Genetic influence on neurogenesis in the dentate gyrus of adult mice

To address genetic influences on hippocampal neurogenesis in adult mice, we compared C57BL/6, BALB/c, CD1(ICR), and 129Sv/J mice to examine proliferation, survival, and differentiation of newborn cells in the dentate gyrus. Proliferation was highest in C57BL/6; the survival rate of newborn cells was highest in CD1. In all strains approximately 60% of surviving newborn cells had a neuronal phenotype, but 129/SvJ produced more astrocytes. Over 6 days C57BL/6 produced 0.36% of their total granule cell number of 239,000 as new neurons, BALB/c 0.30% of 242,000, CD1 (ICR) 0.32% of 351,000, and 129/SvJ 0.16% of 280,000. These results show that different aspects of adult hippocampal neurogenesis are differentially influenced by the genetic background.     

Genetic influences on latent inhibition.

The present study examined the development of latent inhibition in a number of inbred strains of mice. C57BL/6J, DBA/2J, C3H/Ibg, BALB/cByJ, A/J, CBA/J, 129/SvevTac, 129/SvJ, and AKR/J mice were screened for the development of latent inhibition. The latent inhibition paradigm involved 1 day of either 40 preexposures to the conditioned stimulus (CS) or no preexposure. On the following training day, the CS was twice paired with a shock unconditioned stimulus (US). On a subsequent test day, the strength of the CS—US association was measured. Mice preexposed to the CS should show a weaker CS—US association, which would reflect development of latent inhibition. Significant between-strain differences existed. The 129/Svev, C57BL/6, BALB/cByJ, AKR, and DBA/2 mice developed latent inhibition, but 129/SvJ, CBA, A, and C3H mice did not. Thus, genetic variance contributes to variability in the development of latent inhibition. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Obesity and hyperleptinemia in metallothionein (-I and -II) null mice

Metallothionein (MT) has several putative roles in metal detoxification, in Zn and Cu homeostasis, in scavenging free radicals, and in the acute phase response. Mice of mixed 129/Ola and C57BL/6J background with targeted disruption of MT-I and MT-II genes are more sensitive to toxic metals and oxidative stress. We noted that these animals were larger than most strains of mice, and we systematically studied aspects of their physiology and biochemistry relating to energy metabolism. During the first 2 weeks after weaning, the growth rates of MT-null and C57BL/6J mice were similar, but the transgenic mice became significantly heavier at age 5-6 weeks. At age 14 weeks, the body weight and food intake of MT-null mice was 16 and 30% higher, respectively, compared with C57BL/6J mice. Most 22- to 39-week-old male MT-null mice were obese, as shown by increased fat accretion, elevated obese (ob) gene expression, and high plasma leptin levels, similar to those recorded in Zucker fatty (fa/fa) rats. Seven-week-old MT-null mice also had significantly higher levels of plasma leptin and elevated expression of ob, lipoprotein lipase, and CCAAT enhancer binding protein alpha genes as compared with age-matched C57BL/6J mice. These observations indicate that abnormal accretion of body fat and adipocyte maturation is initiated at 5-7 weeks of age, possibly coincident with sexual maturation. Targeted disruption of MT-I and MT-II genes seems to induce moderate obesity, providing a new obese animal model. A link between MT and the regulation of energy balance is implied.     

Detection of new spider toxins from a Nephilengys borbonica venom gland using on-line mu-column HPLC continuous flow (FRIT) FAB LC/MS and MS/MS

The Morris water maze is frequently used to screen mutant mice generated by gene targeting. Targeted ES-cells are often derived from 129/Sv or BALB/c mice, known as poor swimming navigation learners. After mating the founders with C57BL/6 mice, the F2 or F3 hybrid generation is typically used for behavioral testing. In hybrid 129/Sv x C57BL/6 mice, a modification of the betaAPP gene entails impaired swimming navigation learning. This is readily detected despite behavioral variability, because wild-type 129/Sv x C57BL/6 hybrids outperform either of the parental strains and provide a control sample with good baseline performance. However, after backcrossing to the 129/Sv(ev) strain, the mutation effects are no longer detectable, masked by the very poor performance of wild-type 129/Sv(ev) mice. We conclude that F2 and F3 generations of 129/Sv x C57BL/6 crosses provide a suitable genetic background for behavioral testing of transgenic mice, provided that the samples are large enough to compensate for genetic and epigenetic variability and provided that normal performance in the control group is verified by comparison against a large database of mice tested under identical conditions. Creating congenic lines by backcrossing to an inbred strain is unlikely to enhance the sensitivity of the Morris test. Backcrossing to 129/Sv(ev) may even reduce it.     

