Genetic influences on digging behaviors in mice (Mus musculus) in laboratory and seminatural settings

Digging behaviors of several inbred strains of laboratory mice and some of their crosses were examined in three contexts. In laboratory burrow boxes, C57BL/6Abg mice constructed more sophisticated burrow systems than did BALB/cAbg mice. Their F1 hybrids built burrow systems more complex than either parental strain. The same pattern of genetic influence was observed in an outdoor pen. In an escape task that required digging, BALB/c mice escaped more quickly than did C57BL/6 mice; their F1 hybrids showed dominance toward the BALB/c phenotype. These results indicate that behavioral polymorphisms in digging behavior, which may relate to habitat selection, have a genetic basis. The dominance and overdominance toward the better digging parental strain in each type of task suggest the possible evolutionary importance of these digging behaviors.     

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.     

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.     

Strain-dependent effects of post-training dopamine receptor agonists and antagonists on memory storage in mice.

Post-training administration of the selective D1 or D2 agonists SKF 38393 and LY 171555 dose dependently impairs retention of an inhibitory avoidance response in DBA/2 mice. In agreement, the selective D1 or D2 antagonists SCH 23390 and (-)-sulpiride improve retention. These effects are opposite to those observed in the C57BL/6 strain, as previously reported. Moreover, B6D2F1 hybrids present a response to SKF 38393, LY 171555, SCH 23390, and (-)-sulpiride that parallels that of the C57BL/6 strain, thus suggesting that the neural mechanisms underlying the effects of DA agonists or antagonists on memory processes may be inherited through a dominant mode of inheritance.     

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.     

A genetic analysis of stereotypy in the mouse: dopaminergic plasticity following chronic stress

After repeated stressful experiences, DBA/2 (DBA) mice showed an increase in apomorphine-induced climbing while C57BL/6 (C57) mice showed a clear-cut decrease of this behavior. Genetic analysis involving F1 and F2 hybrids and the backcross populations (F1 X C57; F1 X DBA) indicated complete dominance of the C57 genotype and a significant genotype X environment interaction. These findings are discussed in terms of dopaminergic plasticity and of the heuristic value of this animal model in relation to disturbed behaviors triggered by stressful experiences.     

A case of behavioral heterosis in mice: quantitative and qualitative aspects of performance in a water-escape task.

Fourteen hundred and four mice from two inbred strains (Balb/c and C57BL/6), F1, F2, and backcrosses were subjected to four trials in a water-escape task and to a swimming test. Detailed analysis of mice behavior in these situations showed that the "F1 hybrid vigor" affected behavioral characters not directly related to physical vigor but of potential adaptive value. Their superiority was mainly due to more frequent adoption of an efficient behavioral tactic (direct or edge escape paths toward the exit) and more rapid progress with experience in this respect than other generations exhibited. These results clearly show that heterosis is not limited to physical vigor but may extend to behavioral and even psychological characters.     

Chronic stress-induced alterations in mouse colonic 5-HT and defecation responses are strain dependent

Mood disorders and chronic stress are frequently associated with gastrointestinal (GI) symptoms including diarrhoea or constipation. Locally produced serotonin [5-hydroxytryptamine (5-HT)] regulates GI motility and is a key factor in the pathophysiology of stress-associated GI disorders. We aimed to establish whether chronic stress can differentially affect faecal output and colon 5-HT concentration in two inbred mouse strains: BALB/c and C57BL/6 which differ in their ability to cope with stress. Adult male BALB/c and C57BL/6 mice were restrained for 2?h daily for 10 days. Defecation was monitored during each stress session. Twenty-four hours after the last session of stress, plasma corticosterone concentration was higher than control in both strains, indicative of a physiological effect of chronic stress; however, stress-induced diarrhoea was more persistent in C57BL/6 mice. Basal concentration of colon 5-HT was higher in C57BL/6 mice, and stress elicited an increase in colon 5-HT only in this strain. Finally, na?ve BALB/c mice had a higher sensitivity (incidence of diarrhoea) to 5-HT (0.33?mg/kg, i.p.) than C57BL/6 mice. Our results suggest that differential defecation responses to stress may be associated with colon 5-HT concentration, which may in turn reflect the individual sensitivity to 5-HT. In addition, C57BL/6 mice emerge as a relevant model for studying GI alterations induced by chronic stress.     

