Genes on the X chromosome affect development of collagen-induced arthritis in mice

Susceptibility to collagen-induced arthritis (CIA) in mice is associated with a class II gene in MHC (Aq) but also with unknown genes outside MHC. Investigated here is the influence of genes on the X chromosome as well as the role of the X-linked immunodeficiency (xid) mutation. Reciprocal male F1 hybrids, bred to be heterozygous or homozygous for Aq, showed a genetic influence in their susceptibility to develop CIA. Crosses were made between B10.G, B10.Q, DBA/1, SWR/J, C3H.Q and CBA/Ca, and all F1 mice were castrated to avoid sex hormone modulation of the susceptibility. A differential timing of arthritis onset and severity were seen in the reciprocal F1 males. An exception was the reciprocal F1 male offspring from SWR/J and DBA/1 crosses which differed only in disease severity late in the course of the disease. The female F1 crosses did not show the same pattern of differential susceptibility to CIA as the F1 males. To exclude the possible influence of the Y chromosome, F1 males of reciprocal crosses were back-crossed to the parental strains creating offspring with equal X chromosomes but divergent Y chromosomes. No difference in development of arthritis was observed in these. The influence of the xid mutation was investigated next. The xid loci from the CBA/N mouse was bred into DBA/1 strain which is highly susceptible to CIA. The resulting congenic DBA/1-xid strain was resistant to induction of CIA and did not develop an antibody response to type II collagen. We conclude that polymorphic genes on the X chromosome modulate susceptibility to CIA. The results from the experiments with mice carrying xid mutations confirm that such immune modulating genes exist on the sex chromosomes.     

Inheritance of spatial learning ability in inbred mice: A classical genetic analysis.

The inheritance of spatial learning ability in inbred mice was examined by performance of a classical genetic cross between the 2 inbred strains C57BL/6Ibg and DBA/2Ibg. The inbreds were crossed to produce the 1st filial generation (F?) hybrids. F? mice were bred to each other and were backcrossed to the parental strains to produce 3 hybrid generations with recombinant genotypes. The animals were tested for spatial learning ability in the Morris water task. All hybrid generations showed greater spatial learning ability than the inbreds, with F? hybrids showing the greatest degree of spatial learning. The inheritance pattern for spatial learning differed between male and female mice, with males showing a type of inheritance in which dominant genes made the major contribution to the expression of the behavior. Females showed equal contributions of dominance deviation and additive genetic effects. The results are discussed in terms of fitness value to the animals. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Requirement for increased IL-10 in the development of B-1 lymphoproliferative disease in a murine model of CLL

Malignant B-1 cells derived from NZB mice, a murine model of spontaneous autoimmunity and B cell lymphoproliferative disease, produce significantly higher levels of IL-10 mRNA than normal B-1 or B cells. IL-10 may act as an autocrine growth factor for the expansion of malignant B-1 cells. In order to determine if elevated endogenous production of IL-10 was a required element for the malignant transformation of B-1 cells in NZB mice, backcross animals were studied for the linkage between elevated IL-10 expression and the presence of lymphoid malignancy. The phenotypes of aged (NZB x DBA/2)F1 x NZB animals were determined and a strong correlation was found between the elevated levels of IL-10 mRNA and the development of B-1 malignant clones. In contrast, an increased level of IL-10 message was not associated with elevated serum IgM or the presence of anemia or reticulocytosis which is mainly seen in response to autoantibody production. These results indicate that, at least in NZB, the autoimmunity and lymphoproliferation phenotypes are not linked genetically. IL-10 may enhance proliferation and the development of B-1 cell malignancy rather than antibody production by the B-1 cell subpopulation. Thus, IL-10 plays an important role in B-1 malignancies, and downregulation of IL-10 could be a likely site for intervention in B cell malignancies.     

Effects of alcohol on acquisition and retention of passive-avoidance conditioning in different mouse strains.

270 male Ss of the C57BL/6 and DBA/2 inbred mouse strains and of the F1 hybrid of these 2 were trained and tested in a passive-avoidance task under 0-3 gm/kg doses of ethanol. The C57 Ss performed better in acquisition at higher alcohol doses than either the DBA or hybrid Ss. The hybrids showed retention the following day at higher doses than either of the parental strains. The DBA and C57 Ss showed evidence of state-dependent learning at some alcohol doses while the hybrid mice did not. Low doses markedly disinhibited DBA mice in initial exploratory behavior, so that they became identical in this parameter to the other strains which were not so affected. (15 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Influence of social isolation, gender, strain, and prior novelty on plus-maze behaviour in mice

