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Introduction: Phytocannabinoids have emerged as a potential alternative treatment option for individuals experiencing persistent pain. However, evidence-based research regarding their clinical utility in both males and females remains incomplete. In addition, it is unknown whether combining readily available cannabinoids with opioids has a synergistic or subadditive effect on pain modulation. To begin to fill this knowledge gap, we investigated the antinociceptive effects of the phytocannabinoid, CBD, either alone or in combination with opioids in male and female C57BL/6J mice. Results: Using the formalin test, our results show that CBD (10 mg/kg, i.p.) treatment evoked antinociception in phase I, but not in phase II, of the formalin test in male mice. However, in female mice, CBD showed no significant antinociceptive effect. In addition, a direct sex comparison showed that CBD evoked a significant increase in nociceptive behaviors in female versus male mice during phase I of the formalin test. Furthermore, we show that CBD (10 mg/kg, i.p.) in combination with low-dose morphine (1 mg/kg, i.p.) was ineffective at eliciting a synergistic antinociceptive response in both male and female mice. Lastly, consistent with previous literature, we showed that females treated with a relatively higher dose of morphine (10 mg/kg, i.p.) displayed a significant increase in the variability of nociceptive behaviors compared to morphine-treated male mice. Conclusion: Overall, our results suggest that CBD treatment may have beneficial antinociceptive effects during the acute phase of persistent pain, but these effects are more beneficial to males than females. We provide further pre-clinical support that treatments geared toward reducing nociceptive behaviors differentially affect males and females.

Females are uniquely sensitive to drugs of abuse at specific points in their reproductive cycle. Females' endogenous opioid system contributes to both reward-related processes and maternally relevant physiological functions, yet less is known about how adolescent opioid exposure impacts females' future behavior, ranging from parental caregiving to opioid preference. The present study explores 2 questions: (a) are there sex differences in response to adolescent oxycodone exposure, spontaneous withdrawal, and oxycodone preference in adulthood, and (b) to what extent does this pregestational opioid exposure alter females' future maternal caregiving behavior? Female and male mice received 12d of oxycodone or saline injections during mid/late adolescence, and drug was then withheld. Some females were then mated and experienced a drug-free pregnancy. Following parturition, females' maternal behavior and motivation were assessed. All mice then underwent a place conditioning procedure to assess the incentive value of oxycodone during adulthood. Mice displayed similar behavioral responses to oxycodone (e.g., sensitization) and patterns of withdrawal behaviors, independent of sex. Mice showed strong group preferences for the oxycodone-paired chamber, and the strength of these preferences did not differ by sex or maternal status. Postpartum females' maternal behavior and motivation were also similar despite adolescent drug history. Together, results did not suggest overt sex differences in response to adolescent oxycodone exposure and that, in females, a range of motivated behaviors may be relatively resilient to such perturbations during adolescence. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Glioblastoma (GBM) is the most common primary brain cancer in adults where tumor cell heterogeneity and sex differences influence clinical outcomes. Here, we functionally characterize three male and three female patient-derived GBM cell lines, identify protumorigenic BTICs, and create novel male and female preclinical models of GBM. Cell lines were evaluated on the following features: proliferation, stemness, migration, tumorigenesis, clinical characteristics, and sensitivity to radiation, TMZ, rhTNFSF10 (rhTRAIL), and rhBMP4. All cell lines were classified as GBM according to epigenetic subtyping, were heterogenous and functionally distinct from one another, and re-capitulated features of the original patient tumor. In establishing male and female preclinical models, it was found that two male-derived GBM cell lines (QNS108 and QNS120) and one female-derived GBM cell line (QNS315) grew at a faster rate in female mice brains. One male-derived GBM cell line (QNS108) decreased survival in female mice in comparison with male mice. However, no survival differences were observed for mice injected with a female-derived cell line (QNS315). In summary, a panel of six GBM patient-derived cell lines were functionally characterized, and it was shown that BTIC lines can be used to construct sex-specific models with differential phenotypes for additional studies.

Supplemental Digital Content is available in the text., Previously, we have shown that male mice exposed to maternal separation and early weaning (MSEW)—a mouse model of early life stress—display increased mean arterial pressure compared with controls when fed a high-fat diet. As the stimulation of sensory nerves from fat has been shown to trigger the adipose afferent reflex, we tested whether MSEW male mice show obesity-associated hypertension via the hyperactivation of this sympathoexcitatory mechanism. After 16 weeks on high-fat diet, MSEW mice displayed increased blood pressure, sympathetic activation, and greater depressor response to an α-adrenergic blocker when compared with controls (P

Diet composition, calories, and fasting times contribute to the maintenance of health. However, the impact of very low-calorie intake (VLCI) achieved with either standard laboratory chow (SD) or a plant-based fasting mimicking diet (FMD) is not fully understood. Here, using middle-aged male mice we show that 5 months of short 4:10 VLCI cycles lead to decreases in both fat and lean mass, accompanied by improved physical performance and glucoregulation, and greater metabolic flexibility independent of diet composition. A long-lasting metabolomic reprograming in serum and liver is observed in mice on VLCI cycles with SD, but not FMD. Further, when challenged with an obesogenic diet, cycles of VLCI do not prevent diet-induced obesity nor do they elicit a long-lasting metabolic memory, despite achieving modest metabolic flexibility. Our results highlight the importance of diet composition in mediating the metabolic benefits of short cycles of VLCI., Understanding the contribution of diet composition, calories and length of fasting in health maintenance is still challenging. Here the authors compare the effects of cycles of intermittent very low calorie intake achieved with a plant-based fasting mimicking diet or standard laboratory chow to provide insights into the role played by diet composition in mediating the metabolic benefits of short cycles of very low-calorie intake in mice.

Cannabis sativa is a millenary medicinal plant. However, contrary to worldwide paradigm-shifting, countries like Brazil still prohibit C. sativa cultivation and its medicinal use, even though many populations use aerial parts and roots of this plant for healthcare. As such, the objective of this work was to identify substances in the samples of the C. sativa roots, tracing a correlation with antitussive and expectorant effects. Therefore, samples of C. sativa roots were donated by the Polícia Federal Brasileira, and its aqueous extract (AECsR) was prepared with subsequent lyophilization, to maintain the material stability. After that, the material was analyzed by LC-MS to observe its chemical profile. Four samples (AECsR-A, B, C, and D) were tested in animal models of citric acid-induced cough (0.4 M) and phenol red expectoration (500 mg/kg). Using LC-MS it was possible to identify 5 molecules in C. sativa roots: p-coumaroyltyramine, tetrahydrocannabinol-C4, feruoiltyramine, anhydrocanabisativine, and cannabisativine. In experimental protocols, male mice (Mus musculus) were treated with samples of AECsR at doses of 12.5, 25, or 50 mg/kg regardless of the pharmacological test. In these tests, all samples showed the potential to treat cough and promote fluid expectoration, differing only in the dose at which these effects were observed. Therefore, the data showed that the C. sativa roots of the Brazilian Northeast showed antitussive and expectorant effects, even with intense secondary metabolitesʼ variation, which alters its potency, but not its effect. This highlights the importance of this medicinal plant for future therapy and corroborates to traditional use.

Objectives Osteoarthritis is a painful joint disease responsible for walking impairment. Its quantitative assessment by gait analysis in mice may be a relevant and noninvasive strategy to assess the disease severity. In this study, we aimed to determine the severity of osteoarthritis at the tissular and gait levels in unilateral and bilateral posttraumatic murine osteoarthritis. Methods Twenty-four C57BL/6 male mice were randomly assigned to 3 groups ( n = 8/group): controls, unilateral surgery, and bilateral surgery. Posttraumatic osteoarthritis was induced unilaterally or bilaterally by destabilization of the medial meniscus. Gait analysis was performed weekly with the CatWalkTM XT system until the 16th week after surgery. After animal sacrifices, histological and micro–computed tomographic assessment was performed. Results Operated knees showed a significant increase in the histological score compared with controls ( P < 0.001). Calcified anterior medial meniscal bone volume was higher on the ipsilateral side after unilateral destabilization of the medial meniscus ( P < 0.001) and on both sides after bilateral intervention ( P < 0.01). One week after surgery, the mice mean speed decreased significantly in both operated groups ( P < 0.001 and P < 0.05). In the unilateral group, a significant increase in the contralateral hind print area appeared from week 4 to week 16. Conclusions While bilateral destabilization of the medial meniscus induced no detectable gait modification except 1 week after surgery, unilateral model was responsible for a gait disturbance on the contralateral side. Further studies are needed to better define the place of the CatWalkTM in the evaluation of mouse models of osteoarthritis.

