The influence of visual ability on learning and memory performance in 13 strains of mice

We calculated visual ability in 13 strains of mice (129SI/Sv1mJ, A/J, AKR/J, BALB/cByJ, C3H/HeJ, C57BL/6J, CAST/EiJ, DBA/2J, FVB/NJ, MOLF/EiJ, SJL/J, SM/J, and SPRET/EiJ) on visual detection, pattern discrimination, and visual acuity and tested these and other mice of the same strains in a behavioral test battery that evaluated visuo-spatial learning and memory, conditioned odor preference, and motor learning. Strain differences in visual acuity accounted for a significant proportion of the variance between strains in measures of learning and memory in the Morris water maze. Strain differences in motor learning performance were not influenced by visual ability. Conditioned odor preference was enhanced in mice with visual defects. These results indicate that visual ability must be accounted for when testing for strain differences in learning and memory in mice because differences in performance in many tasks may be due to visual deficits rather than differences in higher order cognitive functions. These results have significant implications for the search for the neural and genetic basis of learning and memory in mice.     

Differential acquisition of lever pressing in inbred and outbred mice: comparison of one-lever and two-lever procedures and correlation with differences in locomotor activity

Recent progress in mouse genetics has led to an increased interest in developing procedures for assessing mouse behavior, but relatively few of the behavioral procedures developed involve positively reinforced operant behavior. When operant methods are used, nose poking, not lever pressing, is the target response. In the current study differential acquisition of milk-reinforced lever pressing was observed in five inbred strains (C57BL/6J, DBA/2J, 129X1/SvJ, C3H/HeJ, and BALB/cJ) and one outbred stock (CD-1) of mice. Regardless of whether one or two levers (an "operative" and "inoperative" lever) were in the operant chamber, a concomitant variable-time fixed-ratio schedule of milk reinforcement established lever pressing in the majority of mice within two 120-min sessions. Substantial differences in lever pressing were observed across mice and between procedures. Adding an inoperative lever retarded acquisition in C57BL/6J, DBA/2J, 129X1/SvJ, and C3H/HeJ mice, but not in CD-1 and BALB/cJ mice. Locomotor activity was positively correlated with number of lever presses in both procedures. Analyses of durations of the subcomponents (e.g., time to move from hopper to lever) of operant behavior revealed further differences among the six types of mice. Together, the data suggest that appetitively reinforced lever pressing can be acquired rapidly in mice and that a combination of procedural, behavioral, and genetic variables contributes to this acquisition.     

Genetic differences in response to novelty and spatial memory using a two-trial recognition task in mice

A two-trial memory task, based on a free-choice exploration paradigm in a Y-maze, was previously developed to study recognition processes in Sprague-Dawley rats. Because this paradigm avoids the use of electric shock or deprivation that may have nonspecific effects and does not require learning of a rule, it may be particularly useful for studying memory in mice. Four inbred strains (Balb/cByJ, DBA/2J, C57BL/6J, and SJL/J), an F1 hybrid (C57BL/6 x SJL/J), and one outbred strain (CD1) were used to validate this task in mice and to characterize a strain distribution in response to novelty and working memory. Exploration was measured with a short (2 min) intertrial interval (ITI) between acquisition and retrieval, while memory was examined with longer intervals (30 min, 1 h, and 2 h). A study of the time course of the response to novelty revealed varying degrees of preference and/or habituation to novelty among the different strains, with CD1 exhibiting a very high response to novelty and others showing lower (C57 x SJL hybrids) to complete absence (SJL) of exploration of novelty. Memory span, assessed with increasing ITIs, varied widely among strains from 30 min (C57 x SJL hybrids) to at least 2 h (C57 and BALB). Such demonstrated sensitivity to a wide range of behavioral phenotypes supports the use of this spatial memory task as an effective tool for the study of genetic influences on the response to novelty and recognition processes in mice.     

