Sex-dependent, early cytokine production by NK-like spleen cells following infection with the D variant of encephalomyocarditis virus (EMCV-D)

Spleen cell cultures from diabetes-resistant ICR Swiss females exhibited an increase in expression of Ia antigens 24 hours post-infection (PI) with EMCV-D while comparable spleen cell cultures from diabetes-susceptible males of this strain did not exhibit this increase in Ia antigens expression. A monoclonal antibody specific for mouse interferon-gamma (IFN gamma) eliminated this increase in Ia antigens expression. Interferon-gamma (IFN gamma) and interleukin 2 (IL-2) production by EMCV-D-infected spleen cell cultures were monitored at 4-hour intervals for 24 hours. Female spleen cells produced IFN gamma earlier (less than 16 hours PI) and in greater amounts than did comparably treated male spleen cells. Addition of a monoclonal rat anti-mouse IL-2 to virus-infected cultures did not significantly affect the early (less than 16 hours PI) production of IFN gamma by spleen cells of females. Treatment of the spleen cell donors with rabbit anti-asialo GM1 (AAGM1) abolished early production of IFN gamma in virus-infected female spleen cell cultures and reduced the early IL-2 production by infected male and female cells. These results suggest that an NK-like cell is responsible for the early female IFN gamma production; this may be a factor in the resistance of female ICR Swiss mice to EMCV-D-induced diabetes.     

Adrenal modulation of parental behavior in neonatally gonadectomized C57BL/6J male mice

C57BL/6J male mice ordinarily kill neonatal mouse pups even if they are rendered androgen deficient by neonatal castration. Experiment 1 showed that adrenalectomy during adult life significantly decreased the tendency of neonatally gonadectomized males to kill newborns. Experiment 2 demonstrated that testosterone exposure (via silastic implants) during adult life prevented the effects of adrenalectomy in that killing was elevated and retrieving was reduced in neonatally gonadectomized males. Adrenal androgens may be responsible for maintaining killing behavior in neonatally castrated C57BL/6J male mice.     

Postpubertal isolation decreases infanticide and elevates parental care in C57BL/6J male mice

Postpubertal (60 days of age) but not prepubertal (21 days of age) isolation reduced the normal tendency of C57BL/6J male mice to kill newborn pups (infanticide) and instead dramatically elevated their exhibition of parental care (retrieving of young). These effects were time-dependent in that longer durations of isolation (60 days) were more effective than shorter durations (20 days) of individual housing. Postpubertal isolation of male mice with previous killing experience also resulted in a reduction in infanticide and an elevation in parental care, but these effects were not as dramatic as those observed in naive, nonexperienced animals. The findings are discussed in terms of endocrine and neurochemical changes known to accompany isolation in mice.     

The Y chromosome from autoimmune BXSB/MpJ mice induces a lupus-like syndrome in (NZW x C57BL/6)F1 male mice, but not in C57BL/6 male mice

The Y chromosome of the BXSB mouse has been shown to be responsible for the acceleration of lupus-like autoimmune syndrome in inbred BXSB mice and in their F1 hybrids with NZB or NZW mice. To further define the role of this as yet unidentified gene linked to the BXSB Y chromosome, designated Yaa (Y chromosome-linked autoimmune acceleration), the Y chromosome was transferred from the BXSB strain to nonautoimmune C57BL/6 (B6) mice. The effect of the Yaa gene on the autoantibody formation and the development of glomerulonephritis was investigated in B6 mice and in their F1 hybrids with NZW mice. The presence of the BXSB Y chromosome was not able to induce significant autoimmune responses in B6 mice. However, (NZW x B6)F1 males bearing the BXSB Y chromosome developed a severe lupus-like autoimmune syndrome, as documented by the production of anti-DNA antibodies and gp70-anti-gp70 immune complexes and the development of lethal lupus nephritis. Both sexes of (NZW x B6)F1 hybrids without the BXSB Y chromosome were essentially normal. Our results suggest that (a) the BXSB Y chromosome by itself is not sufficient to initiate autoimmune responses in nonautoimmune B6 mice, and (b) it is able to induce autoimmune responses in mice potentially capable of developing the disease, but whose autosomal abnormality by itself is not sufficient to develop autoimmune diseases.     