A suboptimal blood vitamin C (ascorbate) level increases the risk of several chronic diseases. However, the detection of hypovitaminosis C is not a simple task, as ascorbate is unstable in blood samples. In this study, we examined the serum proteome of mice lacking the gulonolactone oxidase (Gulo) required for the ascorbate biosynthesis. Gulo-/- mice were supplemented with different concentrations of ascorbate in drinking water, and serum was collected to identify proteins correlating with serum ascorbate levels using an unbiased label-free liquid chromatography-tandem mass spectrometry global quantitative proteomic approach. Parallel reaction monitoring was performed to validate the correlations. We uncovered that the serum proteome profiles differ significantly between male and female mice. Also, unlike Gulo-/- males, a four-week ascorbate treatment did not entirely re-establish the serum proteome profile of ascorbate-deficient Gulo-/- females to the optimal profile exhibited by Gulo-/- females that never experienced an ascorbate deficiency. Finally, the serum proteins involved in retinoid metabolism, cholesterol, and lipid transport were similarly affected by ascorbate levels in males and females. In contrast, the proteins regulating serum peptidases and the protein of the acute phase response were different between males and females. These proteins are potential biomarkers correlating with blood ascorbate levels and require further study in standard clinical settings. The complete proteomics data set generated in this study has been deposited to the public repository ProteomeXchange with the data set identifier: PXD027019.

Growth hormone receptor knockout (GHRKO) mice are smaller, long living, and have an increased metabolic rate compared with normal (N) littermates. However, it is known that thermoneutral conditions (30–32°C) elicit metabolic adaptations in mice, increasing the metabolic rate. Therefore, we hypothesized that environmental temperature would affect the expression profile of different adipose tissue depots in GHRKO mice. For this, N (n = 12) and GHRKO (n = 11) male mice were maintained at 23 or 30°C from weaning until 11 months of age. RNA sequencing from adipose tissue depots (epididymal—eWAT, perirenal—pWAT, subcutaneous—sWAT, and brown fat—BAT) was performed. Thermoneutrality increased body weight gain in GHRKO mice, but not in N mice. Only a few genes were commonly regulated by temperature in N and GHRKO mice. The BAT was the most responsive to changes in temperature in both N and GHRKO mice. BAT Ucp1 and Ucp3 expression were decreased to a similar extent in both N and GHRKO mice under thermoneutrality. In contrast, eWAT was mostly unresponsive to changes in temperature. The response to thermoneutrality in GHRKO mice was most divergent from N mice in sWAT. Relative weight of sWAT was almost 4 times greater in GHRKO mice. Very few genes were regulated in N mice sWAT when compared with GHRKO mice. This suggests that this WAT depot has a central role in the adaptation of GHRKO mice to changes in temperature.

Purpose Exposure to high doses of ionizing radiation can result in hematopoietic acute radiation syndrome (H-ARS) and delayed effects of acute radiation exposure (DEARE). There is no radiation medical countermeasure approved by the U.S. Food and Drug Administration which can be used prior to radiation exposure to protect exposed individuals. Different formulations containing synthetic genistein (BIO 300) are being developed to counter the harmful effects of radiation exposure. Materials and methods We investigated the efficacy of a BIO 300 Oral Powder (OP) formulation as a prophylactic radiation medical countermeasure against a lethal dose of cobalt-60 gamma-radiation in CD2F1 male mice while comparing to other formulations of BIO 300 and Neulasta (PEGylated filgrastim), a standard of care drug for H-ARS. Results BIO 300 OP provided significant radioprotection against ionizing radiation in mice when administered twice per day for six days prior to total-body radiation exposure. Its radioprotective efficacy in the murine model was comparable to the efficacy of a single subcutaneous (sc) injection of Neulasta administered after total-body radiation exposure. Conclusions Our results demonstrate that BIO 300 OP, which can be administered orally, is a promising prophylactic radiation countermeasure for H-ARS.

Drug-associated reward memories are conducive to intense craving and often trigger relapse. Simvastatin has been shown to regulate lipids that are involved in memory formation but its influence on other cognitive processes is elusive. Here, we used a mass spectrometry-based lipidomic method to evaluate the impact of simvastatin on the mouse brain in a cocaine-induced reinstatement paradigm. We found that simvastatin blocked the reinstatement of cocaine-induced conditioned place preference (CPP) without affecting CPP acquisition. Specifically, only simvastatin administered during extinction prevented cocaine-primed reinstatement. Global lipidome analysis showed that the nucleus accumbens was the region with the greatest degree of change caused by simvastatin. The metabolism of fatty-acids, phospholipids, and triacylglycerol was profoundly affected. Simvastatin reversed most of the effects on phospholipids induced by cocaine. The correlation matrix showed that cocaine and simvastatin significantly reshaped the lipid metabolic pathways in specific brain regions. Furthermore, simvastatin almost reversed all changes in the fatty acyl profile and unsaturation caused by cocaine. In summary, pre-extinction treatment with simvastatin facilitates cocaine extinction and prevents cocaine relapse with brain lipidome remodeling.

Background Acute intoxication caused by binge ethanol drinking is linked to widespread impairments in brain functions. Various alcohol administration paradigms have been used in animals to model the heterogeneous clinical manifestation of intoxication in people. It is challenging to model a procedure that produces “visible intoxication” in rodents; however, manipulation of variables such as route of alcohol administration, time of availability, frequency, and duration and amount of ethanol exposure has achieved some success. In the current study, we employed a modified drinking-in-the-dark model to assess the validity of this model in producing “post-ethanol consumption intoxication” impairments following prolonged repeated daily voluntary “binge” ethanol consumption. Methods Adult male C57BL/6J mice were allowed a daily 3-h access to non-alcoholic plain or ethanol-containing gel during the dark cycle for a total of 83 days. After the initial 2-month daily DID, ethanol intake patterns were intensely characterized during the next 3 weeks. Immediately following the last DID session (day 83), plain and ethanol gel-consuming mice were then subjected to behavioral tests of locomotor ability and/or anxiety (cylinder, wire grip, open field) followed by blood ethanol concentration measurement. Result Mice exhibited a relatively consistent ethanol consumption pattern during and across daily access periods. Ethanol intake of individual mice positively correlated with blood ethanol concentration that averaged 61.64 ± 2.84 mg/dL (n = 12). Compared to the plain gel-consuming control mice, ethanol gel mice exhibited significant locomotor impairment as well as anxiety-like behavior, with the magnitude of impairments of key indices well correlated with blood ethanol levels. Conclusion The gelatin vehicle-based voluntary ethanol drinking-in-the-dark model reliably produced post consumption acute movement impairments as well as anxiety-like behaviors even after 2 months of daily binge ethanol consumption in male mice. Taken together, this mouse binge ethanol model should facilitate the investigation of mechanisms of binge drinking in subjects chronically abusing ethanol and the search for effective novel treatment strategies.

Aging is the most important risk factor for cardiovascular diseases. Although exercise is known to be beneficial for the health of aging heart, the optimal exercise training intensity to prevent natural aging-induced cardiac damage has not been defined. In this study, we used 32-week-old male mice and randomly divided them into three groups, namely, untrained (UNT) mice, moderate-intensity exercise training (MET) mice, and high-intensity interval training (HIIT) mice. Mice in the two exercise training groups were subjected to exercise 5 days per week for 24 consecutive weeks. Metabolic characteristics, cardiac function and morphology, myocardial remodeling, myocardial fibrosis (collagen III, α-SMA, and TGF-β), oxidative stress (NRF2, HO-1, SOD, and NOX4), and apoptosis (BAX, Bak, Bcl-2, and Bcl-XL) were analyzed 24 weeks after the different treatments. MET improved cardiac function and reduced myocardial remodeling, myocardial fibrosis, and oxidative stress in the aging heart. MET treatment exerted an anti-apoptotic effect in the heart of the aging mice. Importantly, HIIT did not protect against cardiac damage during the natural aging process. These findings suggest that MET may be one of the main methods to prevent cardiac damage induced by natural aging.

