Three murine anxiety models: results from multiple inbred strain comparisons

The literature surrounding rodent models of human anxiety disorders is discrepant concerning which models reflect anxiety-like behavior distinct from general activity and whether different models are measuring the same underlying constructs. This experiment compared the responses of 15 inbred mouse strains (129S1/SvlmJ, A/J, AKR/J, BALB/cByJ, C3H/HeJ, C57BL/6J, C57L/J, CBA/J, CE/J, DBA/2J, FVB/NJ, NZB/B1NJ, PL/J, SJL/J and SWR/J) in three anxiety-like behavioral tasks (light/dark test, elevated zero-maze and open field) to examine whether responses were phenotypically and/or genetically correlated across tasks. Significant strain differences were found for all variables examined. Principal components analyses showed that variables associated with both activity and anxiety-like behaviors loaded onto one factor, while urination and defecation loaded onto another factor. Our findings differ from previous research by suggesting that general activity and anxiety-related behaviors are linked, negatively correlated and cannot easily be dissociated in these assays. However, these findings may not necessarily generalize to other unconditioned anxiety-like behavioral tests.     

Genetic and nongenetic control of the immune response of mice to a synthetic glycolipid, stearylisomaltotetraose

Evidence for genetic control of antibody response to stearylisomaltotetraose (ST-IM4), a chemically defined synthetic glycolipid, was studied in various mouse strains. Anti-glycolipid antibodies were induced by repeated injections of ST-IM4 in complete Freund's adjuvant. C57BL and CBA/J mice were found to be good responders, while A/J, SJL/J, and AKR/J mice were poor responders. Responsiveness is independent of the H-2 genotype since AKR/J and CBA/J mice share the same H-2 locus. In addition, B10.A and B10.PL mice developed antibody levels similar to those of C57BL. The immunoglobulin heavy-chain locus (IgCH) was also found not to control antibody levels to ST-IM4 since C57BL and SJL/J mice share the same IgCH allotype. In C58/J mice, wide variation in response was observed among individual mice. Study of the response to ST-IM4 in 12 breeder pairs from different family lines of the C58/J colony also indicated that the regulation of the immune response to ST-IM4 is apparently more complex than can be explained by single gene control. C58 mice, unlike many other strains, had very low preimmune titers.     

Mapping quantitative trait loci for anxiety in chromosome substitution strains of mice

Anxious behavior in the mouse is a complex quantitative phenotype that varies widely among inbred mouse strains. We examined a panel of chromosome substitution strains bearing individual A/J chromosomes in an otherwise C57BL/6J background in open-field and light-dark transition tests. Our results confirmed previous reports of quantitative trait loci (QTL) on chromosomes 1, 4, and 15 and identified novel loci on chromosomes 6 and 17. The studies were replicated in two separate laboratories. Systematic differences in the overall activity level were found between the two facilities, but the presence of the QTL was confirmed in both laboratories. We also identified specific effects on open-field defecation and center avoidance and distinguished them from overall open-field activity.     

Pharmacological Alterations of Anxious Behaviour in Mice Depending on Both Strain and the Behavioural Situation

A previous study comparing non-emotive mice from the strain C57BL/6/ByJ with ABP/Le mice showed ABP/Le to be more anxious in an open-field situation. In the present study, several compounds affecting anxiety were assayed on ABP/Le and C57BL/6/ByJ mice using three behavioural models of anxiety: the elevated plus-maze, the light-dark discrimination test and the free exploratory paradigm. The compounds used were the full benzodiazepine receptor agonist, chlordiazepoxide, and the antagonist, flumazenil, the GABA_A antagonist, bicuculline, the full 5-HT_1A agonist 8-OH-DPAT, and the mixed 5-HT_1A/5-HT_1B agonist, RU 24969. Results showed the effect of the compounds to be dependent on both the strain and the behavioural task. Several compounds found to be anxiolytic in ABP/Le mice had an anxiogenic effect on C57BL/6/ByJ mice. More behavioural changes were observed for ABP/Le in the elevated plus-maze, but the clearest findings for C57BL/6/ByJ mice were observed in the light-dark discrimination apparatus. These data demonstrate that anxious behaviour is a complex phenomenon which cannot be described by a single behavioural task nor by the action of a single compound.     

