Genotype-dependent mice behavior in cognitive tasks. Effect of noopept

The interstrain differences in performance of C57BL/6J, BALB/c and DBA/2J male mice in two cognitive tasks were found. Mice C57BL/6J showed good learning ability and preservation of memory traces tested 10 days after performance in a simplified version of Morris water maze. Mice BALB/c learned the task but, virtually, no long-term memory traces were revealed, whereas DBA/2J demonstrated poor learning. The effect of nootropic drug Noopept (GVS-111, N-phenil-acetyl-L-prolylglycin ethyl ether) was shown to be genotype-dependent. Its administration (0.5 mg/kg i.p., 15 min before learning) improved the long-term memory in Morris test in BALB/c mice but failed to produce any improvement in C57BL/6J. The ability of mice for extrapolation of the direction of stimulus movement differently changed after Noopept injections: the proportion of correct task solutions increased in C57BL/6J and BALB/c mice, whereas the performance of DBA/2J did not change.     

Dimethylnitrosamine metabolism: II. In vitro activation of dimethylnitrosamine by hepatic and renal tissues from crosses among BALB/c, DBA and C57BL mice

Crosses among BALB/c, C57BL and DBA mice were performed to investigate the genetic mechanisms involved in metabolism of DMN by renal and hepatic tissues. Liver S-9 fractions from parental strain DBA had the greatest potential to activate DMN and liver fractions from parental strain BALB/c had the lowest. No age or sex-related differences were observed within strain. Crossing of either C57BL or DBA to BALB/c mice resulted in F1 hybrids with liver microsomal enzymes that gave results similar to the BALB/c parental strain. There were no sex or age differences within crossbred strains in the potential of liver to activate DMN. In contrast male DBA and C57BL parental mice renal S-9 fractions did not differ significantly from each other but did differ significantly from male BALB/c renal fractions and from female and immature animals of all strains. Crossing of either DBA or C57BL mice with BALB/c mice resulted in male F1 hybrids whose renal S-9 fractions did not differ significantly from males of the parental BALB/c strain. In all instances, male renal S-9 fractions had a significantly greater potential to activate DMN than female or immature animals. F1 DBA X C57BL hybrids had renal S-9 fractions that did not differ significantly from the parental strains. These data suggest that the gene(s) for low DMN metabolism of BALB/c mice are apparently dominant over the genes from both DBA and C57BL. The exact genetic or physiological mechanism needs further elucidation.     

Behavior of mice from different strains: modifications produced by noopept

Genotype-dependent behavioral effects were demonstrated in BALB/c, C57BL/6J [Russian character: see text] DBA/2J mice after injections of nootropic drug Noopept. In an elevated plus maze, drug administration induced an increase in the number of enterings into bright arms in BALB/c mice, whereas the opposite effect was observed in C57BL/6J. After the Noopept administration, animals from all the three strains increased the number of active avoidance reactions in stress-inducing slip-funnel test. A significant intensification of exploration behavior was observed in a closed plus-maze in BALB/c and C57BL/6J. The Noopept affected weakly or had no effect on the behavior of DBA/2J mice.     

Degree of proliferative response to concanavalin A of spleen cells of mice of different strains and production of interleukin-2

Differences in the lymphoproliferative response to Con A of spleen cells allowed one to distinguish a high responder (BALB/c and DBA/2) and low responder (C57BL/6 and CC57BR) mice. BALB/c and DBA/2 mice (H-2d haplotype) produced interleukin 2 better, than C57BL/6 and CC57BR mice (H-2b haplotype). However acceptance of interleukin 2 was better in BALB/c and C57BL/6, than in DBA/2 and CC57BR mice. Summarizing these facts the authors suppose that the differences in interleukin 2 production and acceptance play an important role in the height of lymphoproliferative response.     

Genetically determined differences in ethanol sensitivity influenced by body temperature during intoxication

The present study investigated the importance of body temperature during intoxication in mediating differences between five inbred strains of mice (C57BL/6J; BALB/cJ; DBA/2J; A/HeJ; 129/J) in their acute sensitivity to the hypnotic effects of ethanol. Mice exposed to 22 degrees C after ethanol injection became hypothermic and exhibited statistically significant differences between strains in rectal temperatures at the return of the righting reflex (RORR), duration of loss of the righting reflex (LORR), and blood and brain ethanol concentrations at RORR. Exposure to 34 degrees C after injection offset ethanol-hypothermia and markedly reduced strain-related differences in rectal temperatures and blood and brain ethanol concentrations at RORR. Brain ethanol concentrations at RORR were significantly lower in C57, BALB, DBA and A/He mice exposed to 34 degrees C compared to mice exposed to 22 degrees C during intoxication suggesting that offsetting hypothermia increased ethanol sensitivity in these strains. Taken with previous in vitro studies, these results suggest that genetically determined differences in acute sensitivity to the behavioral effects of ethanol reflect differences in body temperature during intoxication as well as differences in sensitivity to the initial actions of ethanol at the cellular level.     