Due to its wide usage and recent detection in environmental matrices, hexafluoropropylene oxide dimer acid (HFPO-DA, commercial name GenX) has attracted considerable attention. Here, we explored and compared the toxicity of GenX and its novel analogs with that of perfluorooctanoic acid (PFOA) to provide guidance on the structural design and optimization of novel alternatives to poly- and perfluoroalkyl substances (PFASs). Adult male BALB/c mice were continuously exposed to PFOA, GenX, perfluoro-2-methyl-3,6-dioxo-heptanoic acid (PFMO2HpA), and perfluoro-2-methyl-3,6,8-trioxo-nonanoic acid (PFMO3NA; 0, 0.4, 2, or 10 mg/kg/d) via oral gavage for 28 days. The PFOA, GenX, and PFMO3NA treatment groups showed an increase in relative liver weight, and bile acid metabolism was the most significantly affected pathway in all treatment groups, as shown via weighted gene coexpression network analysis. The highest total bile acid levels were observed in the 2 and 10 mg/kg/d PFMO3NA groups. The ratios of primary bile acids to all bile acids increased in the high-dose groups, while the ratios of secondary bile acids showed a downward trend. Thus, bile acid metabolism disorder may be a prominent adverse effect induced by exposure to GenX, its analogs, and PFOA. Results also showed that the hepatotoxicity of PFMO2HpA was lower than that of GenX, whereas the hepatotoxicity of PFMO3NA was stronger, suggesting that PFMO2HpA may be a potential alternative to GenX.

With the continuous popularization of smart medicine, the protective effect of silibinin in the liver has attracted much attention. This study mainly explores the liver protection mechanism and absorption promotion technology of silybin based on intelligent medical analysis. Refining of silibinin: accurately weigh 1.0 g of silibinin in a three-necked flask; gradually add 50 mL of anhydrous methanol, reflux and filter the precipitated solid; and weigh it after drying. ICR male mice were taken as experimental subjects and randomly divided into groups of 10 each. The mice in the normal group and the model group were given intragastrically with 0.5% CMC-Na solution; the mice in the silibinin group were given intragastrically with SB/CMC-Na suspension; the mice in the remaining groups were given low, medium, and high-dose suspensions to their stomachs, and silibinin 23 acylate/CMC-Na suspension was administered at a dose of 10 mL/kg for 7 consecutive days. After that, the mice were fasted for 12 hours. After 6 hours of fasting (18 hours after modeling), the blood cells from their orbits were taken, placed in a 37°C water bath for 30 minutes, and centrifuged at 4000 rpm for 10 minutes, and then the serum was taken; the activity equivalent of AST and ALT in serum was measured; serum determination Medium AST and ALT vitality. The mice were killed by decapitation, fresh liver tissue was immediately collected, and part of it was frozen in liquid nitrogen for the RT-PCR test. The hepatocyte expansion and death were observed using a transmission electron microscope, and the oncosis index (OI) was calculated. Another part of the liver tissue was fixed in 4% paraformaldehyde solution, embedded in paraffin, dehydrated, and sliced at 4 μm. Some sections were stained with conventional HE, and the pathological changes of liver cells were observed under light microscope; some sections were subjected to immunohistochemistry. Only one mouse died when 240 mg/kg of silibinin was given 10 minutes after the model was modeled. However, when 240 mg/kg silibinin was given to the mice 20 minutes after modeling, the mortality rate of the mice rose to 50%, and the therapeutic effect was significantly weakened. This research is helpful to advance the research of silybin in liver protection.

The space radiation environment consists of multiple species of charged particles, including 28Si ions, that may impact brain function during and following missions. To develop biomarkers of the space radiation response, BALB/c and C3H female and male mice and their F2 hybrid progeny were irradiated with 28Si ions (350 MeV/n, 0.2 Gy) and tested for behavioral and cognitive performance 1, 6, and 12 months following irradiation. The plasma of the mice was collected for analysis of miRNA levels. Select pertinent brain regions were dissected for lipidomic analyses and analyses of levels of select biomarkers shown to be sensitive to effects of space radiation in previous studies. There were associations between lipids in select brain regions, plasma miRNA, and cognitive measures and behavioral following 28Si ion irradiation. Different but overlapping sets of miRNAs in plasma were found to be associated with cognitive measures and behavioral in sham and irradiated mice at the three time points. The radiation condition revealed pathways involved in neurodegenerative conditions and cancers. Levels of the dendritic marker MAP2 in the cortex were higher in irradiated than sham-irradiated mice at middle age, which might be part of a compensatory response. Relationships were also revealed with CD68 in miRNAs in an anatomical distinct fashion, suggesting that distinct miRNAs modulate neuroinflammation in different brain regions. The associations between lipids in selected brain regions, plasma miRNA, and behavioral and cognitive measures following 28Si ion irradiation could be used for the development of biomarker of the space radiation response.

Introduction: The present study deals with the effect of Nectaroscordum koelzi fruit extract on acute and chronic inflammation. Methods: A total of 84 NMRI mice were used in this study. The effect of the extract on acute inflammation was analyzed by increasing vascular permeability via acetic acid and xylene induced ear edema among mice. The extract was evaluated in terms of effects on chronic inflammation by means of the cotton pellet test among mice. For the assessment of inflammation degree, the mice paw edema volume was measured by the plethysmometric test. Results: The findings showed that the extract was effective on acute inflammation induced by acetic acid in mice. In the xylene ear edema, N. koelzi extract indicated a significant activity in mice. In the cotton pellet method, the methanol extract produced a significant reduction in comparison with the control and dexamethasone. Mice paw edema volume decreased with the extract. Conclusion: In general, the data from the experiments indicated that the methanol extract of N. koelzi has an anti-inflammatory effect on acute and chronic inflammation. However, the exact contributing mechanisms have not been investigated for the pharmacological effects.

Type I platelet-activating factor-acetylhydrolase (PAF-AH) forms a complex consisting of two catalytic subunits (α1 and/or α2) with a regulatory subunit (β). Although this protein was discovered as an enzyme that degrades an acetyl ester linked at the sn-2 position of platelet-activating factor (PAF), its physiological function remains unknown. In this study, to examine whether knockout mice lacking the catalytic subunits of this enzyme showed a different phenotype from that of wild-type mice, we measured and compared the body weights of knockout mice and control mice. The body weights of knockout mice were significantly increased compared to those of the control mice during 6 to 20 weeks from birth. Food intake was also significantly increased in knockout mice compared with control mice during these periods. Since a decrease in testis weight was reported in the knockout mice, we expected a decrease in testosterone levels. We measured and compared the amounts of testosterone in the serum and testis of knockout and control mice using liquid chromatography-tandem mass spectrometry, and found that testosterone levels in both the serum and testis were significantly decreased in the knockout mice compared with the control mice. These results suggest that a deficiency of type I PAF-AH catalytic subunits causes an increase in body weight, in part, due to reduced testosterone levels in male mice.

Objectives Nonalcoholic fatty liver disease (NAFLD) is exceptionally common around the world. The development of NAFLD is increasing rapidly in the world, along with changes in lifestyle. Excess lipid intake is one of the risk factors for NAFLD. The NAFLD model is induced by a high-fat diet contains SFA, MUFA, and ῳ-6 PUFA. This study aims to assess the effect of high-fat diet variation on liver histology in developing NAFLD models in mice. Methods Thirty-six male mice (Balb/c) were divided into six groups fed a high-fat diet containing beef tallow 60%, beef tallow 45%, vegetable ghee, animal ghee + corn oil, vegetable ghee + corn oil for 28 days and compared to a control group fed a chow diet. All of the mice were fed with a high-fat diet in the form of pellets ad libitum for 28 days. Bodyweight and food intake were measured every day. At the last day of treatment, animals were sacrificed and the Liver were taken for histological analysis. Results This study showed that NAFLD model development was achieved in all group mice fed a high-fat diet with different degrees of NAFLD. Beef tallow 60% had the worst liver histology. Conclusions Thus, based on this study, we found that high-fat diet variations influenced the development of NAFLD models in mice, particularly concerning liver histology.

Gentle stroking, a type of affective touch that holds hedonic and rewarding value, is critical to our daily inter-individual communication. This positive socio-emotional aspect of touch is conveyed through a subclass of C afferents known as C-Tactile fibers in humans with an analogous system in rodents proposed. Here, we describe a novel tactile conditioned place preference paradigm using mice and demonstrate that gentle stroking by an experimenter is rewarding. In order to investigate the relationship between tactile preference and innate sociability, mice were subjected to the classic three-chambered test of social approach, where mice displayed significant preference towards the experimenter's hand. These findings suggest that gentle stroking evoked by an experimenter can play an important role in reward and preference and establish an affiliative relationship between mice and humans. Future research can potentially use this model to examine fiber type involvement and elucidate the significance of these findings for activation of the reward system.