Immune responses of different mouse strains after challenge with equivalent lethal doses of Toxoplasma gondii

Most immunological studies that utilize different strains of inbred mice following T. gondii infection fail to compensate for differences in host susceptibility to the size of the parasite innoculum. To address this concern, susceptible C57BL/6 and resistant CBA/J mice were orally infected with either an equivalent 50% lethal dose (LD50) of brain cysts of the 76K strain of T. gondii (15 cysts in C57BL/6, 400 cysts in CBA/J) or the same dose of parasites in each mouse strain. C57BL/6 mice receiving 400 cysts (LD50 of CBA/J mice) died post infection, whereas CBA/J mice that received 15 cysts (LD50 of C57BL/6 mice) survived. Parasite loads in the brains and serum Toxoplasma-specific IgG1 titers of LD50-infected C57BL/6 mice were significantly higher than those in LD50- or 15 cysts-infected CBA/J mice, whereas splenocyte proliferation to Toxoplasma antigen and the percentage of CD8 alpha+ T cells were reduced in LD50-infected C57BL/6 mice. In contrast, serum IgG2a and IgM titers, the percentage of gamma delta T cells and IFN-gamma expression of spleen of LD50-infected CBA/J mice were higher than those of either 15 cysts-infected CBA/J mice or LD50-infected C57BL/6 mice. These observations demonstrate that the immune response between LD50-infected C57BL/6 and CBA/J mice was more prominent when compared to C57BL/6 or CBA/J mice receiving the same parasite inoculum. These observations would suggest that caution must be excersized in the planning and interpretation of data when the size of the parasite inoculum has not been adjusted for mouse strain.     

Genetic architecture of fear conditioning in chromosome substitution strains: relationship to measures of innate (unlearned) anxiety-like behavior

We measured fear conditioning (FC) in a panel of chromosome substitution strains (CSS) created using the C57BL/6J (B6) and A/J (AJ) inbred strains. Mice were trained to associate a specific context and tone with a foot shock. FC was measured by observing freezing behavior during re-exposure to the context and tone. Freezing to context was more than twofold greater in the AJ strain relative to the B6 strain. Among the CSS we identified four strains with higher (CSS-6, -10, -11, and -18) and two strains with lower (CSS-7 and -14) freezing to context. CSS-10 and -18 also showed higher freezing to tone, while CSS-12 showed less freezing to tone. CSS-1 has been implicated in open-field (OF) and light-dark box (LDB); we observed significant activity differences prior to training but no differences in FC. Chromosomes 6 and 10 have been associated with differences in anxiety-like behaviors, suggesting the existence of pleiotropic alleles that influence both learned and innate fear. By utilizing a genetic reference population, we have identified chromosomes that pleiotropically influence multiple phenotypes hypothesized to reflect a common ethologic construct that has been termed emotionality. The CSS provide a straightforward means of isolating the underlying genetic factors.     

The characteristics of the manifestation of hereditarily induced anxiety in male C57Bl/6J and CBA/Lac mice

Behavior of male mice of C57Bl/6J and CBA/Lac strains was tested in the elevated plus-maze and open field in order to estimate state anxiety in novel conditions. The cube and partition tests were used to reveal trait anxiety in the familiar conditions of the home cage. It is concluded that genetically defined state anxiety is more pronounced in CBA/Lac mice and trait anxiety in C57Bl/6J strain.     

Radiation-induced pulmonary endothelial dysfunction and hydroxyproline accumulation in four strains of mice

C57BL mice exposed to 14 Gy of whole-thorax irradiation develop significant histologic lung fibrosis within 52 weeks, whereas CBA and C3H mice do not exhibit substantial fibrosis during this time. The purpose of the present study was to determine whether this strain-dependent difference in radiation histopathology is associated with genetic differences in pulmonary endothelial metabolic activity or in endothelial radioresponsiveness. C57BL/6J, C57BL/10J, CBA/J, and C3H/HeJ mice were sacrificed 12 weeks after exposure to 0 or 14 Gy of 300-kV X rays to the whole thorax. Lung angiotensin converting enzyme (ACE) activity and plasminogen activator (PLA) activity were measured as indices of pulmonary endothelial function; and lung hydroxyproline (HP) content served as an index of pulmonary fibrosis. Lung ACE and PLA activities in sham-irradiated C57BL/6J and CB57BL/10J mice were only half as high as those in sham-irradiated CBA/J and C3H/HeJ mice. Exposure to 14 Gy of X rays produced a slight but nonsignificant reduction in lung ACE and PLA activity in the C57BL strains, and a significant reduction in the CBA/J and C3H/HeJ mice. Even after 14 Gy, however, lung ACE and PLA activities in CBA/J and C3H/HeJ mice were higher than those in sham-irradiated C57BL/6J and C57BL/10J mice. Lung HP content in all four strains increased significantly after irradiation, but this increase was accompanied by an increase in lung wet weight. As a result, HP concentration (per milligram wet weight) remained constant or increased slightly in both C57BL strains and actually decreased in the CBA/J and C3H/HeJ mice. These data demonstrate significant genetic differences in both intrinsic pulmonary endothelial enzyme activity and endothelial radioresponsiveness among the four strains of mice. Specifically, strains prone to radiation-induced pulmonary fibrosis (C57BL/6J, C57BL/10J) exhibit only half as much lung ACE and PLA activity as do strains resistant to fibrosis (CBA and C3H).     