Genetic differences in BCG-induced resistance to Schistosoma mansoni are not controlled by genes within the major histocompatibility complex of the mouse.

Induction of nonspecific resistance to Schistosoma mansoni infection after the i.v. injection of viable BCG was investigated in outbred mice and a panel of inbred and H-2 congenic strains. Significant protection was induced in CF1, A/J, C57BL/6, C57BL/10, DBA/2, C57BR, and SJL mice. BALB/c mice were not protected whereas CBA and C3H mice expressed intermediate degrees of protection. Expression of the protective phenomenon is not controlled by genes within the MHC as shown by the marked differences in response between BALB/c and DBA/2 (H-2d) as well as between C57BR and C3H (H-2k) mice. H-2 congenic strains with C57BL/10 background (B10.A and B10.D2) were high responders. BALB.B10 mice carrying the high responder (B10) MHC on the nonresponder (BALB/c) background were not protected. The degree of splenic hypertrophy did not correlate with the expression of nonspecific resistance. These results demonstrate that, in addition to controlling specific immune responses, genetic differences influence the nonspecific protective phenomena related to BCG administration as well.     

Genetic differences in nicotine-induced conditioned taste aversion

Genetic differences in nicotine-induced conditioned taste aversion were examined using inbred mice. Adult male C57BL/6J, DBA/2J, BALB/cJ and C3H/heJ mice were adapted to a 2-h per day water access regimen. Subsequently, mice received nicotine injections (0.5, 1.0 or 2.0 mg/kg) immediately after 1-h access to a NaCl flavored solution. DBA and C3H mice developed dosedependent aversions to the nicotine-paired flavor. BALB mice showed only minor reductions in intake with no difference between the nicotine dose groups. C57BL mice did not show development of nicotine-induced conditioned taste aversion. These results demonstrate that nicotine's aversive motivational effect is strongly influenced by genotype. Further, genetic sensitivity (DBA mice) or insensitivity (C57BL mice) to nicotine-induced conditioned taste aversion was similar to reports of genetic sensitivity to ethanol's aversive effect measured in this design.     

Mouse strain differences in induction of micronuclei by base analogues and nucleosides

The frequency of induced micronucleated polychromatic erythrocytes (MNPCEs) was compared in BALB/c, C57BL/6, and DBA/2 mice after intraperitoneal (i.p.) injection of 5-bromodeoxyuridine (BUdR), 5-fluorodeoxyuridine (FUdR), cytosine arabinoside (Ara-C), 6-mercaptopurine (6-MP), 5-bromouracil (5-BU), thymidine (TdR), uridine (UdR), adenosine (AdR) and guanosine (GdR). The experimental procedure was a single i.p. injection followed by harvest at 30 h. The frequency of MNPCEs was significantly increased in all strains by treatment with BUdR, FUdR, Ara-C and 6-MP compared to vehicle control. TdR and UdR induced MNPCEs slightly in BALB/c mice but showed no effect on C57BL/6 and DBA/2 mice. 5-BU, AdR, and GdR did not increase the frequency of MNPCEs in any mouse strain used. These results suggest that BALB/c mice are more susceptible to induction of MNPCEs by clastogenic base analogues and nucleosides than are C57BL/6 or DBA/2 mice.     

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.     

Strain differences in histamine release from mouse peritoneal mast cells induced by compound 48/80 or A23187

Strain differences among BALB/c, BDF1, CDF1, C3 H/He, C57 BL/6, DBA/2, ddy and ICR mice were investigated with respect to the ratios of histamine release from mouse peritoneal mast cells induced by compound 48/80, a Ca2+ dependent histamine releaser, and the Ca2+ ionophore A23187. The ratios of histamine release from mouse peritoneal mast cells induced by compound 48/80 were found to be high in BALB/c, ddY and ICR mice, but low in BDF1, CDF1, C3 H/He, C57 BL/6 and DBA/2 mice. Those induced by Ca2+ ionophore A23187 were high in BALB/c, BDF1, CDF1, C3 H/He, DBA2, ddy and ICR mice but low in C57 BL/6 mice. These results indicate that differences in histamine release from mouse peritoneal mast cells are strain dependent.     