Decreased pancreatic somatostatin (SRIF) concentration in spontaneously diabetic mice

Spontaneously diabetic C57BL/6J obob and C57BL/Ks dbdb mice have been shown to have significantly decreased immunoassayable pancreatic somatostatin concentrations compared to lean littermate controls at 11-12 weeks: obob 1.06+/-0.15 pg/mug protein (n=10) vs control 1.94+/-0.-6 pg/mug protein (n=10) (mean +/- SE; p less than 0.005); dbdb 0.7+/-0.2 pg/mug protein (n=8) vs control 1.5+/-0.2 pg/mug protein (n=8) (mean +/- SE; p less than 0.005). An inverse relationship between circulating insulin levels and pancreatic SRIF concentration is suggested.     

Progesterone and 3α,5α-THP enhance sexual receptivity in mice.

Progesterone (P) and its metabolites' effects on sexual receptivity (lordosis) of mice was examined. P dosages that produced normal circulating concentrations of P and 5α-pregnan-3α-ol-20-one (3α,5α-THP) enhanced lordosis of ovariectomized, sexually experienced C57BL/6J (C57), +/+ C57BL/6J*129SvEv (C57*129), and -/- C57BL/6JX129SvEv (PRKO) mice. Only C57 and C57*129 mice bad increases in progestin receptor (PR)-immunoreactivity (PR-IR) in the hypothalamus. RU38486, a PR antagonist, attenuated lordosis of C57 and C57*129, but not PRKO, mice; epostane, a progestin biosynthesis inhibitor, reduced plasma progestins; and finasteride, a P metabolism inhibitor, reduced plasma 3α,5α-THP and attenuated lordosis of all mice. For sexually naive mice, greater lordosis on initial sexual experience corresponded to greater concentrations of plasma and central progestins and increased central binding of a GABA≈ agonist, muscimol, compared with that seen in mice with lower lordosis on initial mating. Thus, P-facilitated receptivity in mice involves P and 3α,5α-THP and their actions at PRs and GABAA receptors. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Locomotor activity in D2 dopamine receptor-deficient mice is determined by gene dosage, genetic background, and developmental adaptations

Locomotor activity is a polygenic trait that varies widely among inbred strains of mice (). To characterize the role of D2 dopamine receptors in locomotion, we generated F2 hybrid (129/Sv x C57BL/6) D2 dopamine receptor (D2R)-deficient mice by gene targeting and investigated the contribution of genetic background to open-field activity and rotarod performance. Horizontal activity of D2R-/- mice was approximately half that of drug-naive, strain-matched controls but was significantly greater than haloperidol-treated controls, which were markedly hypokinetic. Wild-type 129/SvEv and C57BL/6 mice with functional D2 receptors had greater interstrain differences in spontaneous activity than those among the F2 hybrid mutants. Incipient congenic strains of D2R-deficient mice demonstrated an orderly gene dosage reduction in locomotion superimposed on both extremes of parental background locomotor activity. In contrast, F2 hybrid D2R-/- mice had impaired motor coordination on the rotarod that was corrected in the congenic C57BL/6 background. Wild-type 129/SvEv mice had the poorest rotarod ability of all groups tested, suggesting that linked substrain 129 alleles, not the absence of D2 receptors per se, were largely responsible for the reduced function of the F2 hybrid D2R-/- and D2R+/- mice. Neurochemical and pharmacological studies revealed unexpectedly normal tissue striatal monoamine levels and no evidence for supersensitive D1, D3, or D4 dopamine receptors in the D2R-/- mice. However, after acute monoamine depletion, akinetic D2R+/- mice had a significantly greater synergistic restoration of locomotion in response to SKF38393 and quinpirole compared with any group of D2R+/+ controls. We conclude that D2R-deficient mice are not a model of Parkinson's disease. Our studies highlight the interaction of multiple genetic factors in the analysis of complex behaviors in gene knock-out mice.     