While most pup-naïve adult female mice can display, or be induced (by repeated exposure to pups) to display parental behavior rapidly, adult males are infanticidal or nonparental. The medial prefrontal cortex (mPFC) participates in attentional selection, decision-making, behavioral flexibility, and planning that may be critical in the rapid display of parental or infanticidal behavior. We investigated if NMDA-induced lesions in the mPFC (targeting prelimbic cortex) inhibited maternal or infanticidal behavior in pup-naïve adult female and male mice (C57BL/6), respectively. All Control females displayed full maternal behavior at the first encounter with pups. Lesioned female groups were partially maternal (50%) or nonmaternal (50%). Five repeated exposures of 60-min to pups were needed to induce full maternal behavior in female NMDA-lesioned groups. Control and lesioned males did not show significant differences. Control males displayed nonparental (17%) or infanticidal (83%) behavior, while all lesioned males were infanticidal. There was no difference in general locomotor and exploratory activity (i.e., peripheral crosses, rearings, immobility time) in female or male groups. Nevertheless, females and males of lesioned groups showed a reduction in the number of central crosses and time in the central area of an open field respectively, suggesting an increase in anxiety. Our results show that the mPFC is engaged in the rapid onset of maternal behavior in females, contributing with the motivation and planning of its rapid execution, or reducing the anxiety to the first encounter with pups. In contrast, infanticidal behavior, likely a more impulsive behavior, might require less planning from the mPFC. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Quantification of interindividual variability is a continuing challenge in risk assessment, particularly for compounds with complex metabolism and multi-organ toxicity. Toxicokinetic variability for perchloroethylene (perc) was previously characterized across 3 mouse strains and in 1 mouse strain with various degrees of liver steatosis. To further characterize the role of genetic variability in toxicokinetics of perc, we applied Bayesian population physiologically based pharmacokinetic (PBPK) modeling to the data on perc and metabolites in blood/plasma and tissues of male mice from 45 inbred strains from the Collaborative Cross (CC) mouse population. After identifying the most influential PBPK parameters based on global sensitivity analysis, we fit the model with a hierarchical Bayesian population analysis using Markov chain Monte Carlo simulation. We found that the data from 3 commonly used strains were not representative of the full range of variability in perc and metabolite blood/plasma and tissue concentrations across the CC population. Using interstrain variability as a surrogate for human interindividual variability, we calculated dose-dependent, chemical-, and tissue-specific toxicokinetic variability factors (TKVFs) as candidate science-based replacements for the default uncertainty factor for human toxicokinetic variability of 100.5. We found that toxicokinetic variability factors for glutathione conjugation metabolites of perc showed the greatest variability, often exceeding the default, whereas those for oxidative metabolites and perc itself were generally less than the default. Overall, we demonstrate how a combination of a population-based mouse model such as the CC with Bayesian population PBPK modeling can reduce uncertainty in human toxicokinetic variability and increase accuracy and precision in quantitative risk assessment.

Background Mild traumatic brain injury (mTBI) is common in civilians and highly prevalent among military service members. mTBI can increase health risk behaviors (e.g., sensation seeking, impulsivity) and addiction risk (e.g., for alcohol use disorder (AUD)), but how mTBI and substance use might interact to promote addiction risk remains poorly understood. Likewise, potential differences in single vs. repetitive mTBI in relation to alcohol use/abuse have not been previously examined. Methods Here, we examined how a history of single (1×) or repetitive (3×) blast exposure (blast-mTBI) affects ethanol (EtOH)-induced behavioral and physiological outcomes using an established mouse model of blast-mTBI. To investigate potential translational relevance, we also examined self-report responses to the Alcohol Use Disorders Identification Test-Consumption questions (AUDIT-C), a widely used measure to identify potential hazardous drinking and AUD, and used a novel unsupervised machine learning approach to investigate whether a history of blast-mTBI affected drinking behaviors in Iraq/Afghanistan Veterans. Results Both single and repetitive blast-mTBI in mice increased the sedative properties of EtOH (with no change in tolerance or metabolism), but only repetitive blast potentiated EtOH-induced locomotor stimulation and shifted EtOH intake patterns. Specifically, mice exposed to repetitive blasts showed increased consumption "front-loading" (e.g., a higher rate of consumption during an initial 2-h acute phase of a 24-h alcohol access period and decreased total daily intake) during an intermittent 2-bottle choice condition. Examination of AUDIT-C scores in Iraq/Afghanistan Veterans revealed an optimal 3-cluster solution: "low" (low intake and low frequency), "frequent" (low intake and high frequency), and "risky" (high intake and high frequency), where Veterans with a history of blast-mTBI displayed a shift in cluster assignment from "frequent" to "risky," as compared to Veterans who were deployed to Iraq/Afghanistan but had no lifetime history of TBI. Conclusions Together, these results offer new insight into how blast-mTBI may give increase AUD risk and highlight the increased potential for adverse health risk behaviors following repetitive blast-mTBI.

Despite studies on the effects of medicinal plants on reproductive performance, the effect of extracts broccoli and caraway on serum and testicular oxidative biomarkers, testicular structure and function and sperm quality before and after cryopreservation has not been studied. Sixty-three male mice were divided into nine controlled and treated groups as follow: control, broccoli (200 mg/kg), broccoli (300 mg/kg), caraway (200 mg/kg), caraway (300 mg/kg), broccoli -caraway (200 mg/kg), broccoli (300 mg/kg)-caraway (200 mg/kg), broccoli (200 mg/kg)-caraway (300 mg/kg), broccoli-caraway (300 mg/kg). After 42 days of treatment, the animals were sacrificed and blood sample and testicular tissue were collected for biochemical and histological measurements. Sperm quality was also measured before and after cryopreservation. The results showed that the diameter and number of spermatogonium, primary spermatocytes, spermatids and sperm count were significantly increased by broccoli (300 mg/kg), while level of them were significantly decreased by caraway (300 mg/kg) compared to other groups (p 0.01). Sperm viability and motility after thawing significantly improved by broccoli (300 mg/kg) compared to control. Testosterone levels significantly increased by broccoli (300 mg/kg) compared to control and caraway (300 mg/kg). The serum and testicular SOD and CAT activity significantly increased by broccoli (300 mg/kg) compared to other groups (p 0.05). MDA and DNA fragmentation levels significantly increased by caraway (200 and 300 mg/kg) compared to others (p 0.01). It can be concluded that broccoli extract in a dose-dependent manner than caraway extract could improve serum and testes oxidative biomarkers, testicular structure and function, and sperm quality before and after cryopreservation.

Background: Long-term morphine use is associated with serious side effects, such as morphine-induced hyperalgesia and analgesic tolerance. Previous investigations have documented the association between dopamine (DA) neurons in the ventral tegmental area (VTA) and pain. However, whether VTA DA neurons are implicated in morphine-induced hyperalgesia and analgesic tolerance remains elusive. Methods: Initially, we observed behavioural effects of lidocaine administration into VTA or ablation of VTA DA neurons on morphine-induced hyperalgesia and anti-nociceptive tolerance. Subsequently, c-Fos expression in nucleus accumbens (NAc) shell-projecting and medial prefrontal cortex (mPFC)-projecting VTA DA neurons after chronic morphine treatment was respectively investigated. Afterwards, the effects of chemogenetic manipulation of NAc shell-projecting or mPFC-projecting DA neurons on morphine-induced hyperalgesia and anti-nociceptive tolerance were observed. Additionally, effects of chemogenetic manipulation of VTA GABA neurons on c-Fos expression in VTA DA neurons were investigated. Results: Lidocaine injection into VTA relieved established hyperalgesia and anti-nociceptive tolerance whereas ablation of VTA DA neurons prevented the development of morphine-induced hyperalgesia and anti-nociceptive tolerance. Chronic morphine treatment increased c-Fos expression in NAc shell-projecting DA neurons, rather than in mPFC-projecting DA neurons. Chemogenetic manipulation of NAc shell-projecting DA neurons had influence on morphine-induced hyperalgesia and tolerance. However, chemogenetic manipulation of mPFC-projecting DA neurons had no significant effects on morphine-induced hyperalgesia and anti-nociceptive tolerance. Chemogenetic manipulation of VTA GABA neurons affected the c-Fos expression in VTA DA neurons. Conclusions: These findings revealed the involvement of NAc shell-projecting VTA DA neurons in morphine-induced hyperalgesia and anti-nociceptive tolerance, and may shed new light on the clinical management of morphine-induced hyperalgesia and analgesic tolerance. Perspective: This study demonstrated that NAc shell-projecting DA neurons rather than mPFC-projecting DA neurons in the VTA were implicated in morphine-induced hyperalgesia and anti-nociceptive tolerance. Our findings may pave the way for the discovery of novel therapies for morphine-induced hyperalgesia and analgesic tolerance.