Effect of genotype on the development of aggressive and submissive behavior in the mouse

Aggressive and submissive behaviour was studied in CBA/Lac and C57BL/6J strains of mice during long-term intermale interaction with syngenic partners. It was shown that the aggressiveness of aggressive C57BL/6J animals was more expressive than that of CBA/Lac' ones. The structure of submissive behaviour of this strains' encounters was also significantly different. Prolonged-defeat experience changed the character of submissive behaviour of C57BL/6J, but not of CBA/Lac' ones. Aggression of dominant animals considerably decreased in both strains. It is suggested that CBA/Lac and C57BL/6J mice had different mechanisms of suppression of intermale aggression.     

The dark phase improves genetic discrimination for some high throughput mouse behavioral phenotyping

Dark-phase testing has previously been shown by others to improve the outcome of some 'classical' behavior test situations. However, the importance of such ethological correctness and the effect of the light/dark cycle on high throughput behavioral testing situations such as 'mutant vs. wild type' and 'screening', are less or unknown, respectively. These testing situations differ from the 'classical' in that they are designed primarily to discriminate between genetically different mice rather than provide a detailed assessment of ability or psychosocial state. Here we test the hypotheses that dark-phase testing affects the outcome of high throughput behavioral tests and that dark-phase testing improves discrimination between genetically distinct mice (C57BL/6J, 129S1/SvImJ and B6129F1) using high throughput behavioral tests. Our results demonstrate that, although all successful tests showed some effect of phase, only the SHIRPA primary screen, open-field test and motor learning on the rotarod showed improved strain discrimination in the dark phase. Surprisingly, the social interaction test did not show a clear benefit to either phase, and interestingly, the tail-flick test discriminated strains better in the light phase. However, since the preponderance of our data shows that dark-phase testing improves, or does not affect, strain discrimination, we conclude that for these strains and tests, dark-phase testing provided superior outcomes. If discrimination is not achieved in the dark phase, then light phase-testing would be undertaken.     

Effect of long-term restraint stress on behavior of female C57BL/6J and CBA/Lac inbred mice. Dispersion and cluster analysis]

An augmented exploratory behaviour and motor activity and diminished anxiety after a restraint stress were found in CBA/Lac female mice [corrected] but not in C57BL/6J ones. In the Porsolt test the result was exactly opposite. A possibility of inherent anxiety-depressive pathological condition in the C57BL/6J mice [corrected] developing under the effect of repeated psychological stress, is assumed.     

Substrain specific behavioral responses in male C57BL/6N and C57BL/6J mice to a shortened 21-hour day and high-fat diet

ABSTRACT

Altered circadian rhythms have negative consequences on health and behavior. Emerging evidence suggests genetics influences the physiological and behavioral responses to circadian disruption. We investigated the effects of a 21 h day (T = 21 cycle), with high-fat diet consumption, on locomotor activity, explorative behaviors, and health in male C57BL/6J and C57BL/6N mice. Mice were exposed to either a T = 24 or T = 21 cycle and given standard rodent chow (RC) or a 60% high-fat diet (HFD) followed by behavioral assays and physiological measures. We uncovered numerous strain differences within the behavioral and physiological assays, mainly that C57BL/6J mice exhibit reduced susceptibility to the obesogenic effects of (HFD) and anxiety-like behavior as well as increased circadian and novelty-induced locomotor activity compared to C57BL/6N mice. There were also substrain-specific differences in behavioral responses to the T = 21 cycle, including exploratory behaviors and circadian locomotor activity. Under the 21-h day, mice consuming RC displayed entrainment, while mice exposed to HFD exhibited a lengthening of activity rhythms. In the open-field and light-dark box, mice exposed to the T = 21 cycle had increased novelty-induced locomotor activity with no further effects of diet, suggesting daylength may affect mood-related behaviors. These results indicate that different circadian cycles impact metabolic and behavioral responses depending on genetic background, and despite circadian entrainment.     