Genetic differences in the mouse defense test battery

The mouse defense test battery (MDTB) has been designed to examine anxiogenic- or anxiolytic-like properties of psychoactive drugs through effects on specific defensive behaviors. In the present study, the MDTB was used to evaluate the potential contribution of genetic factors to these behaviors. The data revealed pronounced differences in several defense reactions among four inbred strains (BALB/c, C57BL/6, CBA, DBA/2) and one outbred (Swiss) mouse line. Thus, when subjects were introduced into the apparatus, Swiss and C57BL/6 displayed the highest levels of horizontal and vertical activities, while BALB/c and DBA/2 mice showed intermediate and CBA low activity rates. When subjects were chased by the rat, C57BL/6 mice used flight as the dominant defense strategy, while the defensive responses of BALB/c, C57BL/6, and DBA/2 mice consisted of flight reactions and risk assessment activities. However, when flight or escape was not possible, risk assessment became the predominant feature of the defense repertoire in the C57BL/6 mice. When defensive threat/attack behaviors were required, Swiss, BALB/c, DBA/2, and C57BL/6 mice showed very similar reactions in terms of the magnitude of the responses observed. CBA mice were poorly defensive in all these test situations. Finally, after the rat was removed from the test apparatus, Swiss, DBA/2, and C57BL/6 mice displayed more vertical activities than BALB/c mice. These latter, however, showed an increased level of ambulation compared to the activity recorded before the rat exposure. Together, these findings indicate that genetic factors contribute to defensive behaviors in this animal model of anxiety. The different behavioral profiles displayed by the strains used here may provide the means to obtain a better insight into the neurobehavioral mechanisms involved in anxiety-related disorders. Aggr. Behav. 23:19–31, 1997. © 1997 Wiley-Liss, Inc.     

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

Fifteen male mice from each of 4 inbred strains (C57BL/6J, BALB/cJ, CBA/J, and DBA/2J) were tested 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 that the 3 other low ethanol-selecting strains. A second experiment 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 is a much more potent depressant that 1,2 PD. These results are discussed in terms of the possible role of neural sensitivity in regulating consumption levels of the 2 alcohols.     

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.     

Selective improvement of strain-dependent performances of cognitive tasks by food restriction

Temporary food restriction affects strain differences for behavioral phenotypes in the inbred strains of mice C57BL/6 (C57) and DBA/2 (DBA). Since food restriction is a routine procedure to motivate learning, we evaluated its influence on differences for spatial and non-spatial discrimination between these strains of mice by using two non-associative tasks: the Spatial Novelty Test (SNT) and the Spontaneous Object Recognition Test (SORT). The results confirmed the poor performance of the DBA mice in SNT. Nonetheless, DBA mice were perfectly able to recognize the novel object in SORT. By contrast, C57 mice were good performers in SNT but failed to recognize a novel object in SORT. Finally, food restriction selectively improved C57 performance in SNT and DBA performance in SORT. These results support the view that a food restricting procedure enhances strain differences for discrimination of configurational information.     

Learning strategy selection in the water maze and hippocampal CREB phosphorylation differ in two inbred strains of mice

Learning strategy selection was assessed in two different inbred strains of mice, C57BL/6 and DBA/2, which are used for developing genetically modified mouse models. Male mice received a training protocol in a water maze using alternating blocks of visible and hidden platform trials, during which mice escaped to a single location. After training, mice were required to choose between the spatial location where the platform had been during training (a place strategy) and a visible platform presented in a new location (a cued/response strategy). Both strains of mice had similar escape performance on the visible and hidden platform trials during training. However, in the strategy preference test, C57BL/6 mice selected a place strategy significantly more often than DBA/2 mice. Because much evidence implicates the hippocampus and striatum as important neural substrates for spatial/place and cued/response learning, respectively, the engagement of the hippocampus was then assessed after either place or cue training by determining levels of cAMP response element-binding protein (CREB) and phosphorylated CREB (pCREB) in these two mouse strains. Results revealed that hippocampal CREB levels in both strains of mice were significantly increased after place in comparison to cued training. However, the relation of hippocampal pCREB levels to training was strain dependent; pCREB was significantly higher in C57BL/6 mice than in DBA/2 mice after place training, while hippocampal pCREB levels did not differ between strains after cued training. These findings indicate that pCREB, specifically associated with place/spatial training, is closely tied to differences in spatial/place strategy preference between C57BL/6 and DBA/2 mice.     