Spontaneous calcified tongue lesions in DBA mice

Large numbers of spontaneously occurring polypoid or slightly elevated lesions were observed in the tongue, mainly the dorsum linguae near the margo linguae, of DBA mice. Histologically the lesion consisted of granulation tissue with focal calcification, and involved superficially the tongue muscle. Often the calcareous deposits were encircled by multinuclear giant cells. The frequency of the calcified tongue lesion was high in lines of DBA/2 (DBA/2NCrj, DBA/2NJcl and DBA/2J), and DBA/1 (DBA/1Jcl and DBA/1J); the SM/J, BALB/c, C57BL/6 and C3H/He strains did not have the lesion. Among hybrid mice, CDF1, a hybrid of DBA/2 and BALB/c, a few had the lesions but no BDF1 mice, a hybrid of DBA/2 and C57BL/6, had any. The frequency was high in the hybrids of DBA/1 and SM/J. These results seem to indicate that the occurrence of the tongue calcified lesions was controlled by polygene.     

In vitro immunomodulatory properties of osteogenic and adipogenic differentiated mesenchymal stem cells isolated from three inbred mouse strains

Mesenchymal stem cells (MSCs) are used for cell-based therapies because of their immunomodulatory properties. The immunomodulatory properties of adipogenic (AD) and osteogenic (OS) differentiated adipose tissue-derived MSCs (AD-MSCs) isolated from BALB/c, C57BL/6, and DBA mice were compared. Splenocytes proliferation was suppressed in the presence of AD-MSCs conditioned media in all mice. After OS differentiation, BALB/c AD-MSCs produced higher levels of TGF-β and IL-17 and lower levels of NO than AD-MSCs isolated from C57BL/6 and DBA mice. In addition, OS differentiated AD-MSCs isolated from DBA mice produced lower levels of IL-10 than AD-MSCs isolated from C57BL/6 and DBA mice. After in vitro AD and OD differentiation, AD-MSCs isolated from each mouse produced higher levels of NO and IDO than undifferentiated cells. Additionally, AD-MSCs isolated from C57BL/6 and DBA mice produced higher levels of NO than AD-MSCs isolated from BALB/c mice. Adipose tissue-derived MSCs thus retain their immunomodulatory properties after in vitro OS and AD differentiation in a strain-dependent manner.     

Effects of maternal strain on ethanol responses in reciprocal F1 C57BL/6J and DBA/2J hybrid mice

Variations in maternal behavior, either occurring naturally or in response to experimental manipulations, have been shown to exert long-lasting consequences on offspring behavior and physiology. Despite previous research examining the effects of developmental manipulations on drug-related phenotypes, few studies have specifically investigated the influence of strain-based differences in maternal behavior on drug responses in mice. The current experiments used reciprocal F1 hybrids of two inbred mouse strains (i.e. DBA/2J and C57BL/6J) that differ in both ethanol (EtOH) responses and maternal behavior to assess the effects of maternal environment on EtOH-related phenotypes. Male and female DBA/2J and C57BL/6J mice and their reciprocal F1 hybrids reared by either DBA/2J or C57BL/6J dams were tested in adulthood for EtOH intake (choice, forced), EtOH-induced hypothermia, EtOH-induced activity and EtOH-induced conditioned place preference (CPP). C57BL/6J and DBA/2J mice showed differences on all EtOH responses. Consistent with previous reports that maternal strain can influence EtOH intake, F1 hybrids reared by C57BL/6J dams consumed more EtOH during forced exposure than did F1 hybrids reared by DBA/2J dams. Maternal strain also influenced EtOH-induced hypothermic responses in F1 hybrids, producing differences in hybrid mice that paralleled those of the inbred strains. In contrast, maternal strain did not influence EtOH-induced activity or CPP in hybrid mice. The current findings indicate that maternal environment may contribute to variance in EtOH-induced hypothermia and EtOH intake, although effects on EtOH intake appear to be dependent upon the type of EtOH exposure.     