Hepatic cirrhosis and clearance of fibrinolysis activators]

Strain differences in the antibody response to human IgG (HGG) were observed when aggregated HGG was injected intravenously. Lipopolysaccharide (LPS) administered subsequently markedly enhanced the antibody response to HGG in low responder C57BL/6 mice as compared with that in high responder DDD, C3H/He or (C57BL/6 X DDD)F1 mice. Aggregate-free preparation of HGG at a dose of 0.5 mg induced immunological tolerance in all strains of mice tested. LPS injected subsequently converted tolerogenic, aggregate-free HGG into immunogen in DDD mice but not in C57BL/6 mice. To determine the correlation between adjuvanticity and mitogenicity of LPS, spleen cells from normal mice were cultured in the presence of LPS and 3H-thymidine uptake was measured. Spleen cells of DDD mice incorporated three times as much 3H-thymidine as those of C57BL/6 mice. There seems no strong correlation between both activities of LPS. The data obtained are discussed in terms of strain differences in the macrophage function for processing the antigen.     

Behavioral sensitization to drug stimulant effects in C57BL/6J and DBA/2J inbred mice.

Common features shared by addictive drugs have been difficult to identify. One ubiquitous effect of these drugs is psychomotor stimulation. Further, repeated exposure commonly results in sensitization to drug stimulant effects. This study evaluates sensitization to drugs from several drug classes in C57BL/6J and DBA/2J inbred strain mice. DBA/2J mice showed sensitized responses to ethanol and methamphetamine, whereas C57BL/6J mice developed sensitization to morphine and methamphetamine. Strain susceptibilities to ethanol- and morphine-induced sensitization closely paralleled their sensitivities to the acute stimulant effects of these drugs; this was not the case for methamphetamine. The relative sensitivities of DBA/2J and C57BL/6J mice were not consistent across drugs, suggesting that the stimulant and sensitized responses to these drugs may be mediated by at least partially divergent neural mechanisms. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Ambiguous role of interleukin-12 in Yersinia enterocolitica infection in susceptible and resistant mouse strains

Endogenous interleukin-12 (IL-12) mediates protection against Yersinia enterocolitica in C57BL/6 mice by triggering gamma interferon (IFN-gamma) production in NK and CD4+ T cells. Administration of exogenous IL-12 confers protection against yersiniae in Yersinia-susceptible BALB/c mice but exacerbates yersiniosis in resistant C57BL/6 mice. Therefore, we wanted to dissect the different mechanisms exerted by IL-12 during Yersinia infections by using different models of Yersinia-resistant and -susceptible mice, including resistant C57BL/6 mice, susceptible BALB/c mice, intermediate-susceptible wild-type 129/Sv mice, 129/Sv IFN-gamma-receptor-deficient (IFN-gamma R-/-) mice and C57BL/6 tumor necrosis factor (TNF) receptor p55 chain-deficient (TNFR p55-/-) mice. IFN-gamma R-/- mice turned out to be highly susceptible to infection by Y. enterocolitica compared with IFN-gamma R+/+ mice. Administration of IL-12 was protective in IFN-gamma R+/+ mice but not in IFN-gamma R-/- mice, suggesting that IFN-gamma R-induced mechanisms are essential for IL-12-induced resistance against yersiniae. BALB/c mice could be rendered Yersinia resistant by administration of anti-CD4 antibodies or by administration of IL-12. In contrast, C57BL/6 mice could be rendered more resistant by administration of transforming growth factor beta (TGF-beta). Furthermore, IL-12-triggered toxic effects in C57BL/6 mice were abrogated by coadministration of TGF-beta. While administration of IL-12 alone increased TNF-alpha levels, administration of TGF-beta or TGF-beta plus IL-12 decreased both TNF-alpha and IFN-gamma levels in Yersinia-infected C57BL/6 mice. Moreover, IL-12 did not induce toxicity in Yersinia-infected TNFR p55-/- mice, suggesting that TNF-alpha accounts for IL-12-induced toxicity. Taken together, IL-12 may induce different effector mechanisms in BALB/c and C57BL/6 mice resulting either in protection or exacerbation. These results are important for understanding the critical balance of proinflammatory and regulatory cytokines in bacterial infections which is decisive for beneficial effects of cytokine therapy.     