Landmark-based but not vestibular-based orientation elicits mossy fiber synaptogenesis in the mouse hippocampus

This study tries to shed light on the paradoxical finding that two inbred strains of mice C57BL/6 (C57) and DBA/2 (DBA), with differences in hippocampal function, perform similarly in the water maze (WM). Mice from both strains were trained on WM protocols permitting or preventing the use of vestibular signals. Hippocampal involvement in performance was then assessed by estimation of post-training mossy fiber (MF) synaptogenesis. We found that C57 and DBA mice performed similarly when both visual and vestibular information were available but only C57 mice exhibited new MF synapses. Disruption of vestibular inputs impaired performance in DBA mice but not in C57 mice which still exhibited a post-training increase of hippocampal MF synaptic terminals. This strain-specific dissociation indicates that DBA mice can navigate successfully by relying on vestibular signals without engaging their hippocampus. In contrast, vestibular signals are irrelevant for C57 mice since their suppression neither disrupts their behavior nor prevents the formation of new hippocampal synapses. These findings suggest some caution is required in considering performance on standard WM protocols as an index of hippocampus-based learning. Estimating the extent of post-training mossy fiber synaptogenesis would be helpful in solving this issue.     

Towards mouse models of perseveration: a heritable component in extinction of operant behavior in fourteen standard and recombinant inbred mouse lines

Extinction of instrumental responses is an essential skill for adaptive behavior such as foraging. So far, only few studies have focused on extinction following appetitive conditioning in mice. We studied extinction of appetitive operant lever-press behavior in six standard inbred mouse strains (A/J, C3H/HeJ, C57BL/6J, DBA/2J, BALB/cByJ and NOD/Ltj) and eight recombinant inbred mouse lines. From the response rates at the end of operant and extinction training we computed an extinction index, with higher values indicating better capability to omit behavioral responding in absence of reward. This index varied highly across the mouse lines tested, and the variability was partially due to a significant heritable component of 12.6%.To further characterize the relationship between operant learning and extinction, we calculated the slope of the time course of extinction across sessions. While many strains showed a considerable capacity to omit responding when lever pressing was no longer rewarded, we found a few lines showing an abnormally high perseveration in lever press behavior, showing no decay in response scores over extinction sessions.No correlation was found between operant and extinction response scores, suggesting that appetitive operant learning and extinction learning are dissociable, a finding in line with previous studies indicating that these forms of learning are dependent on different brain areas. These data shed light on the heritable basis of extinction learning and may help develop animal models of addictive habits and other perseverative disorders, such as compulsive food seeking and eating.     

Aggressive behavior in inbred strains of mice during pregnancy

Female aggressive behavior toward adult male ICR/JCl mice was compared for virgin and pregnant mice of five inbred strains (BALB/c, C3H/He, C57BL/6, DBA/2J, and AKR/J). Pregnant females from four strains except BALB exhibited intense aggressive behavior, whereas only virgin AKR females were aggressive. Aggressive behavior began in early pregnancy, was highest in midpregnancy, and declined slightly thereafter until the day of parturition. The level of aggressive behavior showed significant strain differences. The topography of aggressive behavior was also different among the four strains. DBA females showed marked contrast with the other three strains in the temporal changes of aggression in the first phase of encounter. Furthermore, strain specific behavioral pattern of aggression was demonstrated based on six behavioral acts ( Darting , Chasing, Attack, Biting, Wrestling, and Boxing). Virgin and pregnant AKR females showed the identical behavioral pattern of aggression.     

Repeated acquisition and performance chamber for mice: a paradigm for assessment of spatial learning and memory

Molecular genetic manipulation of the mouse offers the possibility of elucidating the function of individual gene products in neural systems underlying learning and memory. Many extant learning paradigms for mice rely on negative reinforcement, involve simple problems that are relatively rapidly acquired and thus preclude time-course assessment, and may impose the need to undertake additional experiments to determine the extent to which noncognitive behaviors influence the measures of learning. To overcome such limitations, a multiple schedule of repeated acquisition and performance was behaviorally engineered to assess learning vs rote performance within-behavioral test session and within-subject utilizing an apparatus modified from the rat (the repeated acquisition and performance chamber; RAPC). The multiple schedule required mice to learn a new sequence of door openings leading to saccharin availability in the learning component during each session, while the sequence of door openings for the performance component remained constant across sessions. The learning and performance components alternated over the course of each test session, with different auditory stimuli signaling which component was currently in effect. To validate this paradigm, learning vs performance was evaluated in two inbred strains of mice: C57BL/6J and 129/SvJ. The hippocampal dependence of this measure was examined in lesioned C57BL/6J mice. Both strains exhibited longer latencies and higher errors in the learning compared to the performance component and evidenced declines in both measures across the trials of each session, consistent with an acquisition phenomenon. These same measures showed little or no evidence of change in the performance component. Whereas three trials per session were utilized with C57BL/65 mice in each component, behavior of 129/SvJ mice could only be sustained for two trials per component per session, demonstrating differences in testing capabilities between these two strains under these experimental conditions and thus precluding the ability to make systematic strain comparisons of learning capabilities. Hippocampal lesions in C57BL/6J mice resulted in substantially longer latencies and increased errors in the learning but not the performance component, demonstrating the importance of this region to spatial learning as measured in the RAPC. In aggregate, this positive reinforcement-based operant paradigm to evaluate murine spatial learning detects strain differences and hippocampal dependence and permits explicit differentiation of the impact of noncognitive contributions to learning measures on a within-subject, within-session basis.     