High-power microwaves (HPMs) have been reported to have hazardous effects on multiple human and animal organs. However, the biological effects of 1.5-GHz HPMs on the reproductive system are not clear. Here, we studied the effects of 1.5 -GHz HPM whole-body exposure on the pathological structure of the testicles and changes in spermatozoa mobility. C57BL/6 mice of groups L, M, and H were exposed to 1.5-GHz HPM fields for two 15-min intervals at the average specific absorption rates of 3, 6, and 12 W/Kg, respectively. The pathological structure of the testicles and spermatozoa, as well as serum testosterone and sperm motility parameters, were evaluated at 6 h, 1 d, 3 d, and 7 d after exposure. As a result, there were no significant pathological or ultrastructural changes in the testicles or spermatozoa and serum testosterone levels. The number of progressively motile spermatozoa, curvilinear velocity, linear velocity, and average path velocity of the exposure group increased at 6 h, decreased at 1 d, and recovered at 3 d. The opposite results were considered a stress response to the thermal effect of the microwaves. Our results indicated that 1.5-GHz HPM whole-body exposure in mice at SARs of 3, 6, and 12 W/Kg for 30 min did not cause obvious damage to the reproductive system.

Background: To investigate the changes of intestinal microbiota and metabolites in sepsis mice with acute gastrointestinal injury before and after the use of antibiotics, and to explore the possible effects of these changes on the body. Methods: Twenty-four 6-8-w-old SPF-grade C57BL/6J male mice were selected, and the mice were randomly divided into three groups. The mice were treated by tail vein injection for 3 days. The intestinal motility of mice after administration was detected. The mice feces were collected for 16S rRNA and Untargeted metabonomics detection. Results: The use of antibiotics in sepsis mice can change the composition of intestinal microbiota and metabolites. LD3, AD3 and LAD3 samples had significant differences in bacterial species. Desulfovibrio was the species with a significant difference in LAD3. In addition, we found that the composition of those intestinal microbiota were correlated with changes in intestinal motility. The untargeted metabolomics analysis showed that the fecal metabolites of LD3 and LAD3 samples were significantly different. In addition to the basic metabolites, Benzoic acid and 4-Hydroxybenzoic acid were also found, and Desulfovibrio was associated with them. Conclusions: The use of antibiotics in sepsis mice can lead to changes in the intestinal microbiota and metabolite levels, which may be related to the severity of acute gastrointestinal injury in sepsis mice. Inhibiting Desulfovibrio in the intestine and using Benzoic acid and 4-Hydroxybenzoic acid as a marker for the production of Desulfovibrio may reduce the inflammatory degree of acute gastrointestinal injury in sepsis.

Hydrogen sulfide (H2S) is a cytoprotective redox-active metabolite that signals through protein persulfidation (R-SSnH). Despite the known importance of persulfidation, tissue-specific persulfidome profiles and their associated functions are not well characterized, specifically under conditions and interventions known to modulate H2S production. We hypothesize that dietary restriction (DR), which increases lifespan and can boost H2S production, expands tissue-specific persulfidomes. Here, we find protein persulfidation enriched in liver, kidney, muscle, and brain but decreased in heart of young and aged male mice under two forms of DR, with DR promoting persulfidation in numerous metabolic and aging-related pathways. Mice lacking cystathionine γ-lyase (CGL) have overall decreased tissue protein persulfidation numbers and fail to functionally augment persulfidomes in response to DR, predominantly in kidney, muscle, and brain. Here, we define tissue- and CGL-dependent persulfidomes and how diet transforms their makeup, underscoring the breadth for DR and H2S to impact biological processes and organismal health., Dietary restriction (DR) can increase protein persulfidation but the tissue specificity of this process is not well understood. Here, the authors compare organ-specific protein persulfidomes in young and aged mice under DR, and show that DR-dependent persulfidome changes depend on cystathionine γ-lyase.

Background: The reticular thalamus gates thalamocortical information flow via finely tuned inhibition of thalamocortical cells in the mediodorsal thalamus. Brain imaging studies in humans show that the psychedelic lysergic acid diethylamide (LSD) modulates activity and connectivity within the cortico-striato-thalamo-cortical (CSTC) circuit, altering consciousness. However, the electrophysiological effects of LSD on the neurons in these brain areas remain elusive. Methods: We employed in vivo extracellular single-unit recordings in anesthetized adult male mice to investigate the dose–response effects of cumulative LSD doses (5–160 µg/kg, intraperitoneal) upon reticular thalamus GABAergic neurons, thalamocortical relay neurons of the mediodorsal thalamus, and pyramidal neurons of the infralimbic prefrontal cortex. Results: LSD decreased spontaneous firing and burst-firing activity in 50% of the recorded reticular thalamus neurons in a dose–response fashion starting at 10 µg/kg. Another population of neurons (50%) increased firing and burst-firing activity starting at 40 µg/kg. This modulation was accompanied by an increase in firing and burst-firing activity of thalamocortical neurons in the mediodorsal thalamus. On the contrary, LSD excited infralimbic prefrontal cortex pyramidal neurons only at the highest dose tested (160 µg/kg). The dopamine D2 receptor (D2) antagonist haloperidol administered after LSD increased burst-firing activity in the reticular thalamus neurons inhibited by LSD, decreased firing and burst-firing activity in the mediodorsal thalamus, and showed a trend towards further increasing the firing activity of neurons of the infralimbic prefrontal cortex. Conclusion: LSD modulates firing and burst-firing activity of reticular thalamus neurons and disinhibits mediodorsal thalamus relay neurons at least partially in a D2-mediated fashion. These effects of LSD on thalamocortical gating could explain its consciousness-altering effects in humans.

Recent evidence suggests that dipeptidyl peptidase-4 (DPP4) inhibition with saxagliptin (Saxa) is renoprotective under comorbid conditions associated with activation of the renin-angiotensin-aldosterone system (RAAS), such as diabetes, obesity, and hypertension, which confer a high cardiovascular risk. Immune system activation is now recognized as a contributor to RAAS-mediated tissue injury, and, importantly, immunomodulatory effects of DPP4 have been reported. Accordingly, we examined the hypothesis that DPP4 inhibition with Saxa attenuates angiotensin II (ANG II)-induced kidney injury and albuminuria via attenuation of immune activation in the kidney. To this end, male mice were infused with either vehicle or ANG II (1,000 ng/kg/min, s.c.) for 3 wk and received either placebo or Saxa (10 mg/kg/day, p.o.) during the final 2 wk. ANG II infusion increased kidney, but not plasma, DPP4 activity in vivo as well as DPP4 activity in cultured proximal tubule cells. The latter was prevented by angiotensin receptor blockade with olmesartan. Further, ANG II induced hypertension and kidney injury characterized by mesangial expansion, mitochondrial damage, reduced brush border megalin expression, and albuminuria. Saxa inhibited DPP4 activity ∼50% in vivo and attenuated ANG II-mediated kidney injury, independent of blood pressure. Further mechanistic experiments revealed mitigation by Saxa of proinflammatory and profibrotic mediators activated by ANG II in the kidney, including CD8(+) T cells, resident macrophages (CD11b(hi)F4/80(lo)Ly6C(−)), and neutrophils. In addition, Saxa improved ANG II suppressed anti-inflammatory regulatory T cell and T helper 2 lymphocyte activity. Taken together, these results demonstrate, for the first time, blood pressure-independent involvement of renal DPP4 activation contributing to RAAS-dependent kidney injury and immune activation. NEW & NOTEWORTHY This work highlights the role of dipeptidyl peptidase-4 (DPP4) in promoting ANG II-mediated kidney inflammation and injury. Specifically, ANG II infusion in mice led to increases in blood pressure and kidney DPP4 activity, which then led to activation of CD8(+) T cells, Ly6C(−) macrophages, and neutrophils and suppression of anti-inflammatory T helper 2 lymphocytes and regulatory T cells. Collectively, this led to kidney injury, characterized by mesangial expansion, mitochondrial damage, and albuminuria, which were mitigated by DPP4 inhibition independent of blood pressure reduction.