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.     

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.     

Sex differences in aggressive behaviour in various strains of mice

Two nonalbino inbred (C57 BL/6 and C3H/He) and one albino strain (Swiss) of mice were compared for female aggression toward intruders: 1 in period of lactation, 2 in nonlactating state and (3) in nonlactating state but previously rubbed with urine of lactating females; and for male aggression toward familiar or unfamiliar opponents. The results showed that resident females of the C57 and Swiss strain vigorously attack lactating intruders introduced into their cages. This effect was mediated by urinary cues emitted by the latter mice. It was also shown that Swiss residents displayed aggression towards nonlactating females, irrespective of their strain. Groups of C57 residents reacted most aggressively towards Swiss females, less aggressively towards C3H intruders, but did not show any aggression towards their own nonlactating conspecifics. In contrast, none of the C3H resident female groups displayed aggression towards intruding females of any category or strain. The results also showed that the males of the three strains displayed little (Swiss and C3H) or no aggression (C57) towards familiar opponents, whereas they directed increased aggressive responses towards unfamiliar ones. Comparisons among the three strains of mice revealed that Swiss males were the most aggressive in either situation. On the other hand, the finding that C3H males showed aggressive responses suggested that male and female aggression are, in this strain, under separate genetic or hormonal control.     

Direct observation and automated scoring of the activity of active and inactive inbred mouse strains

Inbred mouse strains previously found to be low (A/J) and high (C57BL/6J) in open-field activity were tested in a plastic oval runway while their runway activity was directly observed and also monitored by a contact switch recording device. The activity of active C57BL/6J mice was accurately monitored by the recording device, but scores of inactive A/J mice were inflated by a factor between 2 and 3 X. Activity differences between strains were consistently maintained[during repeated tests under both high and very dim illumination if direct observational scores were used. Utilization of scores obtained by the automated recording device resulted in a failure to obtain group differences under the condition of dim illumination. These results were directly related to the mode of locomotion of the two mouse strains.     

Strain-dependent modulation of memory by stress in mice

The effects of immobilization stress were investigated in Swiss Webster (Swiss), DBA/2 (DBA), and C57BL/6 (C57) mice, tested in a passive avoidance situation. Retention performance was impaired in Swiss and DBA mice, and improved in C57 mice, immobilized immediately, but not 2 hr, after training. These effects lasted for less than 7 days in DBA and Swiss mice, while they were still present, in the C57 strain, 14 days after training. The naloxone antagonism of the effects observed was also demonstrated. The results are discussed in terms of the possible role of endogenous opioids, stress hormones, and genetic makeup in the stress-induced modulation of memory processes in the mouse.     

Age differences in acquisition and retention of one-way avoidance learning in C57BL/6NNia and autoimmune mice

Acquisition and 48-h retention of a step-up active avoidance response were studied in separate age groups of C57BL/6NNia mice (aged 1.5, 3.5, 6, 12, or 26 months) and five strains of genetically autoimmune mice differing in life span. The C57BL/6NNia mice showed no change in ability to acquire the avoidance response between 1.5 and 3.5 months, but showed a steady decline in that ability thereafter. Mouse strains with early-onset autoimmune disorder (NZB/B1NJ, MRL/MpJ-lpr, and BXSB/MpJ) showed declines in acquisition capability between 1.5 and 3.5 months of age, whereas mouse strains with mild, late-onset autoimmune disorder (MRL/MpJ- + and NZBWF1/J) showed stable or improved acquisition during that period. Both the C57BL/6NNia and NZB/B1NJ mice showed age-dependent declines in 48-h retention performance by 12 months of age. These findings suggested that while 48-h retention performance deficits were most related to chronological age, avoidance acquisition deficits were related to development of autoimmunity.     

