Differences in one-way active avoidance learning in mice of three inbred strains

DBA/2J, C57BL/6J, and C3H/HeJ mice were given 10 one-way avoidance training trials per day, using an unconditioned stimulus intensity that provided equivalent motivation for learning to mice of all three strains, and were found to differ in their abilities to learn and retain the response. DBA/2J mice acquired the response in fewer days than did the mice of the other two strains, although C57BL/6J mice eventually reached a level of performance similar to that of DBA/2J mice. Both the rate of acquisition and the level at which avoidance performance stabilized were significantly lower in C3H/HeJ, than in DBA/2J or C57BL/6J, mice. In addition, DBA/2J mice showed a significantly greater task retention from one testing day to the next than did C57BL/6J or C3H/HeJ mice.This work was supported by National Institute on Drug Abuse Grants DA04195 and DA06192 to J.L.M. and Mental Health Grant MH-47680 to G.F.K.     

Ontogenetic differences in retention of spatial learning tested with Morris water maze

Two experiments examined retention of spatial learning in rats using a Morris water maze. Retention was scored in terms of probe trial performance when the platform was removed. Latency to reach the platform location, percent of time in the quadrant that had contained the platform, and relative frequency of visits to the platform location were analyzed. Results of the first experiment showed that preweanlings and juveniles exhibited substantial forgetting at 3- and 7-day retention intervals. Forgetting in adults was much lower than that found in the younger animals, and no differences in amount of forgetting appeared between the 3- and 7-day retention intervals at any age. The second experiment showed that forgetting in juveniles was alleviated by a single training trial administered just prior to the probe trial. These results are discussed in terms of ontogenetic differences in memory processing and measurement issues pertinent to the Morris water maze test procedure. © 1997 John Wiley & Sons, Inc. Dev Psychobiol 30: 329–341, 1997     

Inbred strain differences in morphine-induced analgesia with the hot plate assay: A reassessment

Using the hot plate assay of analgesia, several investigators have reported DBA/2J mice to be much more sensitive to morphine and other opioids than C57BL/6J mice using paw-lick as the behavioral end point. In the present studies, we compared DBA/2J, C57BL/6J, and C3H/HeJ mice on two behavioral end points, either (1) the initial response to the hot plate, either a hind paw-lift, paw-shake, or paw-lick, whichever occurred first, or (2) the paw-lick response. In response to either morphine or saline, all three strains showed roughly equivalent latencies to the initial response, but the DBA/2J strain was markedly slow to show paw-lick as a nocifensive response compared to the C57BL/6J strain. As a result, only for the paw-lick response were there significant differences among the three inbred strains in morphine analgesia. Thus, differences in analgesic sensitivity among these strains are largely a function of the behavioral end point used to assess nociception to the hot plate.This work was supported by PHS Grant DA02723, NIDA Contract 271-87-8120, and a grant from the Veterans Administration.     

Sensitivity of immunocompetent cells of DBA/2 and C57Bl/6 mice to cyclophosphamide

T cells were most sensitive to cyclophosphamide in DBA/2 mice, while in C57Bl/6 mice both T and B cells were sensitive. The formation of antibody-producing cells and the production of specific antibodies were delayed in DBA/2 mice immunized after pretreatment with antitumor drug. Accumulation of antibody-producing cells in the spleen was more active in immunized C57Bl/6 mice treated with cyclophosphamide compared to animals not treated with cyclophosphamide.     

Increase in Slow Afterhyperpolarization Led to Learning Delay in DBA mice

We showed that differences in learning capacity between DBA and C57Bl/6 mice correlates with differences in slow afterhyperpolarization amplitude in hippocampal CA1 pyramid neurons. In DBA mice learning capacity is lower, but the amplitude of slow afterhyperpolarizations higher than in C57Bl/6 mice. __________ Translated from Byulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 140, No. 9, pp. 253–256, September, 2005     

Sex differences in anxiety-like behavior and locomotor activity following chronic nicotine exposure in mice