Non-glandular squamous cell carcinoma (NGSCC) is an extremely rare tumor in Tg.raH2 mice. There have been 5 NGSCC in 1615 control male mice (0.31%) and 2 NGSCC in 1560 control female mice (0.13%) on 26-week carcinogenicity studies, with a range of 0 to 1 of per group per sex in each study without statistical significance in 52 male and 51 female studies conducted in Tg.rasH2 mice. Every case of NGSCC was accompanied by profound granulocytosis.

Multiple sequential actions, performed during parental behaviors, are essential elements of reproduction in mammalian species. We showed that neurons expressing melanin concentrating hormone (MCH) in the lateral hypothalamic area (LHA) are more active in rodents of both sexes when exhibiting parental nursing behavior. Genetic ablation of the LHA-MCH neurons impaired maternal nursing. The post-birth survival rate was lower in pups born to female mice with congenitally ablated MCH neurons under control of tet-off system, exhibiting reduced crouching behavior. Virgin female and male mice with ablated MCH neurons were less interested in pups and maternal care. Chemogenetic and optogenetic stimulation of LHA-MCH neurons induced parental nursing in virgin female and male mice. LHA-MCH GABAergic neurons project fibres to the paraventricular hypothalamic nucleus (PVN) neurons. Optogenetic stimulation of PVN induces nursing crouching behavior along with increasing plasma oxytocin levels. The hypothalamic MCH neural relays play important functional roles in parental nursing behavior in female and male mice.

During the influenza pandemic or seasonal influenza outbreak, influenza infection can cause acute influenza-associated encephalopathy/encephalitis (IAE), even death. Patients with severe IAE will also have severe neurological sequelae. Neurologic disorders have been demonstrated in the mice treated with peripheral influenza viruses infection, whether neurotropic or non-neurotropic viruses. However, previous studies focused on the acute phase of infection, and rarely paid attention to a longer range of observations. Therefore, the long-term effect of non-neurotropic virus infection on the host is not very clear. In this study, adult mice were infected with influenza virus H1N1/PR8. Then, spontaneous behavior, body weight, expression of cytokines in brain, spatial learning ability and spatial memory ability were observed, until the complete recovery period. The results showed that cytokines in the brain were highly expressed in the convalescent phase (14 day post inoculation, dpi), especially BDNF, IBA1, CX3CL1 and CD200 were still highly expressed in the recovery phase (28 dpi). Otherwise the emotional and spatial memory ability of mice were impacted in the convalescent phase (14 dpi) and the recovery phase (28 dpi). In brief, BALB/c mice infected with non-neurotropic influenza virus H1N1, the weight and motor ability decreased in acute stage. During the recovery period, the body weight and activity ability were completely restored, whereas the emotion disordered, and the ability of spatial learning and memory were impacted in the infected mice. This long-term behavior impact may be the lag injury caused by non-neurotropic influenza infection.

1. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator of oxidative/electrophilic stress. Studies suggest a role of Nrf2 in regulating bile acid (BA) metabolism in male mice. However, whether Nrf2 is important for BA homeostasis in female mice remains undefined. In this study, we systematically investigated the effect of Nrf2 activation, either through CDDO-imidazolide (CDDO-Im) treatment or genetic modulation of Kelch-like ECH associating protein 1 (Keap1), on BA homeostasis in female mice.2. Both pharmacological and genetic Nrf2 activation increased mRNA levels of multidrug resistance-associated protein 2 and 3 (Mrp2 and Mrp3), two Nrf2 target genes, in livers and ilea of female mice. Both pharmacological and genetic activation of Nrf2 decreased BA concentrations in the liver, which did not appear to be due to increased biliary BA excretion or decreased ileal BA absorption. Importantly, both pharmacological and genetic activation of Nrf2 downregulated hepatic Cyp7a1 mRNA, which might be attributable to the upregulation of the Fxr-Fgf15 signalling in the ileum.3. To conclude, Nrf2 activation lowers BA concentrations in livers of female mice, which appears to be attributable to the decreased hepatic BA synthesis.

Prior studies have suggested that short periods of exposure to environmental enrichment (EE) in rodents induce physiological and behavioral effects. In the present study, our aim was to evaluate if the impact of experiences based on EE could be modulated by the age of onset and the developmental period of exposure. NMRI male mice (n = 64) were exposed to EE or standard environment (SE) and behavioral changes (anxiety, exploration, memory and social interaction) were evaluated. Groups compared were: (a) SE: exposure to SE on post-natal day (PND) 28 and lasting 6 months; (b) EE-6: exposure to EE on PND 28 and lasting 6 months; (c) EE-4: exposure to EE on PND 91 and lasting 4 months; (d) EE-2: exposure to EE on PND 154 and lasting 2 months. Results indicated that in the hole-board task the decrease in exploratory behavior reached significance when EE was initiated at adolescence whereas anxiolytic effects in the elevated plus-maze tend to diminish after a longer period of EE. No significant effects of EE on aggressive behavior or novel object recognition were obtained. Taking these results into account, further studies are needed in order to determine the possible modulating role of age and duration of exposure to enriched environments on behavior. Results obtained could explain some discrepancies reported in previous studies, providing new evidence that could contribute to the design of future research related to the benefits of complex and enriched environments.

Objectives Mutations in the human IQSEC2 gene are associated with drug-resistant epilepsy and severe behavioral dysfunction. We have focused on understanding one human IQSEC2 missense mutation (A350V) for which we have created a corresponding A350V IQSEC2 mouse model by CRISPR which demonstrates seizures when the mice are 15-20 days old and impaired social vocalizations in adulthood. We observed that a child with the A350V mutation stops having seizures when experiencing a fever of greater than 38 °C. In this study, we first sought to determine if we could recapitulate this phenomenon in A350V 15-20 day old mice using a previously established protocol to raise body temperature to 39 °C achieved by housing the mice at 37 °C. We then sought to determine if mice in whom seizure activity had been prevented as pups would develop social vocalization activity in adulthood. Methods 15-20 day old A350V male mice were housed either at 37 °C or 22 °C. Ultrasonic vocalizations of these mice were assessed at 8-10 weeks in response to a female stimulus. Results Housing of 15-20 day old A350V mice at 37 °C resulted in a reduction in lethal seizures to 2% (1/41) compared to 45% (48/108) in mice housed at 22 °C, p = 0.0001. Adult A350V mice who had been housed at 37 °C as pups displayed a significant improvement in the production of social vocalizations. Conclusion Raising the body temperature by raising the ambient temperature might provide a means to reduce seizures associated with the A350V IQSEC2 mutation and thereby allow for an improved neurodevelopmental trajectory.

Objectives. The onset of puberty in humans is followed by an increase in insulin resistance and this transient phenomenon decreases at the end of the puberty. However, the insulin resistance during puberty has not been described in mice. Thus, in the present study we performed a temporal characterization of the development of insulin resistance during puberty in male and female C57BL/6 mice. Methods. From the fourth week of life male (n=18) and female (n=32) C57BL/6 wild-type mice were weekly subjected to insulin tolerance tests until the seventh week of life. Blood glucose levels were determined using a glucose meter through samples collected from the tail tip. Vaginal opening was assessed daily in female mice. Preputial separation was determined in a subgroup of males. Results. We observed a transient increase in the area under the curve of the insulin tolerance tests and in basal glycemia in female mice at the time of vaginal opening (between the fourth and fifth week of life) compared with previous and subsequent weeks of pubertal development. In contrast, male mice show no changes in insulin sensitivity during puberty. Conclusions. Our findings demonstrate that the insulin resistance at puberty can also be observed in female mice and this peak occurs at the time of vaginal opening. Our temporal characterization can be used as a reference for future studies that aim to study glucose homeostasis during puberty in rodents.