Variability in empathic fear response among 11 inbred strains of mice

Empathy is an important emotional process that involves the ability to recognize and share emotions with others. We have previously developed an observational fear learning (OFL) behavioral assay to measure empathic fear in mice. In the OFL task, a mouse is conditioned for context‐dependent fear when it observes a conspecific demonstrator receiving aversive stimuli. In the present study, by comparing 11 different inbred mouse strains that are commonly used in the laboratory, we found that empathic fear response was highly variable between different strains. Five strains – C57BL/6J, C57BL/6NTac, 129S1/SvImJ, 129S4/SvJae and BTBR T⁺ Itpr3^tf/J – showed observational fear (OF) responses, whereas AKR/J, BALB/cByJ, C3H/HeJ, DBA/2J, FVB/NJ and NOD/ShiLtJ mice exhibited low empathic fear response. Importantly, day 2 OF memory was significantly correlated with contextual memory in the classical fear conditioning among the 11 strains. Innate differences in anxiety, locomotor activity, sociability and preference for social novelty were not significantly correlated with OFL. Interestingly, early adolescent C57BL/6J mice exhibited an increase in acquisition of OF. The level of OFL in C57BL/6J strain was not affected by sex or strains of the demonstrator. Taken together, these data strongly suggest that there are naturally occurring OFL‐specific genetic variations modulating empathic fear behaviors in mice. The identification of causal genes may uncover novel genetic pathways and underlying neural mechanisms that modulate empathic fear and, ultimately, provide new targets for therapeutic intervention in human mental disorders associated with impaired empathy.     

Extinction of passive avoidance response in various mouse strains

Dependence of the passive avoidance extinction dynamics on a mouse strain was shown. Mice C57BL/6J and AKR/J extinguished more quickly relative to DBA/2J, CBA/Lac and BALB/c, and this extinction was stable. Individual instability of extinction was characteristic of C3H/HeJ mice. Extinction of the passive avoidance in mice CBA/Lac and BALB/c was slower: with a delay in the beginning and prolonged retention of memory trace of the shock exposure. In DBA/2J mice, the extinction was impaired. These data suggest that DBA/2J, CBA/Lac and BALB/c mice constitute groups of risk with high predisposition to impairment of extinction of memory of aversive events, which is thought to be a symptom of a depressive-like state.     

Exploratory activity of mice of different genetic strains after olfaction disruption by 3-methylindole (skatole)

The behavior of mice of two inbred strains (C57BL/6J and CBA) and their F1 hybrids was evaluated in the open field test after intraperitoneal administration of 3-methylindole (skatole) disrupting epithelium of the main olfactory system. High motor and exploratory activities and emotional sensitivity was observed in intact C57BL/6J mice compared to CBA mice and their hybrids. Anosmia induced by intraperitoneal administration of skatole changed the behavior of C57BL/6J and CBA mice. The direction of the observed changes in the orientation and exploratory behavior of anosmic animals was different. Anosmia decreased motor and exploratory activities in C57BL/6J mice and increase them in CBA mice. Intact hybrid mice demonstrated the predominance of the CBA genotype in the orientation and exploratory activity in the test used. Anosmia in hybrid animals had no significant effect on the orientation and exploratory behavior.     

Effect of a single severe stress on behaviour of males and females in the mouse inbred strains CBA/Lac and C57BL/6J

The effect of single severe stress in the form of forced swimming on the behavior of males and females in the mouse inbred strains CBA/Lac and C57BL/6J were examined in the open field test. Measurements were carried out within two hours after the stress exposure (Trial 1) and repeated 2 hours thereafter (Trial 2). Intact males and females of the both mouse strains which tested in the open field twice too were used as control. An increased latency was found until first escape from the center both in males and females of the CBA/Lac strain within two hours after the end of forced swimming. This parameter was still high in females in the Trial2. Four out of seven behavior parameters were changed in females of the C57BL/6J strain two hours after the stress exposure, but their behavior was similar to control in the Trial 2. The males of the C57BL/6J strain demonstrated the least changed behavior in the open field test after the stress exposure with the exception of increased number of grooming in the Trial 1. Further on, a detailed analysis of repeated testing in the open field within intact and stressed mice of both strains was performed. This comparison allowed revealing hereditary and gender peculiarities in the mouse behavior after single severe stress exposure. The results are discussed in respect to the possible genetically inherent increased traitanxiety in females of C57BL/6J strain and the state of anxiety in females of CBA/Lac strain.     