Smoking appears to increase overall levels of stress, despite self-reports that men and women smoke to control symptoms of anxiety. The overall incidence of anxiety disorders is also significantly higher in women. This study examined whether behavioral sensitivity to chronic nicotine varies across sexes in mice. Male and female C57BL/6J mice were exposed chronically to nicotine in the drinking water (50, 100, or 200 microg/ml) and tested for locomotor activation and anxiety-like behavior in the elevated plus maze (EPM). Female mice were less sensitive to the locomotor activating effects of chronic nicotine. Whereas both males and females showed increases in locomotor activity at the highest (200 microg/ml) concentration of nicotine, only males showed locomotor activation at the middle (100 microg/ml) concentration. The decreased sensitivity in females could not be explained by reduced nicotine intake compared to males. In the EPM, nicotine produced an anxiogenic-like response in females, but had no effect in males. Treatment with the high (200 microg/ml) dose of nicotine reduced the amount of time spent in the open arms of the EPM in female, but not male mice. No differences in the anxiogenic-like response to chronic nicotine was observed between beta2-subunit knockout and wildtype mice, suggesting that beta2-subunit containing nicotinic receptors do not mediate the anxiogenic-like response to chronic nicotine in females. This shows that female mice have an anxiogenic-like response to chronic nicotine, but are less sensitive to nicotine's psychostimulant properties, which may be related to the increased relapse to smoking following abstinence in women.     

Ontogenetic differences in adolescent and adult C57BL/6J and DBA/2J mice: anxiety-like, locomotor, and consummatory behaviors

Adolescence is a highly conserved period during which mammals undergo a number of hormonal, biological, and behavioral changes [Spear [2000] Neurosci. Biobehav. Rev. 24: 417-463]. Ethical constraints limit the research that can be done in human adolescents. Rodents provide a useful model of at least some of the features of adolescence, including increases in body growth, differences in sleep/wake, and eating patterns, as well as differences in risk-taking, novelty seeking, and exploratory behaviors. Much of the available developmental research has utilized rats; however, the use of inbred mouse strains provides a unique means to assess the genetic factors involved in behavioral differences during adolescence. We assessed differences between adults and adolescents in anxiety-like, locomotor, and consummatory behaviors using two commonly used inbred strains of mice, the DBA/2J and C57BL/6J strains. Age and genotype-dependent differences were found in all three behaviors measured, suggesting both factors are important determinants of behavior in mice.     

Evaluation of a simple model of ethanol drinking to intoxication in C57BL/6J mice

Because of intrinsic differences between humans and mice, no single mouse model can represent all features of a complex human trait such as alcoholism. It is therefore necessary to develop partial models. One important feature is drinking to the point where blood ethanol concentration (BEC) reaches levels that have measurable affects on physiology and/or behavior (>1.0 mg ethanol/ml blood). Most models currently in use examine relative oral self-administration from a bottle containing alcohol versus one containing water (two-bottle preference drinking), or oral operant self-administration. In these procedures, it is not clear when or if the animals drink to pharmacologically significant levels because the drinking is episodic and often occurs over a 24-h period. The aim of this study was to identify the optimal parameters and evaluate the reliability of a very simple procedure, taking advantage of a mouse genotype (C57BL/6J) that is known to drink large quantities of ethanol. We exchanged for the water bottle a solution containing ethanol in tap water for a limited period, early in the dark cycle, in the home cage. Mice regularly drank sufficient ethanol to achieve BEC>1.0 mg ethanol/ml blood. The concentration of ethanol offered (10%, 20% or 30%) did not affect consumption in g ethanol/kg body weight. The highest average BEC ( approximately 1.6 mg/ml) occurred when the water-to-ethanol switch occurred 3 h into the dark cycle, and when the ethanol was offered for 4 rather than 2 h. Ethanol consumption was consistent within individual mice, and reliably predicted BEC after the period of ethanol access. C57BL/6J mice from three sources provided equivalent data, while DBA/2J mice drank much less than C57BL/6J in this test. We discuss advantages of the model for high-throughput screening assays where the goal is to find other genotypes of mice that drink excessively, or to screen drugs for their efficacy in blocking excessive drinking.     

Mouse strain differences in operant self-administration of ethanol

By the use of operant conditioning procedures, we determined whether mice from two strains, C57BL/6J and BALB/cJ, differ in ethanol-reinforced behavior. To establish ethanol as a reinforcer, drinking was induced by feeding mice prior to the 30-min experimental session. Initially mice received water and then a series of increasing ethanol concentrations (1, 2, 4, and 8%, w/v) in response to a lever press. The volume of liquid consumed per unit of body weight remained relatively constant across concentrations, and thus the amount of ethanol consumed (g/kg) increased with increases in ethanol concentration. At all concentrations the C57BL/6J mice drank larger volumes than the BALB/cJ mice. After shifting the time of feeding from before to after the session, the consumption of 8% ethanol declined 56% for the C57B/6J mice and 81% for the BALB/cJ mice. To determine if ethanol was serving as a reinforcer, behavior and intake were then compared during ethanol and water availability. The ethanol consumption of the C57BL/6J mice markedly exceeded the water consumption and resulted in blood ethanol levels of 199 ±27 mg/dl. These levels significantly exceeded the 8% ethanol intake of the BALB/cJ mice, while 0% intake was low and not significantly different between strains. The 8% ethanol drinking of the BALB/cJ mice did not differ from their water drinking. Thus, ethanol was established as a positive reinforcer for C57BL/6J mice but not for BALB/cJ mice.This research was supported in part by New Investigator Research Awards AA-06104 and AA-06924 to Frank R. George from the National Institute on Alcohol Abuse and Alcoholism and by Research Scientist Development Award DA-00007 to Richard A. Meisch from the National Institute on Drug Abuse.     