Differential distribution and activation of microglia in the brain of male C57BL/6J mice

Upon certain stimuli, microglia undergo different degrees of transformation in order to maintain homeostasis of the CNS. However, chronic microglia activation has been suggested to play an active role in the pathogenesis of neurodegenerative diseases. The density of microglia and the degree of microglia activation vary among brain regions; such differences may underlie the brain region-specific characteristics of neurodegenerative diseases. In this study, we aim to characterize the temporal and spatial profiles of microglia activation induced by peripheral inflammation in male C57BL/6J mice. Our results showed that, on average, microglia densities were highest in the cortex, followed by the limbic area, basal nuclei, diencephalon, brainstem and cerebellum. Among the 22 examined brain nuclei/regions, the substantia nigra had the highest microglia density. Microglia morphological changes were evident within 3 h after a single intraperitoneal lipopolysaccharides injection, with the highest degree of changes also in the substantia nigra. The lipopolysaccharide-induced microglia activation, determined by maximal cell size, was positively correlated with density of microglia and levels of TNFα receptor 1; it was not correlated with original microglia cell size or integrity of blood–brain barrier. The differential response of microglia also cannot be explained by different types of neurotransmitters. Our works suggest that the high density of microglia and the high levels of TNFα receptor 1 in the substantia nigra make this brain region the most susceptible area to systemic immunological insults.     

C57BL/6J mice exhibit reduced dopamine D3 receptor-mediated locomotor-inhibitory function relative to DBA/2J mice

Previous reports have identified greater sensitivity to the locomotor-stimulating, sensitizing, and reinforcing effects of amphetamine in inbred C57BL/6J mice relative to inbred DBA/2J mice. The dopamine D3 receptor (D3R) plays an inhibitory role in the regulation of rodent locomotor activity, and exerts inhibitory opposition to D1 receptor (D1R)-mediated signaling. Based on these observations, we investigated D3R expression and D3R-mediated locomotor-inhibitory function, as well as D1R binding and D1R-mediated locomotor-stimulating function, in C57BL/6J and DBA/2J mice. C57BL/6J mice exhibited lower D3R binding density (-32%) in the ventral striatum (nucleus accumbens/islands of Calleja), lower D3R mRNA expression (-26%) in the substantia nigra/ventral tegmentum, and greater D3R mRNA expression (+40%) in the hippocampus, relative to DBA/2J mice. There were no strain differences in DR3 mRNA expression in the ventral striatum or prefrontal cortex, nor were there differences in D1R binding in the ventral striatum. Behaviorally, C57BL/6J mice were less sensitive to the locomotor-inhibitory effect of the D3R agonist PD128907 (10 microg/kg), and more sensitive to the locomotor-stimulating effects of novelty, amphetamine (1 mg/kg), and the D1R-like agonist +/- -1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8,-diol hydrochloride (SKF38393) (5-20 mg/kg) than DBA/2J mice. While the selective D3R antagonist N-(4-[4-{2,3-dichlorphenyl}-1 piperazinyl]butyl)-2-fluorenylcarboxamide (NGB 2904) (0.01-1.0 mg/kg) augmented novelty-, amphetamine-, and SKF38393-induced locomotor activity in DBA/2J mice, it reduced novelty-induced locomotor activity in C57BL/6J mice. Collectively, these results demonstrate that C57BL/6J mice exhibit less D3R-mediated inhibitory function relative to DBA/2J mice, and suggest that reduced D3R-mediated inhibitory function may contribute to heightened sensitivity to the locomotor-stimulating effects of amphetamine in the C57BL/6J mouse strain. Furthermore, these data demonstrate that comparisons between C57BL/6J and DBA/2J mouse strains provide a model for elucidating the molecular determinants of genetic influence on D3R function.     

Abnormality in the cerebellar folial pattern of C57BL/6J mice

The characteristic folial pattern of the mouse cerebellum is formed during postnatal development. We observed this process in C57BL/6J (B6) mice in detail, and found an abnormal folial pattern in a specific region (lobules VIII and IX of the vermis) in a substantial number of B6 mice. The frequency of this abnormality increased during postnatal development and reached 55% in the adult. Thus, the present study showed an abnormality in the cerebellar folial pattern of B6 mice, a mouse widely used in knockout studies, and called for caution in the phenotypic analysis of knockout mice of the B6 genetic background.     