Behavioural baseline is a critical determinant of response to drugs and other manipulations. In the present study, the influence of several organismic and procedural variables on basal plus-maze profiles in mice were examined. The methodology incorporated traditional behavioural parameters as well as novel measures derived from ethological analysis. Experiment 1 showed that social isolation for 1-3 weeks enhanced aggression in male DBA/2 mice but did not substantially alter their behaviour on the maze. A reduction in stretch attend postures did, however, suggest a minor reduction in anxiety in socially isolated animals. In Experiment 2, males of both DBA/2 and T1 strains exhibited higher levels of general activity on the maze than their female counterparts. Although additional evidence suggested that DBA/2 (but not T1) females were less anxious than males, no major sex differences were noted. Experiment 3 revealed a significant strain difference in plus-maze profiles, with T1 males showing a lower basal level of anxiety than DBA/2 males. This study also demonstrated that DBA/2 and T1 males react very differently to prior novelty experience, with enhanced anxiety evident in the former and reduced anxiety in the latter. Together, these findings point to a range of organismic and procedural variables that may account for inconsistencies in the literature on the elevated plus-maze.     

Sexual dimorphism in ultrasonic vocalizations of mice (Mus musculus): Gonadal hormone regulation.

Male mice, during courtship and sexual behavior, vocalize substantially more 70-kHz ultrasounds than do females. Four experiments conducted with 109 male and female DBA/2J and ADK2F? mice demonstrated that testosterone propionate (TP) substantially increased ultrasonic emissions and mounting by ovariectomized females and that long-term gonadectomized males and females increased their amount of ultrasound production in response to TP to approximately the same levels. From these results it is suggested that the sexual dimorphism normally seen in ultrasonic vocalizations can be accounted for by the activational effects of androgen in adulthood. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Stimuli for male mouse (Mus musculus) ultrasonic courtship vocalizations: Presence of female chemosignals and/or absence of male chemosignals.

In research on animal chemocommunication, biological odors are sometimes presented by being applied to a "neutral" animal (e.g., castrated or ovariectomized conspecific). This technique is typically utilized when the behavioral response to the odor requires the presence of a conspecific. In 5 experiments, DBA/2J and 2 F? hybrid strains of mice that might be expected to be neutral stimuli were examined for their abilities to elicit ultrasonic courtship vocalizations from male mice. Paradoxically, adult castrated males, adult males that were neonatally castrated, hypophysectomized males, prepubertal females, and hypophysectomized females all elicited more vocalizations than would have been predicted from previous research in which their urine alone was used as the stimulus. These and previous results are consistent with courtship vocalizations being promoted by chemosignals from females and/or by an absence of cues from males. Thus, a truly neutral conspecific for presenting female sex odors may not exist in mice. (19 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Genetic influences on electrical seizure threshold

C57BL/6J (B6) and DBA/2J (D2) mice have been characterized previously as seizure-resistant and seizure-sensitive, respectively, a distinction based primarily upon a differential response to the convulsant effects of various drugs. In the present study, electroconvulsive shock (ECS) was used to assess maximal electroshock threshold (MET) in B6, D2 and hybrid mice. Results revealed that D2 mice have a significantly lower MET compared to B6 mice. There was also a significant gender effect for B6 and F2 mice with females exhibiting a lower MET compared to males. METs for F1 and F2 intercross mice were intermediate between the two parental strains. The difference in variance between F2 and F1 generation mice indicated that about three-quarters of the total variance is due to genetic influence. Taken together, results of this study suggest that the large difference in MET between B6 and D2 mice is a highly heritable trait which may yield to genetic dissection through use of quantitative trait locus mapping.     

Aggressive behaviors in adult SF-1 knockout mice that are not exposed to gonadal steroids during development.

Sex hormones are a major factor responsible for the development of sex differences. Steroidogenic factor 1 (SF-1) is a key regulator of gonadal and adrenal development, and SF-1 knockout mice (SF-1 KO) are born without gonads and adrenal glands. Consequently, these mice are not exposed to gonadal sex steroids. SF-1 KO pups die shortly after birth due to adrenal deficiency. In the present study, SF-1 KO mice were rescued by neonatal corticosteroid injections followed by adrenal transplantations on day 7-8 postnatally. Control mice received corticosteroid injections and were gonadectomized prior to puberty. Mice were observed interacting with ovariectomized hormone primed females and gonad-intact males. In the absence of sex steroid replacement, adult SF-1 KO mice were significantly more aggressive than control mice in tests with stimulus females. After testosterone treatment, control males displayed significantly more aggression towards male intruders than control female mice, or male and female SF-1 KO mice, suggesting a developmental role of gonadal hormones in the expression of aggressive behavior and affirming SF-1 KO mice as a behavioral model to investigate affects of fetal gonad deficiency. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Does a hypertensive reaction to dynamic exercise imply an increased risk of developing essential hypertension?