Reduced frequencies of Mitomycin-C induced sister chromatid exchanges in AKR Mice

Summary The frequencies of base-line and Mitomycin-C (MMC) induced sister chromatid exchanges (SCE) were surveyed in four inbred strains of mice. In contrast to the C57B1/6J, CBA/J, and A/J strains where frequencies of SCE increased linearly with increasing dose of MMC, levels of SCE were significantly lower in AKR/J mice at high MMC concentrations. At a dose of 5 mg/kg MMC, chromosomal aberrations were more frequent in bone marrow cells of AKR/J mice than in C57B1/6J mice. These observations suggest an altered response to DNA damage in the AKR mouse strain.     

Association of glycoprotein gp130 with hereditary catalepsy in mice

Glycoprotein gp130 is involved in the interleukin‐6 (IL‐6) and related cytokines' signaling. Linkage between the gp130 coding gene and freezing reaction (catalepsy) was shown. Here, we compared the expression and function of the gp130 in male mice of catalepsy‐resistant AKR/J strain and catalepsy‐prone congenic AKR.CBA‐D13Mit76 strain created by transferring the gp130 gene allele from catalepsy‐prone CBA/Lac to the genome of AKR/J strain. No difference in the gp130 expression in the frontal cortex, hippocampus and midbrain between AKR and AKR.CBA‐D13Mit76 mice was found. However, AKR.CBA‐D13Mit76 mice were more sensitive to bacterial lipopolysaccharide (LPS). The administration of LPS (50 µg/kg, ip) significantly increased mRNA level of the gene coding IL‐6‐regulated glial fibrillary acidic protein (GFAP) in the midbrain, induced catalepsy and decreased locomotion in the open field and social investigation tests in AKR.CBA‐D13Mit76, but not in AKR mice. The result indicates (1) the association between gp130 and hereditary catalepsy, (2) increased functional activity rather than expression of gp130 in AKR.CBA‐D13Mit76 mice and (3) the involvement of gp130 in the mechanism of LPS‐induced alteration of behavior.     

Comparative analysis of the anxiety-related behaviors in four inbred mice

An anxiety-related behavior is an emotional response of an organism, which is quantitatively measured by several behavioral paradigms. We employed two most frequently used behavioral tests, the open field and light-dark exploration, to comparatively analyze the anxiety-like behaviors in four inbred mice. For an accurate recording of movement, motion analysis software was developed that acquires a real-time video input to generate a behavioral path. Effects of the strains on the test results were evaluated by ANOVA with the Newman-Keuls post hoc comparison. Eight different behavioral indices, four from each tests, were grouped into two classes; the results of duration, center crossing, transition, rearing, and ambulation indicate strain differences of FVB/N>C57BL/6J>/=BALB/cA>/=CBA/N (I), while stretched-attend posture, peeping, and defecation show the tendency of FVB/N=C57BL/6J相似文献   

Kinetics of ectromelia virus (mousepox) transmission and clinical response in C57BL/6j, BALB/cByj and AKR/J inbred mice

Research was undertaken to answer basic questions on susceptibility, clinical response and transmission of ectromelia virus in selected strains of inbred mice. C57BL/6J and AKR/J were found to be markedly more resistant to a virulent strain of ectromelia virus (isolated during the 1979-80 outbreak at the National Institutes of Health) than C57LJ, BALB/cByJ, DBA/2J, A.By/SNJ and C3H/HeJ when infected by footpad inoculation. In C57BL/6J and AKR/J the LD50 was about 7 logs higher than the ID50. With one exception, C57LJ, the LD50 and ID50 titers in the other strains were about equal. In C57LJ the LD50 titer was intermediate. Following intragastric inoculation, virus was isolated from feces of C57BL/6J mice for as long as 46 days and up to 29 days from BALB/cByJ mice. Transmission to cage mates from intragastrically infected C57BL/6J and BALB/cByJ occurred up to 36 and 30 days respectively after infection. Virus was isolated from the spleen in 2 of 5 BALB/cByJ mice and 1 of 7 C57BL/6J mice tested 95 days after gastric inoculation. Following footpad inoculation, BALB/cByJ mice consistently transmitted virus to cage mates before death at 10-12 days. C57BL/6J mice transmitted between days 8 and 17, but not beyond. Virus was maintained in C57BL/6J mice by exposure to infected cage mates for seven passages, which was the most attempted. Clinical signs in infected C57BL/6J mice were usually subtle or inapparent.