Defective Processing of Contextual Information May Be Involved in the Poor Performance of DBA/2 Mice in Spatial Tasks

These experiments examine the influence of context manipulations on radial maze performance in C57BL/6 (C57) and DBA/2 (DBA) mice. Animals from each strain were trained in two distinct contexts—poor cuing vs rich cuing—that were sucessively switched. The results first show that C57 performed better when trained under rich cuing conditions than under poor ones, whereas DBA performed poorly under both conditions. In addition, contextual manipulations were found to produce more drastic effects in C57 than in DBA mice. That is, C57 showed a strong performance decrement following each context shift, whereas DBA mice did not. In particular, the fact that DBA mice performed similarly under rich and poor cuing conditions and also reacted mildly—or did not react—to context shifts suggests a deficit in processing contextual information, which places important constraints on their capability to form spatial representations.     

Nest building in nulligravid,primigravid and primiparous C57BL/6J and DBA/2J mice (Mus musculus)

C57BL/6J (B6) and DBA/2J (D2) mice differ in maternal behavior and nest building, but previous observations on nest building appear to be contradictory. Lactating B6 females spent more time nest building than lactating D2 females [Physiol. Behav. 67 (1999) 599.]; however, pregnant D2 females have been reported to build better nests than pregnant B6 females [Physiol. Behav. 29 (1982) 153.]. To resolve this apparent discrepancy, virgin B6 and D2 females were mated, and the nest quality of nulligravid, primigravid and lactating primiparous females was compared between groups and with that of virgin females. There were no strain differences in the nest ratings of virgin or mated nulligravid females, nor did these groups differ within strains. Pregnant and lactating females of both strains built better nests than nonpregnant females. There was an increase in nest ratings in both strains on the day of parturition. The nest ratings of pregnant and lactating females were higher in B6 than D2 females. The largest strain differences were observed between pregnant B6 and D2 females. One hypothesis to account for these results is that females of these two strains differ in their levels of or sensitivity to hormones during pregnancy and parturition.     

Sweet and Bitter Taste of Ethanol in C57BL/6J and DBA2/J Mouse Strains

Studies of inbred strains of rats and mice have suggested a positive association between strain variations in sweet taste and ethanol intake. However, strain associations by themselves are insufficient to support a functional link between taste and ethanol intake. We used conditioned taste aversion (CTA) to explore the sweet and bitter taste of ethanol and ability to detect sucrose, quinine and ethanol in C57BL/6J (B6) and DBA/2J (D2) mouse strains that are frequently used in alcohol research. The present study showed that C57BL/6J mice generalized taste aversions from sucrose and quinine solutions to 10% ethanol and, reciprocally, aversions to 10% ethanol generalized to each of these solutions presented separately. Only conditioned aversions to quinine generalized to ethanol in the DBA/2J strain but an aversion conditioned to ethanol did not generalize reciprocally to quinine. Thus, considering these two gustatory qualities, 10% ethanol tastes both sweet and bitter to B6 mice but only bitter to D2. Both strains were able to generalize taste aversions across different concentrations of the same compound. B6 were able to detect lower concentrations of quinine than D2 but both strains were able to detect sucrose and (in contrast to previous findings) ethanol at similar concentrations. The strain-dependent gustatory profiles for ethanol may make an important contribution to the understanding of the undoubtedly complex mechanisms influencing high ethanol preference of B6 and pronounced ethanol avoidance of D2 mice.     