The incorporation of drugs into hair: relationship of hair color and melanin concentration to phencyclidine incorporation

Rodents with different hair pigmentation patterns were studied to evaluate the role of melanin in the incorporation of phencyclidine (PCP) into hair. There are two types of melanin in hair and other tissues: eumelanin, a brown-black pigment and pheomelanin, a reddish-yellow pigment. Sprague Dawley (SD; nonpigmented), Dark Agouti (DA; brown), Copenhagen (CP; brown hooded), Long Evans (LE; black hooded), and LBNF1 (deep brown) rats and Swiss-Webster (SW; nonpigmented), C57BL6 (black), and C57BL6 Ay/a (yellow) mice were administered PCP at 10 mg/kg/day for 5 days (n = 5 for each strain). Hair was collected either 14 (rats) or 35 (mice) days (mice) after beginning drug administration and analyzed for PCP, eumelanin, and pheomelanin. PCP concentrations in ng/mg (mean +/- SEM) were as follows: SD, 0.46 +/- 0.13; DA, 12.25 +/- 1.24; CP nonpigmented, 0.12 +/- 0.004; CP pigmented, 9.16 +/- 2.8; LE nonpigmented, 0.66 +/- 0.07; LE pigmented, 21.2 +/- 1.4; LBNF1, 21.64 +/- 3.8; SW, 0.48 +/- 0.36; C57 black, 11.0 +/- 4.03; and C57 yellow, 2.26 +/- 0.55. Eumelanin concentrations in microg/mg (mean +/- SEM) were as follows: DA, 20.50 +/- 1.58; CP pigmented, 19.43 +/- 0.40; LE pigmented, 17.56 +/- 0.61; LBNF1, 27.26 +/- 2.52; C57 black, 37.33 +/- 3.61; and C57 yellow, 1.76 +/- 0.02. Eumelanin was not detected in nonpigmented hair. Pheomelanin concentrations in microg/mg (mean +/- SEM) were as follows: DA, 0.09 +/- 0.00; CP pigmented, 0.20 +/- 0.03; LBNF1, 0.06 +/- 0.01; C57 black, 0.16 +/- 0.05; and C57 yellow, 29.16 +/- 0.97. Pheomelanin was not detected in nonpigmented or LE pigmented hair. These data demonstrate that PCP is incorporated into black hair to a greater extent than yellow or nonpigmented hair. There appears to be a linear relationship between the PCP concentration in hair and the ratio of eumelanin to pheomelanin. Our data suggest that despite variations in PCP concentration because of hair color, they may be normalized by using the ratio of eumelanin to pheomelanin rather than hair weight.     

Mice lacking the type I interleukin-1 receptor do not lose bone mass after ovariectomy

We measured the effects of ovariectomy on the bone mass of mice that lacked type I interleukin-1 receptor (IL-I R1 -/- mice) in two genetic backgrounds (C57BL/6 x 129/Sv and C57BL/6) to investigate the role of interleukin-1 in the actions of estrogen on bone. At three weeks after surgery, ovariectomized wild-type mice decreased trabecular bone volume in the proximal humerus by 70% in a C57BL/6 x 129/Sv background and 48% in a C57BL/6 background compared to sham-operated controls. In contrast, there was no significant decrease in trabecular bone mass in IL-1 R1 -/- mice after ovariectomy. The estrogen status of all groups was confirmed by measurement of uterine wet weight. These results demonstrate that a functional IL-1 response pathway is required for mice to lose trabecular bone mass after ovariectomy in this model and they imply that IL-1 is an important mediator of the effects of ovariectomy on bone mass. Hence, therapeutic interventions that block the effects of IL-1 on bone may be beneficial for treating diseases of rapid bone loss such as post-menopausal osteoporosis.     

Strain-related differences in susceptibility to transient forebrain ischemia in SV-129 and C57black/6 mice