Natural regulatory T cells mediate the development of cerebral malaria by modifying the pro-inflammatory response

Cerebral malaria (CM) is a severe neurologic complication that arises predominantly in children and non-immune adults infected with Plasmodium falciparum. In the current study, the dynamics of CD4⁺CD25⁺Foxp3⁺ regulatory T cells (Tregs) and pro- and anti-inflammatory cytokines were analyzed in P. berghei ANKA (P.bANKA)-infected C57BL/6, BALB/c, and DBA/2 mice. We showed that C57BL/6 mice were susceptible to CM, while BALB/c and DBA/2 mice were resistant to CM and succumbed to hyperparasitemia and severe anemia. The proportion and absolute numbers of Tregs in BALB/c and DBA/2 mice were significantly higher than in C57BL/6 mice. The levels of pro-inflammatory cytokines, such as IFN-γ, TNF-α, IL-6, IL-17 and NO in CM-susceptible C57BL/6 mice were obviously higher than in CM-resistant BALB/c and DBA/2 mice, while the level of the anti-inflammatory cytokine IL-10 was the opposite to that of pro-inflammatory cytokines, confirming that an appropriate balance between pro- and anti-inflammatory immune responses is essential to control the pathogenesis of severe malaria, and Tregs are important regulators if this balance is to be maintained. In vivo depletion of Tregs significantly protected C57BL/6 mice from experimental CM and the production of pro- and anti-inflammatory cytokines was reversed, indicating that this cell population contributes to pathogenesis by modulating the balance of pro- and anti-inflammatory responses. Our data demonstrate that Tregs mediate the incidence and outcome of CM in P.bANKA-infected mice by modifying the pro-inflammatory response.     

Type II collagen-induced murine arthritis: induction of arthritis depends on antigen-presenting cell function as well as susceptibility of host to an anticollagen immune response.

Two sets of ((resistant x susceptible) F1----parent) and (parent----F1) chimeric mice were prepared. In the chimeric combinations involving BALB/c and DBA/1 mice, all (F1----F1) chimeras developed arthritis as well as potent anticollagen responses after immunization with collagen, whereas all (F1----BALB/c) and (BALB/c----F1) chimeras induced neither arthritis nor immune responses. This type of F1 T cells could be activated with APC from DBA/1 but not from BALB/c mice. Thus, the failure of the [F1 in equilibrium with BALB/c] chimeras to mount anticollagen responses was due to a defect at the APC level. Another arthritis-resistant strain, C57BL/6, exhibited adequate APC function, but reduced T cell responsiveness, representing an intermediate responder. In the chimeric combinations involving C57BL/6 and DBA/1 mice, (F1----F1) and (C57BL/6----C57BL/6) chimeras developed very high and very low incidence of arthritis, respectively. (C57BL/6----F1) chimeras developed an appreciable incidence of arthritis under conditions in which this group of chimeras generated intermediate levels of anticollagen responses. In contrast, (F1----C57BL/6) chimeras developed low incidence of disease despite induction of strong responses. Moreover, cells from collagen-immunized (F1----C57BL/6) chimeras, when transferred into T cell-depleted B cell mice of F1 or C57BL/6 strain, produced comparable immune responses in both groups but induced much more severe arthritis in F1 than in C57BL/6 recipients. These results indicate that: i) two types of arthritis-resistant strains can be identified, each of which has anticollagen APC defect as a low responder and reduced T cell responsiveness as an intermediate responder and ii) a discrepancy between the degree of anticollagen responses and clinical arthritis is attributed to the differential susceptibility to anticollagen immune responses.     

Genetic differences in ethanol-induced hyperglycemia and conditioned taste aversion.

Genetic differences in the hyperglycemic response to acute ethanol exposure and ethanol-induced conditioned taste aversion were examined using inbred mice. Adult male C57BL/6J and DBA/2J mice were injected with ethanol (0-6 g/kg, I.P.) and blood glucose levels determined over 4 h. C57 mice demonstrated greater dose-dependent elevations in blood glucose compared to DBA mice. In a conditioned taste aversion procedure, water deprived mice received ethanol injections (1-4 g/kg, I.P.) immediately after access to a NaCl flavored solution. DBA mice developed aversion to the ethanol-paired flavor at a lower dose (2 g/kg) than C57 mice. These results provide further support for a possible inverse genetic relationship between sensitivity to ethanol-induced hyperglycemia and sensitivity to conditioned taste aversion.     