In many species, ejaculation is followed by a state of decreased sexual activity, the post-ejaculatory refractory period. Several lines of evidence have suggested prolactin, a pituitary hormone released around the time of ejaculation in humans and other animals, to be a decisive player in the establishment of the refractory period. However, data supporting this hypothesis is controversial. We took advantage of two different strains of house mouse, a wild derived and a classical laboratory strain that differ substantially in their sexual performance, to investigate prolactin’s involvement in sexual activity and the refractory period. First, we show that there is prolactin release during sexual behavior in male mice. Second, using a pharmacological approach, we show that acute manipulations of prolactin levels, either mimicking the natural release during sexual behavior or inhibiting its occurrence, do not affect sexual activity or shorten the refractory period, respectively. Therefore, we show compelling evidence refuting the idea that prolactin released during copulation is involved in the establishment of the refractory period, a long-standing hypothesis in the field of behavioral endocrinology., Valente et al. compared two different strains of mouse that differ in sexual performance. They found that prolactin is released during sexual behaviour—however pharmacological manipulation of prolactin demonstrated that it is not a determinant of sexual activity or refractory period.

The effects of social isolation on an individual's behavior is an important field of research, especially as public health officials encourage social distancing to prevent the spread of pandemic disease. In this study we evaluate the effects of social isolation on physical activity in mice. Utilizing a pixel-based tracking system, we continuously monitored the movement of isolated mice compared with paired cage mates in the home cage environment. We demonstrate that mice that are socially isolated dramatically decrease their movement when separated from their cage mate, and especially in the dark cycle, when mice are normally most active. When isolated mice are re-paired with their original cage mate, this effect is reversed, and mice return to their prior levels of activity. These findings suggest a close link between social isolation and physical activity, and are of particular interest in the wake of coronavirus disease 2019, when many are forced into isolation. Social isolation may affect an individual's overall activity levels in humans too, which may have unintended effects on health that deserve further consideration.

In susceptible individuals, memories of stressful experiences can give rise to debilitating socio-affective symptoms. This occurs even when the ability to retrieve such memories is limited, as seen in patients suffering from traumatic amnesia. We therefore hypothesized that the encoding, rather than retrieval, mechanisms of stress-related memories underlie their impact on social and emotional behavior. To test this hypothesis, we used combinations of stress-enhanced and state-dependent fear conditioning, which engage different encoding mechanisms for the formation of stress-related memories. We found that the encoding of stress-enhanced state-dependent memories robustly and sex specifically impairs sociability in male mice and disrupts the asymmetry of dentate gyrus (DG)/CA3 activity accompanying social interactions. These deficits were restored by chemogenetic inactivation of oxytocin receptor-positive interneurons localized in the hilus (Oxtr-HI), and by inactivation of dorsohippocampal efferents to the caudal lateral septum. Together, our data suggest that disrupted patterning of dorsohippocampal DG/CA3 activity underlies stress-induced sociability deficits, and that Oxtr-HI can be a cellular target for improving these deficits.

There were gender differences in the prevalence and severity of allergic diseases. Group 2 innate lymphoid cells (ILC2s) were recently reported to play a critical role in allergic diseases. We investigated the sex-dependent differences in ILC2-dominant allergic airway inflammation model using T\B cell-deficient mice, and determined the gender differences of ILC2 levels in patients with asthma and allergic rhinitis. Female mice exhibited higher levels of inflammatory infiltration and large production of IL-5 and IL-13, especially for ILC2 levels compared to male mice with the induction of IL-33. However, no significant differences were found for the levels of circulating ILC2s between the genders of patients. The treatment of testosterone significantly decreased the intracellular type 2 cytokines in ILC2s and the proliferation of pure ILC2s in response to epithelial cytokines. Our study suggested the sex differences and the involvement of androgen on ILC2s in allergic diseases.

The a disintegrin and metalloprotease (ADAM) family proteins comprise a group of membrane-anchored proteins. ADAM32 is expressed specifically in testis and is closely related phylogenetically to ADAM2 and ADAM3, which are known to be critical for fertilization in mice. To assess the biological role of ADAM32, we analyzed Adam32-mutant mice. We found that male mice lacking ADAM32 have normal fertility, testicular integrity, and sperm characteristics. ADAM32 was found to exist at lower levels than ADAM2 and ADAM3 in wild-type testis and sperm, respectively. The present study demonstrates that ADAM32 is dispensable for fertility and appears to be functionally unrelated to ADAM2 and ADAM3 in mice.

Inflammation during critical windows of development contributes to behavioral affect later in life. In this of Neuron, Cao et al. (2021) demonstrate a novel mechanism through which early life Tlr4-dependent inflammation in microglia permanently alters neuronal function and leaves male mice susceptible to stress-induced depressive-like behaviors.

Objectives Abdominal electromyogram or visceromotor response (VMR) elicited by bladder distension is a validated as a measure of bladder nociception in mice, however it is not without its limitations. The aim of this study is to address some of these limitations and validate voiding evoked VMR as a measure of bladder nociception mice. Methods Using both male and female C57BL/6 mice we assessed the VMR response to cytometry- induced voiding before and after instillation of 0.5% acetic acid into the bladder. We then delivered intravesical lidocaine to confirm the VMR response as nociceptive. VMR and correlative cystometric bladder pressures were analyzed. Results We found that the VMR can be evoked by continuous fluid infusion into the bladder of both male and female mice. This response is potentiated after bladder injury and can be attenuated by administration of a local anesthetic, providing strong evidence that this method can be used to evaluate bladder nociception. Further, evaluation of cystometric pressure traces obtained during VMR recording revealed that intercontraction intervals were not altered after bladder injury in either male or female mice. However, we did observe a decrease in peak threshold pressures after bladder injury in female mice, which could be rescued by lidocaine administration. Conclusions In conclusion, this technique can measure the VMR and bladder nociception associated with voiding in both female and male mice. Although confounds still exist with the use of anesthesia, further exploration of non-anesthetized voiding-evoked VMR is warranted.

New findings What is the central question of this study? What is the effect in male and female offspring of a protein-deficient diet producing intrauterine growth restriction (IUGR) in maternal mice on morphometric, metabolic and behavioural parameters before and after a challenge with a fat diet? What is the main finding and its importance? Male and female mice presented different growth trajectories after birth. IUGR favoured increased adiposity in male mice, and high-fat diet-induced anxiety-like behaviour in female mice. Abstract As there is sexual dimorphism in the response to maternal manipulations, we aimed to analyse the effects of intrauterine growth restriction (IUGR) in both sexes on morphometric, metabolic and behavioural parameters throughout postnatal development, and after challenge with a hyperlipidic diet. Female Swiss mice (n = 59) were distributed into two groups (SD: standard diet, n = 26; and PDD: isocaloric protein-deficient diet, n = 33), 2 weeks before mating and during the gestational period. After birth, offspring from SD and PDD dams were cross-fostered and nurtured by SD dams until postnatal day (PND) 28. At PND 60 all animals were challenged with a hypercaloric diet for 4 weeks. Offspring birth weight was significantly reduced in the PDD group compared to the SD group (P = 0.0001), but only male offspring presented a rapid catch-up during the first 21 days of development. Although no differences in body weight were observed between groups after the challenge with the hyperlipidic diet, an increase in the relative perigonadal white adipose tissue (P = 0.009) and a decrease in gross gastrocnemius muscle weight (P = 0.010) were observed in the PDD males. In relation to behavioural tests, there was an increase in locomotion in both sexes (P = 0.0001), and a decrease in female grooming (P = 0.006) in the PDD group. Additionally, females from the PDD group showed increased hyperlipidic food intake. In conclusion, IUGR affected both sexes, with females showing prominent behavioural modifications and males presenting altered body composition elicited by a hyperlipidic diet.