Behavior genetic analysis of Water-T-Maze learning in inbred strains of mice,their hybrids,and selected second generation crosses

Summary The Water-T-Maze was used to investigate the genetically determined apparatus-dependent behavior of mice. Special importance was attached to the mode of inheritance involved. For this purpose we used NMRI, C3H/HeJ, Balb/c, Balb/cN, DBA/2, C57Bl/6 inbred mouse strains, together with their offspring and the F₂-hybrids of C3H/HeJ and DBA/2. Furthermore investigations were carried out to examine the effect of the environment on the expression of behavior. After these experiments had proved that there is a predominantly genetic derivation for behavioral expression, a possible relationship between the conditioning effect and the age of the animals was investigated. The animal's age has quantitative effects on the expression of behavior, but it does not lead to any qualitative behavioral changes. Nevertheless early conditioning of the animals apparently manifests itself in long-term memory. On the whole the mode of inheritance in Water-T-Maze learning appears to imply a polygene-dependent model in which clear dominant effects are present, as shown in the results of the F₂-generation. No sex-related differences were observed. In general, the results demonstrate a definite involvement of genetic factors in the areas of conditioning and behavior.     

Effects of acute and chronic stress and of genotype on oxotremorine-induced locomotor depression of mice

The locomotor behavior of unstressed and stressed mice of two inbred strains, DBA/2 and C57/BL6, was investigated. Animals were tested in a toggle-floor box apparatus, 30 min after saline or oxotremorine treatment (ip). A dose of oxotremorine that did not depress the activity of na?ve mice (0.01 mg/kg) was chosen. Stressed mice were injected 24 h after either a single 2-h stress session (acute stress) or the last of 14 daily stress sessions of tube restraining (chronic stress). Acute stress did not modify the depressant effect of oxotremorine on locomotor behavior in either strain. On the contrary, chronic stress induced a clear sensitization of DBA but not C57 mice to the depressant effect of oxotremorine. These findings show that chronic stress may result in modifications of the cholinergic function, and its behavioral correlates, and that these changes are modulated by the genetic makeup.     

Strain differences in open field activity after learning in mice

Male mice of albino and pigmented strains were tested on their open field activity after maze learning and passive avoidance conditioning. The results indicated that the albino strains Balb/c, NMRI, Swiss albino and hybrids of these, reacted with an open field activity increase after maze learning in contrast to the pigmented strains C3H/He, C57BL/6J and DBA/2N. Only Swiss albino displayed an increased ambulatory level after passive avoidance conditioning for the whole experimental time. It is suggested that an ambulatory increase after learning is related to fur color and not to the initial open field activity level, nor to the learning time or the learning capacity.     

Task complexity as a factor in eliciting heterosis in mice: aversively motivated behaviors.

Three inbred strains of mice (A/J, DBA/2J, and C57BL/6J) and their six reciprocal F1 hybrids were tested in activity levels before and after shock, inhibitory avoidance, one-way avoidance, and shuttle avoidance. In the activity and inhibitory situations the hybrids generally exhibited an intermediate pattern of inheritance. In the one-way avoidance task complete dominance was the rule, whereas in the shuttle task overdominance was apparent in all the hybrid strains. Overdominance was found to be more evident in tasks requiring increased versatility of associative processes. It is suggested that when the task involves relatively simple contingencies or reflexive behaviors, increased versatility is not necessary and consequently the hybrid advantage is not apparent. When the task involves integrative capacities, the hybrid advantage emerges.     

