pathologies. Most fructose is cleared by the portal system and metabolized in the liver; however, systemic levels of fructose can rise with increased consumption. We tested whether there were sex differences in the renal responses to a high-fructose diet in mice. Two-month-old male and female C57BL6/129/SV mice ( n = 6 mice per sex per treatment) were randomized to receive control or high-fructose (65% by weight) diets as pelleted chow ad libitum for 3 mo. Fructose feeding did not significantly affect body weight but led to a 19% and 10% increase in kidney weight in male and female mice, respectively. In male mice, fructose increased the expression (∼50%) of renal cortical proteins involved in metabolism, including glucose transporter 5 (facilitative fructose transporter), ketohexokinase, and the insulin receptor (β-subunit). Female mice had lower basal levels of glucose transporter 5, which were unresponsive to fructose. However, female mice had increased urine volume and plasma K+ and decreased plasma Na+ with fructose, whereas male mice were less affected. Likewise, female mice showed a two- to threefold reduction in the expression Na+-K+-2Cl− cotransporter 2 in the thick ascending limb and aquaporin-2 in the collecting duct with fructose relative to female control mice, whereas male mice had no change. Overall, our results support greater proximal metabolism of fructose in male animals and greater distal tubule/collecting duct (electrolyte homeostasis) alterations in female animals. These sex differences may be important determinants of the specific nature of pathologies that develop in association with high fructose consumption.

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Molecular diagnosis of acute and chronic infection of Trypanosoma evansi in experimental male and female mice

Onderstepoort Journal of Veterinary Research ◽

10.4102/ojvr.v86i1.1638 ◽

2019 ◽

Vol 86 (1) ◽

Author(s):

Tahani S. Behour ◽

Shawky M. Aboelhadid ◽

Wahid M. Mousa ◽

Adel S. Amin ◽

Saeed A. El-Ashram

Keyword(s):

Trypanosoma Evansi ◽

Molecular Techniques ◽

Male Mice ◽

Male And Female ◽

Chronic Stage ◽

Female Mice ◽

Parasitaemia Level ◽

Centrifugation Technique ◽

Polymerase Chain ◽

Primer Sets

Trypanosoma evansi is enzootic in camels in Egypt, and water buffaloes act as a reservoir for camel infection. Molecular techniques have contributed towards understanding the epidemiology of T. evansi. Trypanosoma evansi was detected in acute and chronic stages of the disease in male and female mice by polymerase chain reaction (PCR) using two primers. Two experiments were conducted. In experiment I, two groups consisting of 26 female and 26 male mice received 104 trypanosome by I/P inoculation for each mouse. In experiment II, 42 female and 42 male mice were inoculated I/P with 102 trypanosome/mouse. In addition, five mice were kept as uninfected control for each group. Mice were monitored daily for parasitaemia level during the pre-patent period using the micro-haematocrit centrifugation technique (MHCT) and conventional PCR. The primer pairs, (Trypanosoma brucei) TBR1/2 and TeRoTat1.2 (T. evansi Rode Trypanozoon antigen type [RoTat] 1.2), detected the infection after 24 hours earlier than MHCT in both experiments. The course of infection that was detected by MHCT revealed three waves of parasitaemia in female mice and two waves in male mice in the chronic stage of infection. In addition, PCR was able to detect T. evansi in different organs in the chronic stage (i.e. disappearance of parasite from blood). Application of the two primer sets on blood samples from camels showed that all samples were positive by TBR1/2 primers and only 32 of 44 were positive by TeRoTat1.2 primers. Acutely and chronically Trypanosoma-infected mice were detected by PCR in blood and organs. TBR1/2 primers were more sensitive than TeRoTat1.2 primers in detecting Trypanosoma-infected mice, and more reliable in detecting field-infected camels and excluding carrier animals.

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