BACKGROUND AND PURPOSE: We explored susceptibility to injury after global ischemia in SV-129 and C57Black/6 mice, two commonly used-background strains in genetically engineered mice. METHODS: Mice (n = 84) were subjected to 15, 30, or 75 minutes of bilateral common carotid artery (BCCA) occlusion followed by reperfusion for 72 hours. BCCA occlusion was performed under halothane or chloral hydrate anesthesia, in one experiment, mean arterial blood pressure and regional cerebral blood flow (laser Doppler flowmetry) were matched by controlled exsanguination. Baseline absolute blood flow measurements were obtained in both strains using a tracer, N-isopropyl-[methyl 1,3-14C]-p-iodoamphetamine, indicator fractionation technique (n = 5 per group). Vascular anatomy of the circle of Willis was visualized by intravascular perfusion of carbon black ink (n = 10 per group). Cerebrovascular reactivity was assessed by measuring the diameter of pial vessels (intravital microscopy) to acetylcholine (ACh) superfusion (0.1 to 10 mmol/L) in a closed cranial window preparation (n = 29). RESULTS: Resting blood flow values did not differ between groups in striatum, cerebellum, and brain-stem regions. SV-129 mice were less susceptible than C57Black/6 mice to ischemic injury (0.0 +/- 0.0 versus 1.3 +/- 0.3 damage in hippocampal CA1 region after 30 minutes of ischemia in SV-129 and C57Black/6, respectively; P < .01). Cellular damage (grade 1 to 3 injury) comparable to 30-minute BCCA occlusion was achieved only after 75 minutes of ischemia in SV-129 mice (1.1 +/- 0.3). Ischemic damage was also significantly less in SV-129 mice after blood pressure and flow were matched during ischemia in halothane-anesthetized SV-129 mice (0.5 +/- 0.3 versus 1.4 +/- 0.2, P < .05), or after chloral hydrate anesthesia (0.4 +/- 0.2 versus 1.5 +/- 0.4, P < .05). Hypoplastic posterior communicating arteries were found in all 10 C57Black/6 mice and may explain the greater susceptibility of these mice to injury after BCCA occlusion. More robust vasodilation to ACh in C57Black/6 mice could also indicate genetic differences in responses to vasoactive substances. CONCLUSIONS: C57Black/6 mice exhibit enhanced susceptibility to global cerebral ischemic injury, an incompletely formed circle of Willis, and augmented pial vessel dilation to ACh compared with SV-129 mice. Our findings suggest that strain differences may confound results when genetically engineered mice generated from more than a single background strain are used.     

Psychomotor stimulant effects of cocaine in rats and 15 mouse strains.

Relative to intravenous drug self-administration, locomotor activity is easier to measure with high throughput, particularly in mice. Therefore its potential to predict differences in self-administration between genotypes (e.g., targeted mutations, recombinant inbred strains) is appealing, but such predictive value is unverified. The main goal of this study was to evaluate the utility of the locomotor assay for accurately predicting differences in cocaine self-administration. A second goal was to evaluate any correlation between activity in a novel environment, and cocaine-induced hyperactivity, between strains. We evaluated locomotor activity in male and female Sprague–Dawley rats and 15 mouse strains (129S1/SvImJ, 129S6/SvEvTac, 129X1/SvJ, A/J, BALB/cByJ, BALB/cJ, C3H/HeJ, C57BL/6J, CAST/EiJ, DBA/2J, FVB/NJ, SJL/J, SPRET/EiJ, and outbred Swiss Webster and CD-1/ICR), as well as cocaine self-administration in BALB substrains. All but BALB/cJ mice showed locomotor habituation and significant cocaine-induced hyperactivity. BALB/cJ mice also failed to self-administer cocaine. BALB/cByJ mice showed modest locomotor habituation, cocaine-induced locomotion, and cocaine self-administration. As previously reported, female rats showed greater cocaine-induced locomotion than males, but this was only observed in one of 15 mouse strains (FVB/NJ), and the reverse was observed in two strains (129X1/SvJ, BALB/cByJ). The intriguing phenotype of the BALB/cJ strain may indicate some correlation between all-or-none locomotion in a novel environment, and stimulant and reinforcing effects of cocaine. However, neither novelty- nor cocaine-induced activity offered a clear prediction of relative reinforcing effects among strains. Additionally, these results should aid in selecting mouse strains for future studies in which relative locomotor responsiveness to psychostimulants is a necessary consideration. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Biphasic effects of ethanol on open-field activity: Sensitivity and tolerance in C57BL/6N and DBA/2N mice.