Active avoidance performance in genetically defined mice

It has been concluded by several investigators that active avoidance performance in mice is primarily influenced or even determined by a single gene. The genetically defined strains C57BL/6 and BALB/c have provided evidence that an aberrant development of pyramidal cells and mossy fiber configuration in the hippocampus of BALB/c mice also is determined by a single gene. As a test of the generality of the single gene influence on avoidance learning, and to examine the relationship of the hippocampal defect to avoidance learning, adult male mice of the inbred progenitor strains C57BL/6ByJ and BALB/cByJ and their seven recombinant inbred strains were tested in a variant of the shuttle-box paradigm used in previous studies. BALB/c were found to acquire the avoidance response at a faster rate than C57BL/6, consistent with most earlier reports, but performances of the recombinant inbred strains failed to dichotomize about the progenitor strains. The rank order of performance scores for the recombinant inbred strains was different from that reported in previous studies. Thus the present data failed to support the interpretation of a single major gene influencing active avoidance learning. It is concluded that avoidance learning and performance cannot be considered as unitary variables and that the interaction of genetic with environmental factors, including the conditions of the specific testing situation, are important considerations in any interpretation of genetic effects. No relationship between the hippocampal lamination defect and avoidance performance was demonstrated.     

Genotype modulates prenatal stress effects on aggression in male and female mice

Prenatal stress (heat and restraint) significantly increased postpartum aggression (proportion of animals fighting and/or the intensity of the behavior) in C57BL/6J female mice and reduced the behavior in DBA/2J females. For intermale aggression, prenatal stress increased the behavior (intensity of aggression) in C57BL/6J males but did not affect aggressive behavior in DBA/2J animals. Infanticidal behavior (the killing of young) exhibited by male mice was not influenced by prenatal stress in either strain. Relative anogenital distance measurements in neonates at birth did not serve as a reliable predictor of strain variation in prenatal stress effects. Prenatal stress did not influence this measure of prenatal androgen exposure in DBA/2J or C57BL/6J females. For males, prenatal stress elevated relative anogenital distance in C57BL/6J mice and decreased this measure in DBA/2J animals. Prenatal stress effects on aggressive behavior in male and female mice therefore depend upon genotype. Strain-dependent differences may be modulated by differences in endocrine reactivity to prenatal stress/and or differential central neural tissue sensitivity to hormones.     

Automated Measurement of Mouse Freezing Behavior and its Use for Quantitative Trait Locus Analysis of Contextual Fear Conditioning in (BALB/cJ × C57BL/6J)F2 Mice

The most commonly measured mouse behavior in fear conditioning tests is freezing. A technical limitation, particularly for genetic studies, is the method of direct observation used for quantifying this response, with the potential for bias or inconsistencies. We report the use of a computerized method based on latency between photobeam interruption measures as a reliable scoring criterion in mice. The different computer measures obtained during contextual fear conditioning tests showed high correlations with hand-scored freezing; r values ranged from 0.87 to 0.94. Previously reported strain differences between C57BL/6J and DBA/2J in context-dependent fear conditioning were also detected by the computer-based system. In addition, the use of computer-scored freezing of 199 (BALB/cJ×C57BL/6J)F₂ mice enabled us to detect a suggestive gender-dependent chromosomal locus for contextual fear conditioning on distal chromosome 8 by QTL analysis. Automation of freeze scoring would significantly increase efficiency and reliability of this learning and memory test.     

The Y chromosome, social signals, and offense in mice

Offense is one type of aggression in mice (Mus musculus/Mus domesticus). Offense was measured in a panel of testers design for two congenic strains of mice. The two congenic strains were DBA1Bg and DBA1. C57BL10-YBg. These differ in the Y chromosome. Offense was measured for the following dyadic pairs: Group 1 (DBA1 tested against a DBA1 opponent); Group 2 (DBA1 tested against a DBA1.C57BL10-Y opponent); Group 3 (DBA1.C57BL10-Y tested against a DBA1.C57BL10-Y opponent); and Group 4 (DBA1.C57BL10-Y tested against a DBA1 opponent). Group 1 was more aggressive than Group 3, whereas Group 2 was no more aggressive than Group 4. Thus, when the experimental and opponent pairs have the same Y chromosome, the congenics differ in offense, whereas when the experimental and opponent pairs have different Y chromosomes, the congenics do not differ in offense. These findings are consistent with the hypothesis that these Y chromosomes affect the display of and response to social or other stimuli for offense of mice. These stimuli may be individual recognition chemosignals in urine.