用适应性实验对ICR、BALB/c和C57BL/6小鼠探索行为及记忆能力的评价

用洞板仪和旷场行为红外线检测系统对远交群ICR小鼠、近交系BALB/c小鼠和近交系C57BL/6小鼠的探洞、直立和跨格行为进行了测试,并通过适应性实验比较了它们的探索行为和记忆能力。研究发现:在各项试验中,ICR小鼠表现出最强的探索能力,而C57BL/6小鼠的探索能力最差;ICR小鼠还表现出比另外两个品系小鼠更强的对新环境的适应性,其记忆也明显优于C57BL/6小鼠。实验结果提示:小鼠探洞行为的适应性实验可以用来测试小鼠的记忆能力,而小鼠的直立行为在一定程度上也反映了其对周围环境、事物的探索和认知。这些结果为今后在研究小鼠神经生物学时的行为学指标选择问题提供了参考依据,同时也提示了在进行小鼠行为学实验时,根据不同研究目的选择不同品系的重要性。     

C57BL/6 and BALB/c bronchoalveolar macrophages respond differently to exercise.

Macrophages from prototypical Th1 strains (e.g., C57BL/6) and Th2 strains (e.g., BALB/c) are classified as M-1 and M-2 phenotypes. We investigated the different phagocytic responses between M-1 and M-2 bronchoalveolar macrophages (BAMs) under resting and two various exercise conditions. At rest, M-1 BAMs showed higher phagocytic capacity of unopsonized particles, higher expression of MARCO (macrophage receptor with collagenous structure), and higher generation of NO than M-2 BAMs. Severe exercise, but not moderate exercise, significantly enhanced both phagocytosis of unopsonized particles and expression of MARCO in M-2 BAMs. In contrast, M-1 BAMs were unaffected by either exercise protocol. The phagocytosis of unopsonized particles was largely mediated by MARCO, especially in M-1 BAMs. Secreted products from cultured M-2 BAMs isolated after severe exercise, but not those from M-1 BAMs, enhanced BAM phagocytosis. The cultured M-1 BAMs secreted phagocytosis inhibitors, and this effect could be blocked by NO antagonists. Moreover, the extent of phagocytosis suppression induced by M-1 BAM-secreted products correlated with their production of nitrite/nitrate. Exogenous NO donors as well as NO derivatives, nitrite and nitrate, suppressed the BAM phagocytosis. We propose that while the severe exercise-enhanced phagocytosis in M-2 BAMs was largely mediated by MARCO up-regulation and secretion of stimulators, the lack of exercise effect in M-1 BAMs could be partially due to the constitutive secretion of NO-related suppressors. In conclusion, genetically different mice use different strategies in regulating BAM activity under resting conditions and in response to various exercise paradigms.     

Comparison of West African and Congo Basin Monkeypox Viruses in BALB/c and C57BL/6 Mice

Although monkeypox virus (MPXV) studies in wild rodents and non-human primates have generated important knowledge regarding MPXV pathogenesis and inferences about disease transmission, it might be easier to dissect the importance of virulence factors and correlates of protection to MPXV in an inbred mouse model. Herein, we compared the two clades of MPXV via two routes of infection in the BALB/c and C57BL/6 inbred mice strains. Our studies show that similar to previous animal studies, the Congo Basin strain of MPXV was more virulent than West African MPXV in both mouse strains as evidenced by clinical signs. Although animals did not develop lesions as seen in human MPX infections, localized signs were apparent with the foot pad route of inoculation, primarily in the form of edema at the site of inoculation; while the Congo Basin intranasal route of infection led to generalized symptoms, primarily weight loss. We have determined that future studies with MPXV and laboratory mice would be very beneficial in understanding the pathogenesis of MPXV, in particular if used in in vivo imaging studies. Although this mouse model may not suffice as a model of human MPX disease, with an appropriate inbred mouse model, we can unravel many unknown aspects of MPX pathogenesis, including virulence factors, disease progression in rodent hosts, and viral shedding from infected animals. In addition, such a model can be utilized to test antivirals and the next generation of orthopoxvirus vaccines for their ability to alter the course of disease.     