Why do (NZB x NZW)F1 mice develop an autoimmune lupus-like syndrome? The second exons of the class II genes of NZB and NZW are identical to their counterparts of H-2d and H-2u haplotypes. Several lines of evidence suggest that this allows the production of a mixed haplotype molecule, I-E alpha dE beta z, and that this molecule plays a key role in the development of autoimmunity.     

Predatory behavior in laboratory mice: Strain and sex comparisons.

Measured latency to attack live crickets in 26 male and 26 female naive, non-food-deprived laboratory mice from a genetically heterogenous stock (HS/Ibg) and in 7 inbred strains (10 male and 10 female Ss for each strain). The HS/Ibg, Is/Crgl, C57BL/Crgl, and C3H/Crgl Ss had the shortest latencies to attack crickets. The RIII/Crgl and BALB/cCrgl Ss were intermediate, while DBA/2Crgl and A/Crgl were slowest. Among the inbred strains sex differences were nonexistent or inconsistent from strain to strain. However, HS/Ibg males were more likely to attack than were females. Enough females attack for cricket killing to be a useful form of attack behavior for genetic experiments. In nearly all Ss latency decreased from the 1st to the 2nd trial, indicating that cricket killing is rapidly learned in adult mice of a wide variety of genotypes. (16 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Lung tumour incidence in mice treated with hydrazine sulphate

Lung tumour incidence in mice fed with hydrazine sulphate (1.1 mg/day/mouse) was studied in male and female mice of Swiss, Strong "A" and F1 cross of ICRC (female) X C3H (Jax) (male), as well as in C17 males. Swiss strain mice showed 100% lung adenocarcinomas. None of the treated mice of different strains had liver tumours. Hydrazine sulphate also induced adenocarcinomas of lung in Strong "A" and F1 cross of ICRC females X C3H (Jax) males but it produced lymphomas of lung in C17 strain. Female mice of Swiss strain and F1 hybrids showed greater susceptibility to hydrazine sulphate than the males. It was interesting to observe that protein and vitamin B deficiency in the diet shortened the tumour induction period in Swiss strain mice.     

Strain and sex differences on olfactory discrimination learning in C57BL/6J and DBA/2J inbred mice (Mus musculus).

In this study, the authors explored potential strain and sex differences in nonspatial cognitive ability. Beginning around 90 days of age, male and female C57BL/6J (C57) and DBA/2J (DBA) inbred mice (Mus musculus) were tested on a task of simple odor discrimination learning with 3 repeated reversals. Males learned the task more readily than females, and DBA mice learned the task more readily than C57 mice. All differences became evident after repeated testing. Similarity of perseveration measures indicated the differences were not due to inhibitory deficits. Instead, a phase analysis localized differences to a transitional period of reversal learning. Females increased transitional errors that more likely indicated adaptive sampling strategies than memory failures. C57 females used this strategy indiscriminately, but DBA females sampled as a function of environmental uncertainty. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Resting B cells from autoimmune lupus-prone New Zealand Black and (New Zealand Black x New Zealand White)F1 mice are hyper-responsive to T cell-derived stimuli

To determine whether B cells from New Zealand Black (NZB) and (New Zealand Black x New Zealand White)F1 (NZB/W) mice possess intrinsic defects that lead to altered immune responsiveness, we purified resting B cells from these mice and compared their surface phenotype and function with those of resting B cells isolated from BALB/c and DBA/2 nonautoimmune mouse strains. Flow cytometric analysis of freshly isolated resting B cells revealed that NZB and NZB/W resting B cells are conventional B2-type cells similar to their nonautoimmune counterparts. Despite this, resting B cells from young NZB and NZB/W mice express lower levels of CD23 on their surface and aberrant levels of intracellular IgM. Upon stimulation, resting B cells from young NZB and NZB/W mice demonstrate increased proliferation, IgM secretion, or enhanced expression of costimulatory molecules in response to a variety of different T cell-derived stimuli, including cytokines and signals generated through CD40. Therefore, B cell hyper-responsiveness to T cell stimuli is immunodominant or codominant in NZB/W mice. Taken together, our results suggest that intrinsic B cell hyper-responsiveness may play a role in the pathogenesis of autoimmune disease in NZB and NZB/W mice. The increased clonal expansion of these B cells together with increased Ig production and enhanced costimulatory capacity serve to amplify the immune response. In the context of normal but incomplete T cell tolerance, B cell hyperresponsiveness to the limited signals provided by partially tolerant T cells may be sufficient to yield an autoantibody response.     

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 dose-dependent 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 aversion 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.     

Sex differences in learning and memory in mice: Effects of sequence of testing and cholinergic blockade.