Male C57BL/6N (C57) and DBA/2N (DBA) inbred mice were found to differ in open-field behavior after an acute ip injection of ethanol and in the development of tolerance to repeated injections. DBA Ss showed only increased activity for 28 min after ethanol doses up to 2.67 g/kg when compared with saline-injected controls; C57 Ss showed dose-related increases in activity during the first 4 min, followed by dose-related decreases in activity. The effects endured for at least 60 min after injection in both strains. In a 3rd experiment, Ss were injected daily with saline or 2 g/kg ethanol and tested on Days 1, 5, 9, and 13 for open-field activity. On the 17th day, all Ss were tested after an ethanol injection; neither strain showed tolerance to the activity-stimulating effect of ethanol. Some evidence for tolerance to the effect of ethanol to reduce activity in C57's was found. In a 4th experiment, twice-daily injections of ethanol for 10 days produced marked tolerance to the depressant effect of an injection on the 11th day in C57 Ss; no tolerance to the stimulant effect of ethanol was found. DBA Ss injected twice daily for 19 days did not display tolerance when tested on Days 10 or 20, instead showing more marked stimulation of activity after ethanol than mice treated chronically with saline. Implications for the genetic control of responses to ethanol are discussed. (21 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Chronic ethanol administration down-regulates cannabinoid receptors in mouse brain synaptic plasma membrane

The effects of chronic ethanol (EtOH) consumption on the central nervous system may be related in part to its action on biological membranes by altering various receptor functions. In the current study, we examined the effects of chronic EtOH (4 day inhalation) on cannabinoid receptors (CB1) labeled with [3H]CP55,940 in synaptic plasma membranes (SPM) isolated from mouse brain. Our results indicate the presence of a high level of CB1 receptors in controls (Bmax=12.0+/-0.3 pmol mg-1 protein) which decreased significantly (-58%) in SPM from mouse brain chronically exposed to EtOH. This effect occurs without any changes in the receptor affinity (Kd=2. 3+/-0.3 nM for control and 2.9+/-0.3 nM for EtOH group, P>0.05). Dissociation kinetic results showed a dissociation rate constant (K-1) of 0.09+/-0.01 min-1 for control and this dissociation rate constant decreased significantly in the chronic EtOH treated mice brain (0.05+/-0.01 min-1, P<0.05). The competition studies with anandamide resulted in a substantial decrease in [3H]CP55,940 binding in both the control and EtOH group, with a decrease (P<0.05) in the Ki values in the SPM of chronic EtOH exposed mice. Hill transformation analysis showed an nH close to one in control (0. 92+/-0.01). This did not change significantly after chronic EtOH (0. 95+/-0.01) administration, which indicates the existence of a single class of receptor for [3H]CP55,940 binding in SPM from control and EtOH treated mice. The observed down-regulation of CB1 receptors by chronic EtOH may indicate the involvement of cannabinoid receptors in EtOH tolerance and dependence.     

IL-4 protects adult C57BL/6 mice from prolonged Cryptosporidium parvum infection: analysis of CD4+alpha beta+IFN-gamma+ and CD4+alpha beta+IL-4+ lymphocytes in gut-associated lymphoid tissue during resolution of infection

Resistance of adult C57BL/6 mice to severe Cryptosporidium parvum infection is dependent on CD4+alpha beta+ TCR lymphocytes. In this study, we demonstrated that treatment with anti-IFN-gamma mAb extended oocyst excretion 18 days longer, and anti-IL-4 mAb extended oocyst excretion at least 11 days longer than isotype control mAb treatment. Analysis of the specific activity of anti-IFN-gamma mAb present in treated mouse sera suggested that IFN-gamma may have a limited role in the resolution phase of infection. Changes were also documented in numbers of CD4+alpha beta+IFN-gamma+ and CD4+alpha beta+IL-4+ lymphocytes in Peyer's patches and intraepithelium of adult C57BL/6 mice during resolution of C. parvum infection. Resistance to initial severe infection was associated with CD4+alpha beta+IFN-gamma+ lymphocytes, and eventual resolution of infection was associated with CD4+alpha beta+IL-4+ lymphocytes. Analysis of cytokine expression following in vitro stimulation with C. parvum Ags during resolution of infection demonstrated consistent increases in CD4+alpha beta+IL-4+ lymphocytes, but not CD4+alpha beta+IFN-gamma+ lymphocytes. The relevance of CD4+alpha beta+IL-4+ lymphocytes in protection against C. parvum was then evaluated in C57BL/6 IL-4 gene knockout mice (IL-4(-/-)). Adult IL-4(-/-) mice excreted oocysts in feces approximately 23 days longer than IL-4(+/+) mice. Further, anti-IFN-gamma mAb treatment increased the severity and the duration of infection in IL-4(-/-) mice compared with those in IL-4(+/+) mice. Together, the data demonstrated that IFN-gamma was important in the control of severity of infection, and either IFN-gamma or IL-4 accelerated termination of infection. However, neither IL-4 nor IFN-gamma was required for the final clearance of infection from the intestinal tract of adult mice.     