Immune Cells from SR/CR Mice Induce the Regression of Established Tumors in BALB/c and C57BL/6 Mice

Few experimental models are available for the study of natural resistance to cancer. One of them is the SR/CR (spontaneous regression/complete resistance) mouse model in which natural resistance to a variety of cancer types appeared to be inherited in SR/CR strains of BALB/c and C57BL/6 mice. The genetic, cellular, and molecular effector mechanisms in this model are largely unknown, but cells from the innate immune system may play a significant role. In contrast to previous observations, the cancer resistance was limited to S180 sarcoma cancer cells. We were unable to confirm previous observations of resistance to EL-4 lymphoma cells and J774A.1 monocyte-macrophage cancer cells. The cancer resistance against S180 sarcoma cells could be transferred to susceptible non-resistant BALB/c mice as well as C57BL/6 mice after depletion of both CD4+/CD8+ leukocytes and B-cells from SR/CR mice. In the responding recipient mice, the cancer disappeared gradually following infiltration of a large number of polymorphonuclear granulocytes and remarkably few lymphocytes in the remaining tumor tissues. This study confirmed that the in vivo growth and spread of cancer cells depend on a complex interplay between the cancer cells and the host organism. Here, hereditary components of the immune system, most likely the innate part, played a crucial role in this interplay and lead to resistance to a single experimental cancer type. The fact that leukocytes depleted of both CD4+/CD8+ and B cells from the cancer resistant donor mice could be transferred to inhibit S180 cancer cell growth in susceptible recipient mice support the vision of an efficient and adverse event free immunotherapy in future selected cancer types.     

An X-encoded alloantigenicity between BALB/c and C57BL/6 strains of mice

To detect minor barriers to histocompatibility that might be encoded on the X chromosome in mice, we grafted reciprocal sets of (C57BL/6xBALB/c)F1, (C57BL/6xDBA/2)F1, and (BALB/cxDBA/2)F1 mice with tail skin from the respective paternal inbred strain. Our histogenic analysis suggests that, compared with the C57BL/6 mouse strain, the BALB/c strain generates X-linked antigen loss. In contrast, we detected no X-linked histogenic differences between strains C57BL/6 and DBA/2, or DBA/2 and BALB/c. To localize this X-linked barrier to histocompatibility, we produced a panel of 25 [(BALB/cxC57BL/6)F1xC57BL/6]N2 males that were grafted with C57BL/6 skin to determine which carried the BALB/c-derived component(s) necessary for graft rejection. DNA marker analysis showed one region of overlapping BALB/c-derived X-chromosomal segments among the graft rejecters, suggesting that this antigen-loss haplotype ( H-hix(c), for histoincompatibility on the X chromosome, c haplotype) may be restricted within the DXMit55 to the Xq telomere interval (which excludes only the centromeric tip of the X). Further backcrossing of H-hix(c) to C57BL/6 resulted in fewer rejecter mice than expected by the N4 generation, suggesting that a second, unlinked locus is also involved in this X-linked alloantigenicity. The vigorous rejection of male (C57BL/6xBALB)F1 and female (B6.C- H2(d)xC57BL/6)F1 skin by (BALB/cxC57BL/6)F1 males, as well as the assessment of markers on Chromosome 17 among N2 and N4 graft-recipient males, suggests that this second locus is H2, and that H-hix(b)-encoded alloantigens require both H2(b) and H2(d)-encoded presentation molecules for efficient graft rejection.     