PAPq PROPESP Edital 2019/Universidade Federal do Par? 307749/2004-5/Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico 471077/2007-0/Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico PROCAD-AMAZ?NIA Grant No. 88881.370785/2019-01./Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior Universidade Federal do Par?. N?cleo de Pesquisas em Oncologia. Programa de P?s-Gradua??o em Oncologia e Ci?ncias M?dicas. Hospital Universit?rio Jo?o de Barros Barreto. Bel?m, PA, Brazil / Universidade Federal do Par?. Instituto de Ci?ncias Biol?gicas. Hospital Universit?rio Jo?o de Barros Barreto. Laborat?rio de Investiga??es em Neurodegenera??o e Infec??o. Bel?m, PA, Brazil. Universidade Federal do Par?. Instituto de Ci?ncias Biol?gicas. Hospital Universit?rio Jo?o de Barros Barreto. Laborat?rio de Investiga??es em Neurodegenera??o e Infec??o. Bel?m, PA, Brazil. Universidade Federal do Par?. Instituto de Ci?ncias Biol?gicas. Hospital Universit?rio Jo?o de Barros Barreto. Laborat?rio de Investiga??es em Neurodegenera??o e Infec??o. Bel?m, PA, Brazil. Universidade Federal do Par?. N?cleo de Pesquisas em Oncologia. Programa de P?s-Gradua??o em Oncologia e Ci?ncias M?dicas. Hospital Universit?rio Jo?o de Barros Barreto. Bel?m, PA, Brazil / Universidade Federal do Par?. Instituto de Ci?ncias Biol?gicas. Hospital Universit?rio Jo?o de Barros Barreto. Laborat?rio de Investiga??es em Neurodegenera??o e Infec??o. Bel?m, PA, Brazil. Universidade Federal do Par?. N?cleo de Pesquisas em Oncologia. Programa de P?s-Gradua??o em Oncologia e Ci?ncias M?dicas. Hospital Universit?rio Jo?o de Barros Barreto. Bel?m, PA, Brazil / Universidade Federal do Par?. Instituto de Ci?ncias Biol?gicas. Hospital Universit?rio Jo?o de Barros Barreto. Laborat?rio de Investiga??es em Neurodegenera??o e Infec??o. Bel?m, PA, Brazil. Universidade Federal do Par?. N?cleo de Pesquisas em Oncologia. Programa de P?s-Gradua??o em Oncologia e Ci?ncias M?dicas. Hospital Universit?rio Jo?o de Barros Barreto. Bel?m, PA, Brazil / Universidade Federal do Par?. Instituto de Ci?ncias Biol?gicas. Hospital Universit?rio Jo?o de Barros Barreto. Laborat?rio de Investiga??es em Neurodegenera??o e Infec??o. Bel?m, PA, Brazil / Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Laborat?rio de Microscopia Eletr?nica. Ananindeua, PA, Brasil. Most animal model studies of autism spectrum disorders (ASD) were performed in males. Thus, little is known about the mechanisms underlying disease progression in females. Here, we searched for potential influences of sex and environment on gestational valproic acid-induced behavioral abnormalities using hippocampal-dependent tasks, and on number and morphometry of microglia of the molecular layer of the dentate gyrus (Mol-DG). We compared male and females BALB/c control mice with BALB/c mice gestationally exposed to VPA with regards to exploratory activity and risk assessment in novel environments. Pregnant females and males on gestational day 12.5 received VPA in saline (600 mg/kg body weight) or an equal volume of saline by gavage. After weaning, female and male offspring were housed separately either in standard laboratory cages (SE) or enriched cages (EE). At 5 months of age, these mice underwent behavioral testing and had their brains processed for microglia IBA1 immunolabeling. Compared with control mice, VPA-exposed mice exhibited abnormal behavior in exploring novel environments and assessing risk, and these effects were significantly greater in females than in males and less intense among mice from enriched cages. Three-way ANOVA revealed that environment, sex and valproic acid conditions interacted and altered the behavior results. Microglia number and volume of the Mol-DG were significantly higher in VPA-exposed groups raised in standard cages. The results of counting the intersects of microglia branching on Sholl's circles analyzed with permutational MANOVA, demonstrated that in comparison with males, there was a greater reduction in the number of intersections in females raised in standard cages. These findings suggest that the increased microglia and morphological changes might be associated with behavioral dysfunction in ASD. Moreover, the somatomotor and cognitive stimulation of environmental enrichment started at weaning may be beneficial for reducing behavioral abnormalities and reduction of microglia response in adulthood.

Aging is associated with reduced amplitude and earlier timing of circadian (daily) rhythms in sleep, brain function, and behavior. We examined whether age-related circadian dysfunction extends to the metabolic function of the brain, particularly in the prefrontal cortex (PFC). Using enzymatic amperometric biosensors, we recorded lactate concentration changes in the PFC in Young (7 mos) and Aged (19 mos) freely-behaving C57BL/6N male mice. Both Young and Aged mice displayed diurnal and circadian rhythms of lactate, with the Aged rhythm slightly phase advanced. Under constant conditions, the Aged rhythm showed a reduced amplitude not seen in the Young mice. We simultaneously observed a relationship between arousal state and PFC lactate rhythm via electroencephalography, which was modified by aging. Finally, using RT-qPCR, we found that aging affects the daily expression pattern of Glucose Transporter 1 (GLUT-1).

Background Circadian differences in the induction, maintenance, or emergence from volatile anaesthesia have not been well studied. Methods The minimal alveolar concentration (MAC) for preventing movement in response to a painful stimulus, MAC for loss of righting reflex (MACLORR), and MAC for recovery of righting reflex (MACRORR) in C57BL/6J male mice with isoflurane or sevoflurane exposure were measured during either the light or dark phase. Time to onset of loss of righting reflex (TimeLORR) and recovery of righting reflex (TimeRORR) upon exposure to 1 MAC of isoflurane or sevoflurane were determined. EEG was also monitored in the light and dark phase under isoflurane or sevoflurane exposure. The noradrenergic toxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) was used to deplete noradrenergic neurones in the locus coeruleus to explore the impact of norepinephrine on these measurements. Results MACLORR, TimeLORR, and MAC did not show light- or dark-phase-dependent variations for either isoflurane or sevoflurane exposure. However, MACRORR was higher and TimeRORR was shorter in the dark phase than in the light phase for both isoflurane and sevoflurane exposure. The EEG delta wave power was higher but theta wave power was lower in the light phase than that in the dark phase during the rest state and emergence of anaesthesia. These light- and dark-phase-dependent changes in emergence were abolished in DSP-4-treated mice. Conclusion Our data show that circadian differences exist during emergence but not during induction or maintenance of sevoflurane or isoflurane anaesthesia. The locus coeruleus noradrenergic system may contribute to these differences.

Benzene is a well-known human carcinogen that is one of the major components of air pollution. Sources of benzene in ambient air include cigarette smoke, e-cigarettes vaping and evaporation of benzene containing petrol processes. While carcinogenic effects of benzene exposure have been well studied, less is known about metabolic effects of benzene exposure. We show that chronic exposure to benzene at low levels induces severe metabolic imbalance in a sex-specific manner, which is associated with hypothalamic inflammation and endoplasmic reticulum (ER) stress. Benzene exposure rapidly activates hypothalamic ER stress and neuroinflammatory responses in male mice, while pharmacological inhibition of ER stress response by inhibiting IRE1α-XBP1 pathway significantly alleviates benzene-induced glial inflammatory responses. Additionally, feeding mice with Acarbose, a clinically available anti-diabetes drug, protected against benzene induced central and peripheral metabolic imbalance. Acarbose imitates the slowing of dietary carbohydrate digestion, suggesting that choosing a diet with a low glycemic index might be a potential strategy for reducing the negative metabolic effect of chronic exposure to benzene for smokers or for people living/working in urban environments with high concentrations of exposure to automobile exhausts.

Ethanol exposure during development is associated with deficient social behavior, such as aggressive behavior, and ethanol consumption is associated with violent crimes, thus raising the possibility that individuals with fetal alcohol spectrum disorder may exhibit exacerbated social deficits in response to ethanol exposure. The present study evaluated the effects of ethanol exposure during the brain growth spurt period (i.e., a critical time period during which ethanol's effects are augmented) on aggressive behavior and ethanol-induced aggression during adolescence. From postnatal Day 2 (PD2) to PD8, Swiss mice received either ethanol (5 g/kg, i.p.) or saline on alternate days. On PD39, aggressive behavior was assessed using the resident-intruder paradigm in male mice, and social dominance was investigated using the tube dominance test in both males and females. Testis structure and testosterone levels were evaluated in male mice. Early ethanol exposure increased the gonadosomatic index and the number of Leydig cells. The thickness of the seminiferous tube decreased. No difference in testosterone levels was found. The ethanol-exposed resident mice exhibited increased number and duration of aggressive episodes only when challenged with a low ethanol dose (1 g/kg) before confrontation. Female mice early-exposed to ethanol won more confrontations in the tube dominance test. The present findings suggest a critical brain growth spurt period that is susceptible to ethanol-induced alterations of social dominance behavior in females. Although basal levels of aggression were unaffected, early ethanol exposure resulted in greater susceptibility to ethanol-induced aggression in adolescent male mice.