Spatial learning induces differential changes in calcium/calmodulin-stimulated (ACI) and calcium-insensitive (ACII) adenylyl cyclases in the mouse hippocampus

Several lines of evidence indicate that Ca2+/calmodulin-stimulated isoforms of adenylyl cyclase (AC) are involved in long-term potentiation and in certain forms of learning. Recently, we found that training in different types of learning task differentially activates Ca2+-sensitive versus Ca2+-insensitive AC activities in certain brain regions, indicating that AC species other than those stimulated by Ca2+/calmodulin may play an important role in learning processes (Guillou, Rose, & Cooper, 1999). Here, we report the effects of spatial reference memory training in a radial arm maze on the levels of AC1 and AC2 mRNA in the dorsal hippocampus of C57BL/6 mice. Acquisition of the task was associated with a learning-specific and time-dependent increase of AC1 mRNA expression selectively in subfields CA1-CA2. In contrast, AC2 mRNA levels were either reduced or not reliably affected depending on the stage of acquisition. Moreover, no significant changes in AC expression were observed either in the dorsal hippocampus of mice trained in a non-spatial (procedural) version of the task or in cortical regions of mice learning the spatial or procedural task. The regional specificity of these effects indicates that the formation of spatial and non-spatial memory requires distinct contributions from Ca2+-sensitive and Ca2+-insensitive AC in the hippocampus. It is suggested that downregulation of AC2 throughout all hippocampal subfields may play a permissive role during the acquisition of spatial learning whereas an upregulation of AC1 specifically in subfield CA1, may be critical to accurately encode, store or use spatial information.     

Effects of the heterosomes and maternal environments on aggressive behavior in Mus musculus

This is a study of the offense type of aggression in males of the DBA/1Bg and C57BL/10Bg inbred strains of mice and their two reciprocal F1 hybrids. It uses three test paradigms for dyadic encounters: the homogeneous set test, an identity panel of testers, and the standard opponent test. There were no reciprocal F1 hybrid differences for any of the 12 behavioral measures of aggression in the homogeneous set test or the standard opponent test. For the panel of testers paradigm, reciprocal F1 hybrid differences occurred when the tester (opponent) was an F1 hybrid male, but not when the tester (opponent) was an RB/1 or C57BL10 male. When B10RB1F1 males were the testers (opponents), B10RB1F1 hybrid males were more aggressive than RB1B10F1 hybrid males across 10 of the 12 behavioral measures. Conversely, when RB1B10F1 males were the testers (opponents), RB1B10F1 males were more aggressive than B10RB1F1 males across 9 of the 12 behavioral measures. These results conform to the following empirical rule: A significant difference between reciprocal F1 hybrids is observed for these behavioral measures when one of the hybrids has both of its heterosomes (X and Y chromosomes) and its maternal environment identical to those of its opponent and the other hybrid has none of these identical to those of its opponent. These results are consistent with a model in which on some genetic backgrounds, but not on others, similarity of the heterosomes and maternal environments can influence the display of or response to social or other stimuli for the offense type of aggression in mice. These stimuli may be individual recognition chemosignals in urine.     

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.     

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.     

Pharmacological evidence for a role of D2 dopamine receptors in the defensive behavior of the mouse

In this study the role of the DA system in the expression of defensive behavior of the mouse was investigated. C57BL/6 mice subjected to three daily defeat experiences (24 h apart) exhibited an increase of defensive behaviors (upright and sideways postures and escape) as well as a decrease of activity and a decrease of social investigation compared with undefeated mice (controls) when confronted with nonaggressive Swiss mice 24 h after the last aggressive confrontation. The selective D2 DA receptor antagonist (-)-sulpiride administered before confrontation with nonaggressive opponents (fourth day) dramatically decreased defensive behaviors and produced an increase of social investigation. The selective D1 DA receptor antagonist SCH 23390 did not affect either defence or social investigation. In further experiments the behavioral effects of the selective D1 agonist SKF 38393 and of the selective D2 agonist LY171555 on naive C57BL/6 mice interacting with nonaggressive opponents of the same strain were assessed. SKF 38393 in doses up to 30 mg/kg did not produce any significant behavioral changes while LY171555 produced a clear-cut dose-dependent increase of defensive behavior as well as a decrease of social investigation and activity and an increase of immobility. The behavioral profile produced by the D2 agonist did not differ from that produced by defeat experiences. These results indicate that D2 receptors play a major role in the expression of defensive behavior in the mouse. The hypothesis that alteration in D2 receptor functioning may produce hyperdefensiveness possibly due to altered perceptive processes is discussed.     

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.