Beta 2-microglobulin knockout mice are highly susceptible to polyoma virus tumorigenesis

Polyoma virus is highly oncogenic when inoculated into immunocompromised adult mice and neonatal mice of specific inbred strains. Although T lymphocytes are known to be essential in controlling polyoma virus tumorigenesis, the importance of class I MHC-restricted CD8+ T cells in mediating tumor resistance remains unclear. Here, we investigated the tumorigenicity of polyoma virus in adult mice rendered CD8+ T cell-deficient by homozygous (-/-) disruption of the beta 2-microglobulin (beta 2m) or CD8 alpha (CD8) genes. Nearly all (94%) of the virus-infected adult C57BL/6 beta 2m-/- mice developed tumors, and 20% of the virus-inoculated adult C57BL/6CD8-/- mice developed hindlimb paralysis, which is indicative of vertebral tumors. Only 2 of 20 virus-inoculated adult normal C57BL/6 mice developed tumors. Despite these different tumor susceptibilities, persistent viral DNA was detected in multiple organs of mice of all three strains. Multifocal lymphoplasmacytic interstitial infiltrates were present in the kidneys and lungs of virus-infected C57BL/6 beta 2m-/- and in the lungs of virus-inoculated C57BL/6CD8-/- mice. These infiltrates were composed primarily of B cells and colocalized with staining for the major viral capsid protein, VP1. No infiltrates or VP1 staining was detected in the kidneys of infected C57BL/6 mice. Using a highly sensitive RT-PCR bioluminescence immunoassay, we investigated and detected persistent polyoma T protein and VP1 messages in both C57BL/6 beta 2m-/- and C57BL/6 mice. C57BL/6 beta 2m-/- and C57BL/6 mice had equivalent serum virus-neutralizing antibody titers. These results provide in vivo evidence that class I MHC-restricted CD8+ T cells are involved in mediating protection against polyoma virus tumor development.     

Voluntary selection of and tolerance to 1,2 propanediol (propylene glycol) by high and low ethanol-selecting mouse strains.

Tested 15 male mice from each of 4 inbred strains (C57BL/6J, BALB/cJ, CBA/J, and DBA/2J) to determine their voluntary self-selection of a 10% solution of 1,2 propanediol (1,2 PD), a 3-carbon alcohol of low toxicity. As with ethanol, the C57BL/6J strain consumed significantly greater amounts than the 3 other low ethanol-selecting strains. Exp II with 140 Ss determined that the 3 low-selecting strains suffered significantly greater depression of the central nervous system from 1,2 PD than the high selecting C57BL strain. It was also found that ethanol was a much more potent depressant than 1,2 PD. Results are discussed in terms of the possible role of neural sensitivity in regulating consumption levels of the 2 alcohols. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Immunoregulation in experimental murine Trypanosoma congolense infection: anti-IL-10 antibodies reverse trypanosome-mediated suppression of lymphocyte proliferation in vitro and moderately prolong the lifespan of genetically susceptible BALB/c mice

We infected highly susceptible BALB/c and relatively resistant C57BL/6 mice with cloned Trypanosoma congolense and followed the effects of these infections on the circulating parasite numbers, mouse mortality and cytokine expression. C57BL/6 mice controlled their parasitaemia and survived for up to 163 +/- 12 days, while BALB/c mice could not control their parasitaemia and succumbed to the infection within 8.4 +/- 0.5 days. Susceptible BALB/c mice had dramatically higher plasma levels of IL-10 than the resistant C57BL/6 mice from day 7 forward. This was preceded by an earlier and higher level induction of splenic IL-10 messenger RNA (mRNA) expression in the infected BALB/c mice. There was a strong negative correlation between the splenocyte proliferative responses to Concanavalin-A (Con-A) and their production of IL-10 in these infected BALB/c mice. Co-treatment of the Con-A-stimulated spleen cell cultures with monoclonal anti-IL-10 antibodies, but not isotype-matched control antibodies, could completely reverse this suppression of the splenocyte proliferative response. Finally, in three experiments, anti-IL-10 antibody treatment in vivo reduced the peak circulating parasitaemia of infected BALB/c mice by 43% and increased their median survival periods by 38% relative to isotype-matched control antibody-treated mice.