Strain differences in basal and post-citalopram extracellular 5-HT in the mouse medial prefrontal cortex and dorsal hippocampus: relation with tryptophan hydroxylase-2 activity

We used the microdialysis technique to compare basal extracellular serotonin (5-HT) and the response to citalopram in different strains of mice with functionally different allelic forms of tryptophan hydroxylase-2 (TPH-2), the rate-limiting enzyme in brain 5-HT synthesis. DBA/2J, DBA/2N and BALB/c mice carrying the 1473G allele of TPH-2 had less dialysate 5-HT in the medial prefrontal cortex and dorsal hippocampus (DH) (20-40% reduction) than C57BL/6J and C57BL/6N mice carrying the 1473C allele. Extracellular 5-HT estimated by the zero-net flux method confirmed the result of conventional microdialysis. Citalopram, 1.25, 5 and 20 mg/kg, dose-dependently raised extracellular 5-HT in the medial prefrontal cortex of C57BL/6J mice, with maximum effect at 5 mg/kg, but had significantly less effect in DBA/2J and BALB/c mice and in the DH of DBA/2J mice. A tryptophan (TRP) load enhanced basal extracellular 5-HT in the medial prefrontal cortex of DBA/2J mice but did not affect citalopram's ability to raise cortical and hippocampal extracellular 5-HT. The impairment of 5-HT synthesis quite likely accounts for the reduction of basal 5-HT and the citalopram-induced rise in mice carrying the mutated enzyme. These findings might explain why DBA/2 and BALB/c mice do not respond to citalopram in the forced swimming test. Although TRP could be a useful strategy to improve the antidepressant effect of citalopram (Cervo et al. 2005), particularly in subjects with low 5-HT synthesis, the contribution of serotonergic and non-serotonergic mechanisms to TRP's effect remains to be elucidated.     

Efficiency alleles of the Pctr1 modifier locus for plasmacytoma susceptibility

The susceptibility of BALB/c mice to pristane-induced plasmacytomas is a complex genetic trait involving multiple loci, while DBA/2 and C57BL/6 strains are genetically resistant to the plasmacytomagenic effects of pristane. In this model system for human B-cell neoplasia, one of the BALB/c susceptibility and modifier loci, Pctr1, was mapped to a 5.7-centimorgan (cM) chromosomal region that included Cdkn2a, which encodes p16(INK4a) and p19(ARF), and the coding sequences for the BALB/c p16(INK4a) and p19(ARF) alleles were found to be polymorphic with respect to their resistant Pctr1 counterparts in DBA/2 and C57BL/6 mice (45). In the present study, alleles of Pctr1, Cdkn2a, and D4Mit15 from a resistant strain (BALB/cDAG) carrying DBA/2 chromatin were introgressively backcrossed to the susceptible BALB/c strain. The resultant C.DAG-Pctr1 Cdkn2a D4Mit15 congenic was more resistant to plasmacytomagenesis than BALB/c, thus narrowing Pctr1 to a 1.5-cM interval. Concomitantly, resistant C57BL/6 mice, from which both gene products of the Cdkn2a gene have been eliminated, developed pristane-induced plasma cell tumors over a shorter latency period than the traditionally susceptible BALB/cAn strain. Biological assays of the p16(INK4a) and p19(ARF) alleles from BALB/c and DBA/2 indicated that the BALB/c p16(INK4a) allele was less active than its DBA/2 counterpart in inducing growth arrest of mouse plasmacytoma cell lines and preventing ras-induced transformation of NIH 3T3 cells, while the two p19(ARF) alleles displayed similar potencies in both assays. We propose that the BALB/c susceptibility/modifier locus, Pctr1, is an "efficiency" allele of the p16(INK4a) gene.     

Streptobacillus moniliformis epizootic in barrier-maintained C57BL/6J mice and susceptibility to infection of different strains of mice

We report a Streptobacillus moniliformis epizootic in barrier-maintained SPF mice. Although various inbred and F1 hybrid strains of mice have been kept in this animal facility, only C57BL/6J Han [corrected] mice showed clinical signs of disease. During the course of the epizootic, 825 breeding animals (approximately 36% of the breeders) died or had to be killed because of severe clinical signs. Although sequential treatment with ampicillin and chlortetracycline gave good therapeutic results, the animal facility was vacated in order to exclude any risk of cross-contamination of the other rodent colonies in our institute. The source and route of transmission of S. moniliformis could not be elucidated. To investigate strain dependent differences experimental infection of different strains of mice with our S. moniliformis isolate was performed. After oral infection only C57BL/6J showed the typical signs of a cervical lymphadenitis and gave an immunological response. BALB/cJ, C3H/He, DBA/2J, CB6F1 and B6D2F1 mice were not affected except in two cases of DBA/2J and B6D2F1 mice where seroconversion was observed. After intravenous infection of C57BL/6J, DBA/2J [corrected] and BALB/cJ all animals showed positive titers in the indirect immunofluorescence test (IIF). One hundred percent of the C57BL/6J, forty percent of the DBA/2J, and none of the BALB/cJ mice developed severe symptoms. The results demonstrate that the susceptibility to streptobacillosis is predominantly influenced by genetic factors.