Afferent connections of the parabrachial nucleus in C57BL/6J mice

Although the mouse is an experimental model with an increasing importance in various fields of neuroscience, the characteristics of its central gustatory pathways have not yet been well documented. Recent electrophysiological studies using the rat and hamster have revealed that taste processing in the brainstem gustatory relays is under the strong influence of inputs from forebrain gustatory structures. In the present study, we investigated the organization of afferent projections to the mouse parabrachial nucleus (PbN), which is located at a key site between the brainstem and gustatory, viscerosensory and autonomic centers in the forebrain. We made injections of the retrograde tracer fluorogold centered around the “waist” area of the PbN, whose neurons are known to be highly responsive to taste stimuli. Retrogradely labeled neurons were found in the infralimbic, dysgranular and agranular insular cortex as well as the claustrum; the bed nucleus of the stria terminalis and the substantia innominata; the central nucleus of the amygdala; the lateral and medial preoptic areas, the paraventricular, the dorsomedial, the ventromedial, the arcuate, and the lateral hypothalamic areas; the periaqueductal gray, the substantia nigra pars compacta, and the ventral tegmental area; the supratrigeminal nucleus, rostral and caudal nucleus of the solitary tract; the parvicellular intermediate and gigantocellular reticular nucleus; the caudal and interpolar divisions of the spinal trigeminal nucleus, dorsomedial spinal trigeminal nucleus, and the area postrema. Numbers of labeled neurons in the main components of the gustatory system including the insular cortex, bed nucleus of the stria terminalis, central nucleus of the amygdala, lateral hypothalamus, and rostral nucleus of the solitary tract were quantified. These results are basically consistent with those of the previous rat and hamster studies, but some species differences were found. Functional implications of these afferent inputs are discussed with an emphasis on their role in taste.     

Asbestos-induced autoimmunity in C57BL/6 mice

Environmental impacts on autoimmunity have significant public health implications. Epidemiological studies have shown associations between exposure to airborne silicates, such as crystalline silica or asbestos, and autoimmunity, but the etiology remains unclear. The purpose of this study was to test the hypothesis that asbestos could lead to a specific pattern of autoantibodies and pathology indicative of systemic autoimmune disease (SAID). Female C57Bl/6 mice were instilled intratracheally with 2 doses x 60 microg/mouse of amphibole asbestos (tremolite), wollastonite (a non-fibrogenic control fiber), or saline alone. Serum samples were collected and urine was checked for protein bi-weekly for 7 months. By 26 weeks, the asbestos-instilled animals had a significantly higher frequency of positive anti-nuclear antibody (ANA) tests compared to wollastonite and saline groups. The majority of positive ANAs showed homogeneous or combined homogeneous/speckled patterns, and tested positive for antibodies to dsDNA and SSA/Ro 52. Serum isotyping showed no significant changes in IgM, IgA, or IgG subclasses. However, there was an overall decrease in the mean IgG serum concentration in asbestos-instilled mice. IgG immune complex deposition was demonstrated in the kidneys of asbestos-instilled mice, with evidence of glomerular and tubule abnormalities suggestive of glomerulonephritis. Flow cytometry demonstrated moderate changes in the percentages of CD25+ T-suppressor cells and B1a B-cells in the superficial cervical lymph nodes of the asbestos-instilled mice. These data demonstrate that asbestos leads to immunologic changes consistent with the development of autoimmunity. This study provides a non-autoimmune prone murine model for use in future elucidation of mechanisms involved in asbestos-induced autoimmune disease.     

Friend virus replication in normal and immunosuppressed C57BL/6 mice

Young adult C57BL/6 mice are resistant to the replication of Friend virus. We show here that this resistance is not absolute. In 7-week old C57BL/6 mice injected with NB-tropic Friend virus iv, high titers of SFFV could be recovered from the spleen at 8 days after infection but by 21 days, no virus was detectable. A single dose of anti-Thy 1.2 monoclonal antibody iv before FV infection permitted continued replication of SFFV in these animals. This finding strongly supports the hypothesis that SFFV replication in C57BL/6 mice is restricted by a T cell-mediated immune response.     

Age and brightness discrimination learning by C57BL/6J mice

Groups of 20–34 C577BL/6J mice, aged 75, 225, 375, and 525 days, learned a brightness discrimination for water. The error scores of the 75- and 525-day groups were almost identical, and both made significantly more errors than the 225-day-old mice. Both immature and older mice appear to be deficient in learning ability compared to young adults.     