Knockout of the TauT Gene Predisposes C57BL/6 Mice to Streptozotocin-Induced Diabetic Nephropathy

Diabetic nephropathy is the leading cause of end stage renal disease in the world. Although tremendous efforts have been made, scientists have yet to identify an ideal animal model that can reproduce the characteristics of human diabetic nephropathy. In this study, we hypothesize that taurine insufficiency is a critical risk factor for development of diabetic nephropathy associated with diabetes mellitus. This hypothesis was tested in vivo in TauT heterozygous (TauT ^+/-) and homozygous (TauT^-/-) knockout in C57BL/6 background mice. We have shown that alteration of the TauT gene (also known as SLC6A6) has a substantial effect on the susceptibility to development of extensive diabetic kidney disease in both TauT ^+/- and TauT^-/-mouse models of diabetes. These animals developed histological changes characteristic of human diabetic nephropathy that included glomerulosclerosis, nodular lesions, arteriosclerosis, arteriolar dilation, and tubulointerstitial fibrosis. Immunohistochemical staining of molecular markers of smooth muscle actin, CD34, Ki67 and collagen IV further confirmed these observations. Our results demonstrated that both homozygous and heterozygous TauT gene deletion predispose C57BL/6 mice to develop end-stage diabetic kidney disease, which closely replicates the pathological features of diabetic nephropathy in human diabetic patients.     

Helicobacter pylori infection in wild-type and cytokine-deficient C57BL/6 and BALB/c mouse mutants

Helicobacter pylori causes gastroduodenal ulcer disease in humans. T lymphocytes and their cytokines are thought to play a substantial role in the control of H. pylori infection. To determine the importance of T helper (Th) cytokines and background genes we investigated the natural course of H. pylori infection in BALB/c and C57BL/6 wild-type or mutant mice deficient for either interleukin (IL)-4 or interferon (IFN)-gamma. H. pylori SPM 326 persisted for at least six months in C57BL/6 but was cleared by BALB/c wild-type mice nine weeks postinfection. H. pylori was recovered more frequently from IFN-gamma(-/-) BALB/c and IFN-gamma( -/-) C57BL/6 mice than from the respective wild-type animals. In contrast, IL-4 deficiency had no detectable effect on H. pylori recovery rates from either strain of mice. Our data suggest a protective role of IFN-gamma by mediating inflammation in murine H. pylori infection. In addition, our data emphasize that background genes which differ between BALB/c and C57BL/6 mice regulate the clearance of H. pylori.     

Generation of C57BL/6 knockout mice using C3H x BALB/c blastocysts

The International Mouse Knockout Consortium aims to generate a knockout mouse for every single gene on a C57BL/6 background. Our ability to generate such mice is hampered by the poor economics of producing blastocysts to achieve germline transmission of C57BL/6 embryonic stem (ES) cells. We demonstrate superior utility of (C3H x BALB/c)F1 blastocysts compared with BALB/c blastocysts, with blastocyst numbers and germline transmission from subsequent chimeras at a rate 2- to 3-fold higher than that produced with BALB/c blastocysts.     

Kinetics of antibody response in BALB/c and C57BL/6 mice bitten by Phlebotomus papatasi

Background

Phlebotomine sand flies are blood-sucking insects transmitting Leishmania parasites. In bitten hosts, sand fly saliva elicits specific immune response and the humoral immunity was shown to reflect the intensity of sand fly exposure. Thus, anti-saliva antibodies were suggested as the potential risk marker of Leishmania transmission. In this study, we examined the long-term kinetics and persistence of anti-Phlebotomus papatasi saliva antibody response in BALB/c and C57BL/6 mice. We also tested the reactivity of mice sera with P. papatasi salivary antigens and with the recombinant proteins.

Methodology/Principal Findings

Sera of BALB/c and C57BL/6 mice experimentally bitten by Phlebotomus papatasi were tested by ELISA for the presence of anti-saliva IgE, IgG and its subclasses. We detected a significant increase of specific IgG and IgG1 in both mice strains and IgG2b in BALB/c mice that positively correlated with the number of blood-fed P. papatasi females. Using western blot and mass spectrometry we identified the major P. papatasi antigens as Yellow-related proteins, D7-related proteins, antigen 5-related proteins and SP-15-like proteins. We therefore tested the reactivity of mice sera with four P. papatasi recombinant proteins coding for most of these potential antigens (PpSP44, PpSP42, PpSP30, and PpSP28). Each mouse serum reacted with at least one of the recombinant protein tested, although none of the recombinant proteins were recognized by all sera.