Intracranial self-stimulation facilitates a spatial learning and memory task in the Morris water maze

Learning and memory improvement by post-training intracranial self-stimulation has been observed mostly in implicit tasks, such as active avoidance, which are acquired with multiple trials and originate rigid behavioral responses, in rats. Here we wanted to know whether post-training self-stimulation is also able to facilitate a spatial task which requires a flexible behavioral response in the Morris water maze. Three experiments were run with Wistar rats. In each of them subjects were given at least five acquisition sessions, one daily, consisting of 2-min trials. Starting from a random variable position, rats had to swim in a pool until they located a hidden platform with a cue located on its opposite site. Each daily session was followed by an immediate treatment of intracranial self-stimulation. Control subjects did not receive the self-stimulation treatment but were instead placed in the self-stimulation box for 45 min after each training session. In the three successive experiments, independent groups of rats were given five, three and one trial per session, respectively. Temporal latencies and trajectories to locate the platform were measured for each subject. Three days after the last acquisition session, the animals were placed again in the pool for 60 s but without the platform and the time spent in each quadrant and the swim trajectories were registered for each subject. A strong and consistent improvement of performance was observed in the self-stimulated rats when they were given only one trial per session, i.e. when learning was more difficult. These findings agree with our previous data showing the capacity of post-training self-stimulation to improve memory especially in rats with little training or low conditioning levels, and clearly prove that post-training self-stimulation can also improve spatial learning and memory.     

The effects of cold,rotation, and genotype on the production of ultrasonic calls in infant mice

There has been a revival of interest recently in the ultrasonic calls of infant rodents as investigators are using them to assess neurobehavioral development and animal models of anxiety. We compared the rates of ultrasonic calling of infant mice of two genotypes in two situations, cold and rotation. The subjects of study were 169 mouse pups from 29 litters and of two F₁ genotypes, C57BL/10J × DBA/2J and C57BL/10J × SJL/J. Half of each litter was recorded in a cool situation for 20 seconds and the other half was recorded while rotating at 10 rpm for 20 seconds. All pups were recorded on days of age 2 to 8. Rotation elicited calling at about twice the rate as cool temperature on each day of age and on average across days; situation (cold or rotation) accounted for over 50% of the variation between litters. Genotype also altered call rate, and on some days situation and genotype interacted. In studies of neurobehavioral development and the effects of pharmacological agents on infant mice, it is particularly important to understand the roles of the stimuli and genotypes employed.     

KA诱发癫痫反复发作损伤大鼠空间学习记忆及中脑多巴胺能神经元

目的探讨颞叶癫痫反复发作(Spontaneous recurrent se izure,SRS)对大鼠空间学习记忆影响及中脑内多巴胺能神经元变化。方法以红藻氨酸(kain ic ac id,KA)制备颞叶癫痫大鼠模型,以是否出现SRS为标准将KA大鼠分为伴有反复发作和不伴有反复发作组,盐水为对照组。分别进行水迷宫行为测试,评价其学习记忆能力;并用酪氨酸羟化酶(Tyrosine hydroxylase,TH)免疫组化方法来观察各组大鼠中脑内多巴胺能神经元变化。结果KA处理后,按照Rac ine描述标准,KA组动物发作全部达到4~5级。KA后3周大鼠19只出现SRS,16只未见SRS;Morris水迷宫发现,在5 d的空间学习记忆测试中,反复发作KA大鼠的寻找潜伏期明显长于不伴有SRS的KA大鼠和盐水对照组(P<0.01),而不伴有SRS组与盐水对照组没有明显差别;伴有SRS的KA组大鼠总共穿过平台次数显著少于不伴有SRS的KA组大鼠和盐水对照组(P<0.01)。TH免疫组织化学结果发现与不伴有SRS的KA大鼠和盐水对照组比较,伴有SRS的KA大鼠在腹侧被盖的多巴胺能神经元大量脱失(P<0.01)。结论KA大鼠癫痫反复发作可能与空间学习记忆障碍和在腹侧被盖多巴胺能神经元大量脱失相关。     

Single-locus control of saccharin intake in BXD/Ty recombinant inbred (RI) mice: Some methodological implications for RI strain analysis

Thesac locus, with a major effect on saccharin preference, was discovered by Fuller (1974) in C57BL/6J (B6), DBA/2J (D2), and derived crosses, and is now supported in the BXD/Ty recombinant inbred (RI) series by a marked bimodal distribution in saccharin preference among 20 strains. The B6 allele led to increased saccharin preference compared to the D2 allele. Since the search for bimodal distributions reflecting major gene loci is an essential part of RI strain analysis, a new statistical method is proposed to test for bimodality, and comparisons are made to previously proposed methods. Another new RI method, quantitative trait loci (QTL) analysis, allows provisional detection and mapping of minor as well as major gene loci. Using this method as a screen, significant associations with saccharin preference were suggested with marker loci on portions of six chromosomes. One of these, theD12nyu1 locus on chromosome 12, was independently supported in a panel of standard (non-RI) inbred strains also tested for saccharin preference. It is unclear whether this reflects thesac locus.This work was supported by NIDA Contracts 271-87-8120 and 271-90-7405, PHS Grants DA05228, AA08621, and AA08125, and two grants from the Department of Veterans Affairs.     