Topiramate attenuates the stress-induced increase in alcohol consumption and preference in male C57BL/6J mice

Stress increases the risk for alcohol abuse and relapse behaviors. However, there are hardly any medications to counteract stress-induced alcoholism and relapse behaviors. The present study examined the effects of topiramate (intraperitoneal injections of 10, 20, and 30mg/kg) in its ability to attenuate alcohol consumption on exposure to restraint stress in C57BL/6J mice on a 2-choice test procedure. Mice were either restrained for 1h/day for 5 successive days or left unrestrained. Subsequently, the effects of topiramate were studied in post-restraint days. Results showed that restrained animals increased alcohol consumption and alcohol preference significantly compared to control group on day 5. On post-restraint days, topiramate reduced alcohol consumption and alcohol preference on days 2-5 compared to saline. This experiment suggests that one mechanism of topiramate in reducing alcohol consumption and alcohol preference may involve an interaction with stress.     

白藜芦醇通过调节iNOS抑制C57BL/6J小鼠动脉粥样硬化的机制探讨

目的:探讨白藜芦醇(resveratrol,RES)对卵巢切除小鼠血脂四项总胆固醇(CHOL)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)以及血清一氧化氮(nitric oxide,NO)含量、胸主动脉的过氧亚硝基阴离子(peroxynitrite anion,ONOO-)及诱导型一氧化氮合酶(inducible nitric oxide synthase,iNOS)蛋白表达水平的影响。方法:雌性C57小鼠经卵巢切除建立去势模型后,分为假手术组、单纯去势组、假手术高脂组、模型高脂组和RES组。单纯去势组和假手术组给予普通饲料,其余给予高脂饲料。14周后,收集血清检测各组血清的CHOL、TG、LDL-C和HDL-C水平,硝酸还原酶法测血浆NO水平,油红O染色观察动脉粥样硬化(atherosclerosis,AS)情况,DAB染色测定血管ONOO-及iNOS水平,免疫印迹测定血管组织的iNOS表达。结果:模型高脂组血清CHOL、TG、LDL-C和NO较正常对照组升高(P0.05);与模型高脂组相比,RES组可降低小鼠血清的TC、TG、LDL-C和NO(P0.05);14周后,AS模型成功建立,模型高脂组有明显的AS病理改变,单纯去势组无明显AS斑块,RES组AS病变明显减轻;高脂喂养14周后,模型高脂组血管组织的iNOS及ONOO–表达也较正常对照组明显提高(P0.05);与模型高脂组相比,RES组可降低小鼠胸主动脉的iNOS表达(P0.05),与此同时,血管ONOO-含量较模型高脂组降低。结论:RES可以抑制iNOS表达,减少NO生成,防治动脉粥样硬化。     

肺炎衣原体感染致C57BL/6J小鼠内皮功能异常

目的：研究肺炎衣原体感染对C57BL/6J小鼠主动脉内皮依赖舒张反应及动脉粥样硬化形成的影响。方法：32只C57BL/6J小鼠分为肺炎衣原体感染并胆固醇饲料喂养组、胆固醇饲料喂养组、肺炎衣原体感染组和对照组，喂养24周，取主动脉弓标本分析动脉粥样硬化斑块面积，远端胸主动脉作血管舒张功能测定，血样品作血脂、一氧化氮水平及内皮素浓度测定。结果：肺炎衣原体感染并胆固醇饲料喂养组、胆固醇饲料喂养组和肺炎衣原体感染组乙酰胆碱引起的动脉平均最大舒张百分数明显低于对照组(P＜0.01)，且一氧化氮水平也较低，单纯肺炎衣原体感染小鼠无明显动脉粥样硬化形成。结论：肺炎衣原体感染可损害C57BL/6J小鼠动脉内皮功能，一氧化氮途径可能参与其发展。     

Difference in glucose intolerance between C57BL/6J and ICR strain mice with streptozotocin/nicotinamide-induced diabetes

Blood glucose and plasma insulin levels between C57BL/6J and ICR strain mice with nicotinamide (NA) and streptozotocin (STZ)-induced diabetes were compared to establish a suitable strain of the experimental diabetic mouse model. The mice were intraperitoneally treated twice with STZ (100 mg/kg) 15 min after injection of NA (120 mg/kg) at a 1-day interval, and non-fasting blood glucose level was then weekly monitored for 5 weeks. The blood glucose level in ICR mice gradually increased and was about 2-times higher than that in C57BL/6J mice at the end of the observation. The plasma insulin level in ICR mice was comparatively low, compared with that in C57BL/6J mice. ICR mice were also markedly glucose-intolerant when oral glucose tolerance test was performed. These results indicate that ICR strain is more sensitive than C57BL/6J strain as a mouse model with NA/STZ-induced mild diabetes.     