Conclusions

Our data confirmed the concept of using anti-sand fly saliva antibodies as a marker of sand fly exposure in Phlebotomus papatasi–mice model. As screening of specific antibodies is limited by the availability of salivary gland homogenate, utilization of recombinant proteins in such studies would be beneficial. Our present work demonstrates the feasibility of this implementation. A combination of recombinant salivary proteins is recommended for evaluation of intensity of sand fly exposure in endemic areas and for estimation of risk of Leishmania transmission.     

小鼠动物实验方法系列专题(三) 三硝基苯磺酸诱导的C57/BL6小鼠结肠炎模型的建立方法

2,4,6-三硝基苯磺酸(TNBS)诱导的小鼠结肠炎模型是研究人类炎性肠病(inflammatory bowl disease,IBD)的主要手段之一,但在实际应用中,常用的C57/BL品系小鼠却对TNBS有较高耐受性,不易建模。本文主要介绍一种可以有效诱导C57/BL6小鼠TNBS结肠炎的方法,并对疾病评价指标进行了具体的描述。对基因工程小鼠IBD模型的研究具有重要意义。     

Humanized TLR7/8 Expression Drives Proliferative Multisystemic Histiocytosis in C57BL/6 Mice

A humanized TLR7/TLR8 transgenic mouse line was engineered for studies using TLR7/8 ligands as vaccine adjuvants. The mice developed a spontaneous immune-mediated phenotype prior to six months of age characterized by runting, lethargy, blepharitis, and corneal ulceration. Histological examination revealed a marked, multisystemic histiocytic infiltrate that effaced normal architecture. The histological changes were distinct from those previously reported in mouse models of systemic lupus erythematosus. When the mice were crossed with MyD88^−/− mice, which prevented toll-like receptor signaling, the inflammatory phenotype resolved. Illness may be caused by constitutive activation of human TLR7 or TLR8 in the bacterial artificial chromosome positive mice as increased TLR7 and TLR8 expression or activation has previously been implicated in autoimmune disease.     

Lactation-induced WAP-SV40 Tag Transgene Expression in C57BL/6J Mice Leads to Mammary Carcinoma

Two transgenic lineages were generated by directing the expression of SV40 T antigen to the mammary gland of inbred C57BL/6J mice using the whey acidic protein (WAP) promoter. In one lineage, WAPTag 1, multiparous female mice developed mammary adenocarcinoma with an average latency period of 13 months. The histopathological phenotype was heterogeneous, tumours occurred in a stochastic fashion, normal tissue was located next to neoplastic tissue, the mammary tumours usually developed and were remarkably similar to that observed in human cases. In addition, male and virgin females developed a poorly differentiated SV40 T antigen-positive soft tissue sarcoma, also at 13 months of age. In the other lineage, WAPTag 3, some parous females developed mammary tumours, but most mice succumbed to osteosarcomas arising from the os petrosum at 5.5 to 6 months of age and on necropsy, renal adenocarcinomas were also found. Appearance of these unexpected tumour types demonstrates the non-specific e...     