Sexual dimorphism in spatial and cued navigation using the Morris water maze was examined in C57BL/6 mice both with and without administration of scopolamine, a cholinergic blocker. In Exp 1, female and male mice learned to perform first a spatial, then a cued, navigation task. Both performed a spatial task similarly; males, however, performed a cued task better than females. In Exp 2, the sequence of navigation testing was reversed. Both performed similarly on a cued task; however, males performed a spatial task better than females. In both experiments, females were more sensitive than males to the effects of scopolamine. No significant confounding sex differences were found in either spontaneous activity or passive avoidance retention. These data indicate that sex differences in spatial and cued tasks are dependent on the sequence of task presentation and implicate a role for the cholinergic system in these differences. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Interleukin-1 receptor deficiency in brains from NZB and (NZB/NZW)F1 autoimmune mice

Interleukin-1 receptors (IL-1R) are expressed in the brain and the anterior pituitary of normal mice (C3H/He, Swiss), and appear to be involved in the neuroendocrine control of the immune response. Here we have studied the IL-1R density in the brain and the pituitary from several strains of autoimmune mice (NZB, (NZB/NZW)F1, MRL/MP-lpr), using quantitative autoradiography with recombinant human [125I]IL-1 alpha as a ligand. IL-1R was similar in the brain of C3H/He, Swiss and NZW (controls) and MRL/MP-lpr mice. In NZB mice a profound deficit (10% of control mice) in IL-1R was observed exclusively in the dentate gyrus. In (NZB/NZW)F1 the deficit was about 50%. These observations were independent of sex and age. Pituitary receptors were not affected in all the strains except NZW (30% increase). Competition experiments demonstrated that the affinity of IL-1R was not modified in dentate gyrus of (NZB/NZW)F1 and NZW mice. Thus, the number of IL-1R was the only parameter affected. This deficit was not reversed by corticosterone treatment (0.2 mg/20 g body weight, i.p.) and was poorly modified by lipopolysaccharide treatment (0.1 mg/20 g body weight, i.p.) compared to C3H/He mice. In conclusion, this central IL-1R deficit is unlikely to be the consequence of occupancy by abnormal synthesis of brain IL-1. This abnormality is tissue-specific with hereditary autosomal transmission. The role of central IL-1R in neuroimmunoendocrine interactions and in autoimmunity remains to be clarified.     

Paclitaxel reduces anti-dsDNA antibody titer and BUN, prolonging survival in murine lupus

We evaluated the effect of paclitaxel on the severity of autoimmunity in the murine model of systemic lupus erythematosus (SLE), NZB x NZW F1 mice. Fifteen 20 week old (NZB x NZW) F1 female mice were given a dose of 10 mg/kg paclitaxel by the intraperitoneal route on three alternate days followed by 7.5 mg/kg on three additional alternate days. This pattern of treatment was repeated every 4 weeks for a period of 28 weeks. 20 control mice were injected intraperitoneally with an equal volume of the vehicle used. Serum anti-double stranded DNA (dsDNA) antibody titers and the blood urea nitrogen (BUN) were significantly diminished in the paclitaxel treated group compared to the vehicle treated group. While the onset of proteinuria appeared to be delayed in the experimental group, the difference was not significant. Survival rate improved significantly in paclitaxel treated group (p = 0.04 by log-rank test). These results suggest that paclitaxel is beneficial in the suppression of autoimmunity in this strain of mice by reducing the anti-dsDNA antibody titer and the BUN, prolonging survival.     

The intersex difference in the production of alloantibodies and growth of tumour allografts in mice

The comparisons of immune responses to tumour allografts in male and female mice showed the following intersex differences: 1. Production of humoral antibodies is, in general, higher in females; since, however, the time course of titres differs for haemagglutinating and cytotoxic antibodies as well as with the sex, the titre of the same antibody may be higher in males at certain time intervals when the peak is delayed and the production in females is already declining. 2. In recipients specifically presensitized with spleen extract as well as in controls, the growth of allogeneic tumour (SaI) exhibits quantitative intersex differences being reduced in females. In the initial phase of growth, following the spleen extract, the facilitation (enhancement) of the tumour allograft is apparent olny in males, whereas in females it is delayed. 3. The facilitating effect of antibodies passively transferred from males or females corresponds mainly to the sex and strain of the recipient, only rarely to the sex of the producer. 4. In CBA strain mice, females are more resistant to the growth of SaI and also mortality from the primary tumour is lower in females; in contrast, the frequency of metastases in females is higher. 5. In the IC strain, where the sex effect on tumour growth is particularly pronounced, the consequences of castration were concordant with the inferred hormonal control of the allograft response: in males, the relatively high percentage of lethal spontaneous takes (60%) was reduced following castration (to 13%), whereas the opposite trend was observed in females, namely an increase from 0% in sham-operated controls to 23% in the castrated group.