Punta Toro virus infection of C57BL/6J mice: a model for phlebovirus-induced disease

Punta Toro virus infections of inbred strains of mice have been characterized and evaluated as a model in which to study various aspects of the host response to phlebovirus infections and the requirements for protective immunity. The Adames strain of Punta Toro virus was found to be strongly hepatotropic and lymphotropic and the outcome of infection was largely a function of age. C57BL/6J mice of less than 5 weeks of age uniformly developed fulminant hepatocellular necrosis with mean survival times of 4.2 days. Resistance to lethal infection increased with age such that greater than 95% of 8-week-old mice survived challenge. The kinetics of viremia, antibody production, and hematological changes in 4- and 8-week animals indicated that the survival of the older animals is related to their ability to delay virus replication and the development of hepatic lesions during the initial 48 h of infection and their ability to terminate virus replication and clear virus from the circulation 4 to 5 days after infection. The mechanisms responsible for this resistance were studied using anti-interferon serum, immunosuppression, and passive immunization.     

Age-related immunohistochemical studies of A and D cells in pancreatic islets of C57BL/6J mice

Sections of pancreatic islets from C57BL/6J mice aged 3, 14, and 24 months, consisting of islets derived from the dorsal primordium (DPI) and from the ventral primordium (VPI), were immunostained using the peroxidase-antiperoxidase (PAP) procedure for localization of glucagon (A cells) and somatostatin (D cells). The density (A or D cell area/islet area) of immunopositive cells were determined using computer-assisted image analysis. The density of A cells was significantly less in VPI of 14- and 24-month-old mice compared to 3-month-old mice. The density of A cells in 24 month DPI was less than 3 month DPI but no different from 14 month DPI. The mean area (microns 2) of A cells (only in DPI) was significantly less at 24 months compared to the 3 and 14 month groups. There were no differences in somatostatin staining when comparing the three age groups, although at all ages the density of D cells was always greater in the DPI. In conclusion, the major difference between the young and older mice was a deficiency of glucagon-stained cells in older mice. These results might be important in explaining improved glucose tolerance in aged C57BL/6J mice.     

Aluminum in the organs and diet of ageing C57BL/6J mice

Total aluminum concentrations increased with ageing in the liver and kidney of male C57BL/6J mice, remained unchanged in brain and heart, and decreased with ageing in femur and lung for mice ranging in age from 56 to 1186 days. Ligating one kidney did not significantly increase aluminum concentrations in the various organs. Feeding 1 X 10(-2) M aluminum chloride (270 ppm Al) in the drinking water beginning at 604 days of age decreased the average life span by 6.7%. We conclude that very little aluminum accumulation occurs with ageing in the organs tested in this study, in spite of a high dietary intake. Other organs might show a change. Only one aluminum concentration was used in this study which accelerated the rate of ageing as indicated by a change in the survival curve. The effect of higher or lower aluminum concentrations remains to be seen.     

Angiotensin II stimulates intake of ethanol in C57BL/6J mice.

The influence of intracerebroventricular (i.c.v.) infusion of angiotensin II on intake of water and ethanol solutions was determined in C57BL/6J mice. Compared to other mice, C57 mice do not show an aversion to ethanol solutions. With both water and ethanol solutions available, the C57 mice consumed 40-60% of their total daily fluid intake as ethanol solution when the concentration of ethanol solution offered was 4-14%. When given a choice between 0.3 M KCl and either 4 or 10% ethanol solution, the mice clearly preferred the ethanol solution. With water only available, i.c.v. infusion of angiotensin II increased intake from 3-5 mL/day (baseline) to 11-12 mL/ day (Day 4 of infusion). A similar increase in intake occurred in mice with access to a nonpreferred solution of 0.3 M KCl. In comparison, when only 4% ethanol solution was available, angiotensin II increased intake to 7-8 mL/day, and when only 10% ethanol solution was available, intake was transiently increased. The results demonstrated that thirst for water caused by i.c.v. infusion of angiotensin II in C57 mice is similar to that observed in BALB/C mice. Unlike BALB/C mice, however, i.c.v. infusion of angiotensin II stimulated intake of ethanol solution. The failure of angiotensin II to cause a large increase in 4% ethanol solution or a sustained increase in 10% ethanol solution intake does not seem to be caused by an aversion to the taste of ethanol solution, but most likely due to postingestional factors.