In vitro studies of the natural humoral antitumor reactivity of BALB/c and C57BL/6J mice

Summary Antitumor antibodies were produced in vitro by spleen cells harvested from 12- to 18-month-old C57BL/6J and BALB/c mice with a naturally occurring complement-dependent serum cytotoxicity for tumor cells. The antibodies were of the IgM class and had a complement-dependent cytotoxic reactivity on EL4 cells, which was not absorbed by normal thymus cells. No natural antibodies were produced by untreated spleen cells from 1- or 3-month-old mice of the same two strains, which had no natural serum reactivity. However, after a treatment with an anti-Thy-1 serum and complement before culturing, spleen cells from 3-month-old mice, but not 1-month-old mice, produced the natural antitumor cytotoxic antibodies in vitro. When antibody-producing spleen cells from 12-month-old mice were cultured in vitro together with spleen cells from the unreactive 3-month-old syngeneic mice, inhibition of the antibody production occurred. This inhibiting capacity increased between 1 and 6 months of age and was abrogated by a treatment with an anti-Thy-1 serum and complement or with an anti-Ly-2 serum, whereas the passage of the inhibiting spleen cells on an anti-IgG column did not modify the inhibiting capacity. The in vitro data confirm previous in vivo findings on the nature, specificity and systems of regulation of the natural antitumor cytotoxic antibodies.     

High-Efficient FLPo Deleter Mice in C57BL/6J Background

Conditional gene manipulation in mice becomes a routine for genetic studies of mammalian gene functions. Additional site-specific recombinases such as FLP or φ31 provide one more level of gene manipulation flexibility. The recombination activity of the currently available FLP deleter mice remains low. We generated a new FLP deleter mouse line with the mouse codon-optimized FLPo gene in C57BJ/6 background, which showed superior recombination efficacy in comparison to FLPe deleter mice. 100% complete removal of FRT-flanked Neo cassette was observed in all F1 progeny mice carrying both FLPo and Neo cassette, which can be transmitted to F2 generation independent of FLPo activity. Our new FLPo transgenic mice (on pure C57BJ/6 background) will largely facilitate the gene targeting process and is valuable for conditional gene manipulation.     

C57BL/6J-HBV转基因小鼠的繁育与检测

目的　摸清C57BL 6J -HBV转基因小鼠的繁育规律 ,建立可靠的HBsAg表达检测方法。方法　对C57BL 6J-HBV转基因小鼠两种不同交配方式的繁殖性能和HBsAg的表达情况进行比较研究 ;应用免疫组化的方法证实血清学诊断HBsAg的准确性并用激光扫描共聚焦显微镜确定HBsAg在肝细胞中的表达部位。结果与结论　从繁殖性能来看 ,两种交配方式窝产仔数差异不显著 (P >0 .0 5 ) ,而离乳数差异具有显著性 ( 0 .0 1

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A Comparison of Mouse Parvovirus 1 Infection in BALB/c and C57BL/6 Mice: Susceptibility,Replication, Shedding,and Seroconversion