The contribution of endogenous opioids to food reward is dependent on sex and background strain

Complex behaviors such as those associated with reward to unconditioned positive reinforcers are polygenic processes. In studies using genetically modified mice specific for the endogenous opioid systems an observed phenotype in a complex behavior is likely to be dependent on interacting genes which, in inbred mouse lines, influence that phenotype. To address this issue we examined operant responding for palatable food reinforcers in mice lacking the expression of beta-endorphin, enkephalin or both peptides congenic to two different genetic backgrounds; C57BL/6J and DBA/2J. These two inbred strains were chosen because their endogenous opioid states differ and they respond differently to exogenous opioids in many behavioral assays. We found that wildtype and mutant C57BL/6J mice acquired operant responding for food reinforcers faster than DBA/2J mice, regardless of their opioid genotype. Although wildtype DBA/2J mice had a significant deficit in acquisition of bar-pressing behavior to reach a pre-established performance criterion, no subsequent deficit was observed under two different schedules of reinforcement. Additionally, we found that mice lacking enkephalin had decreased motivation to bar press for palatable food reinforcers under a progressive ratio regardless of sex or background strain. In contrast, the only subset of beta-endorphin-deficient mice that had decreased motivation to bar press under a progressive ratio was males on the C57BL/6J background. Of the two classical endogenous opioid peptides with preferential activation of the mu opioid receptor, the knockout models would suggest that enkephalins play a more consistent role than beta-endorphin in mediating the motivation for food reward when tested under a progressive ratio.     

MPTP对小鼠空间学习记忆和脑内强啡肽免疫反应的影响

为了观察1 -甲基- 4 -苯基- 1, 2, 3, 6 四氢吡啶(MPTP)对C57BL/6小鼠空间学习记忆能力和脑内强啡肽(DYN)表达强度的影响,本研究给予小鼠皮下注射MPTP20mg/kg,连续8d,制备Parkinson病(PD)模型。与对照组相比,MPTP处理小鼠爬竿(P<0. 01)和游泳(P<0. 01)分数明显降低。Morris水迷宫实验结果显示:MPTP处理小鼠寻找平台潜伏期明显延长(P<0.01),在目标及对侧象限游泳时间所占百分比分别明显降低(P<0. 01)和增加(P<0. 01)。免疫细胞化学结果表明中脑黑质致密部的酪氨酸羟化酶(TH)免疫阳性神经元数目明显减少(P<0. 01)。同时在前额叶皮层(P<0. 01 )、背侧海马的CA1区(P<0. 05)和齿状回苔状纤维通路(P<0. 05)、背侧尾核(P<0. 01)的DYN免疫反应活性明显增强。本实验结果表明:用MPTP处理诱发的PD小鼠模型伴有空间学习和记忆能力的下降;并提示前额叶皮层、背侧海马的CA1区、齿状回苔状纤维通路和背侧尾核内DYN表达的增多可能与MPTP小鼠空间学习和记忆能力下降有关。     

Differential effect of hyperglycaemia on the immune response in an experimental model of diabetes in BALB/cByJ and C57Bl/6J mice: participation of oxidative stress

Diabetes is associated with an increased risk of death from infectious disease. Hyperglycaemia has been identified as the main factor contributing to the development of diseases associated with diabetes mellitus. However, experimental evidence indicates individual susceptibility to develop complications of diabetes. In this context, the aim of this work was to study the immune response in a streptozotocin‐induced type 1 diabetes in two mouse strains: BALB/cByJ and C57Bl/6J. The participation of hyperglycaemia and oxidative stress was also analysed. Diabetic BALB/cByJ mice showed a decrease in both the in‐vivo and in‐vitro immune responses, whereas diabetic C57Bl/6J mice had higher blood glucose but exhibited no impairment of the immune response. The influence of hyperglycaemia over the immune response was evaluated by preincubation of lymphocytes from normal mice in a high glucose‐containing medium. T and B cells from BALB/cByJ mice showed a decrease in cell viability and mitogen‐stimulated proliferation and an increase in apoptosis induction. An increase in oxidative stress was implicated in this deleterious effect. These parameters were not affected in the T and B lymphocytes from C57Bl/6J mice. In conclusion, BALB/cByJ mice were sensitive to the deleterious effect of hyperglycaemia, while C57BL/6J were resistant. Although an extrapolation of these results to clinical conditions must be handled with caution, these results highlight the need to contemplate the genetic background to establish models to study the deleterious effect of diabetes in order to understand phenotypical variations that are of clinical importance in the treatment of patients.