This study characterized the effects of challenge with a field isolate of mouse parvovirus 1 (MPV1e) in C57BL/6NCrl (B6) and BALB/cAnNCrl (C) mice. We found that C mice were more susceptible to MPV1e infection than were B6 mice; ID₅₀ were 50 to 100 times higher after gavage and 10-fold higher after intraperitoneal injection in B6 as compared with C mice. To evaluate the host strain effect on the pathogenesis of MPV1e, B6 and C mice were inoculated by gavage. Feces and tissues, including mesenteric lymph nodes (MLN), ileum, spleen and blood, were collected for analysis by quantitative PCR (qPCR) to assess infection and fecal shedding and by RT-qPCR to evaluate replication. Peak levels of MPV1e shedding, infection, and replication were on average 3.4, 4.3, and 6.2 times higher, respectively, in C than in B6 mice. Peaks occurred between 3 and 10 d after inoculation in C mice but between 5 and 14 d in B6 mice. Multiplexed fluorometric immunoassays detected seroconversion in 2 of 3 C mice at 7 d after inoculation and in all 3 B6 mice at 10 d. By 56 d after inoculation, viral replication was no longer detectable, and fecal shedding was very low; infection persisted in ileum, spleen, and MLN, with levels higher in C than B6 mice and highest in MLN. Therefore, the lower susceptibility of B6 mice, as compared with C mice, to MPV1e infection was associated with lower levels of infection, replication, and shedding and delayed seroconversion.Abbreviations: B6, C57BL/6; C, BALB/c; MFI, median fluorescence intensity; MFIA, multiplexed fluorometric immunoassay; MLN, mesenteric lymph node; MMV, mouse minute virus; MPV, mouse parvovirus; NS1, nonstructural protein 1; qPCR, quantitative PCR; r, recombinant; Rn, normalized reporter value; VP2, virus capsid protein 2Parvoviruses are small (20 to 28 nm), nonenveloped icosahedral single-stranded DNA viruses that infect a diverse range of vertebrate and arthropod species. Much of what is understood about the biology and pathogenesis of autonomous parvoviruses has been derived from studies of the original murine parvoviral isolates, particularly the prototypic and immunosuppressive strains of mouse minute virus (MMV).^9,13,32 Because autonomous parvoviruses have a requirement and predilection for proliferating cells to replicate, they are primarily teratogenic pathogens. In contrast, rodent parvovirus infections of older animals are usually asymptomatic, because the cells that divide in mature animals, such as enterocytes, lymphoreticular cells, and hematopoietic cells, are largely spared.^2,47,48 The most common parvovirus of laboratory mice, mouse parvovirus 1 (MPV1), was first isolated²⁹ from mouse T-lymphocyte cultures that had lost viability or the ability to proliferate when stimulated. In contrast to MMV,^10,27,40 MPV1 has not been shown to cause disease in newborn or immunodeficient mice^19,45 but nevertheless has been reported to modulate the immune response of infected mice.^30,31Adventitious infections of laboratory mice with MPV1 and other parvoviruses continue to occur regularly, despite biosecurity improvements that have successfully excluded once-common pathogens such as Sendai virus.^22,37,39 One reason for the continued occurrence of these infections is that nonenveloped parvovirus virions are environmentally stable and resistant to disinfection.^18,49 Furthermore, related to their tendency to persist in host tissues even after seroconversion and their predilection for dividing cells, parvoviruses have been among the most frequent viral contaminants of transplantable tumor lines and other rodent-derived biologic reagents.^34,35 Inoculation of parvovirus-contaminated biologic reagents into experimental animals can contribute to the incidence of parvoviral outbreaks. Currently, mouse populations typically are housed in microisolation cages and are monitored for MPV1 infections through the use of soiled bedding sentinels. An MPV1 infection of the principal animals may not be transmitted to sentinels when the prevalence of infection is low, as is often the case after contamination, or when the sentinels are comparatively resistant to infection because of their genetic background or age.^7,16,17 However, a recent study found that sentinel age did not affect the likelihood of MPV1 infection.¹⁷The C57BL/6 (B6) mouse strain is popular in biomedical research and is commonly used as the background strain for spontaneous and genetically engineered mutations. We and others have noted that B6 mice are less likely to be MPV1 seropositive than are mice of other strains and stocks, even in facilities where MPV1 is widespread.⁴⁴ There has been speculation that B6 mice might not seroconvert when infected with MPV1. However, data reported here and by others^7,15 indicate that B6 mice are less likely to seroconvert because they are comparatively resistant to MPV1 infection; when they become infected, they do seroconvert. The current study evaluated whether resistance of B6 mice to infection with MPV1, as compared with BALB/c (C) mice, varies with virus inoculation route and correlates with differences in the time course and levels of viral infection, replication, and shedding and of humoral immunity.Most studies of MPV1 in mice have been performed with the cultivable MPV1a strain.^{7,19,30,31,45} Cultivable murine parvoviruses are known to differ from wildtype strains genetically and in their cell tropisms, pathogenicity, and transmissibility in vivo. For example, MPV1d, a noncultivable field isolate, was more readily transmitted to sentinels than was MPV1a.¹¹ We therefore chose to perform the current experiments with MPV1e,^3,4 a representative field strain that we originally isolated from an adventitiously infected barrier colony⁴⁴ and that has been propagated only in mice.