Genetic strain differences in platelet aggregation of laboratory mice

To investigate the physiological role of novel genes and proteins in platelet activation, various knockout mice have been produced. A number of standard inbred mouse strains each possessing genetically unique characters such as high tumor generation, hyperglycemia or hyperlipidemia, have been bred. In breeding knockout mice for investigation of specific physiological functions, appropriate selection of parental or backcross strains is necessary. Thus, examination of strain-specific platelet characteristics is important. In the present study, platelet aggregation responses of 13 laboratory mouse strains, 129/Sv, A, AKR, BALB/c, C3H/He, C57BL/6J, CBA, DBA/1, DBA/2, ddY, FVB, ICR, and NZW, and the diabetic strain C57BL/KsJ db/db, were compared. Marked strain differences were observed in ADP- and collagen-induced platelet aggregation. The highest responses with both were seen in AKR/J and NZW/N, whereas the lowest were seen in DBA/2 and DBA/1. There was a 5-fold difference in the platelet aggregation threshold index (PATI) for ADP-induced PRP aggregation between AKR/J (0.6 microM) and DBA/2 (3.0 microM). With whole blood aggregation, the highest response was seen in AKR, whereas the lowest was seen in DBA/2 and DBA/1. The present study demonstrated that there is considerable strain difference in platelet aggregation among laboratory mice, which should be taken into account in backcrossing knockout strains.     

Genetic variance contributes to naltrexone-induced inhibition of sucrose intake in inbred and outbred mouse strains

The study of genetic variance in opioid receptor antagonism of sucrose and other forms of sweet intake has been limited to reductions in sweet intake in mice that are opioid receptor-deficient or lacking either pre-pro-enkephalin or beta-endorphin. Marked genetic variance in inbred mouse strains has been observed for sucrose intake across a wide array of concentrations in terms of sensitivity, magnitude, percentages of kilocalories consumed as sucrose and compensatory chow intake. The present study examined potential genetic variance in systemic naltrexone's dose-dependent (0.01-5 mg/kg) and time-dependent (5-120 min) ability to decrease sucrose (10%) intake in eleven inbred (A/J, AKR/J, BALB/cJ, CBA/J, C3H/HeJ, C57BL/6J, C57BL/10J, DBA/2J, SJL/J, SWR/J, 129P3/J) and one outbred (CD-1) mouse strains. A minimum criterion sucrose intake (1 ml) under vehicle treatment, designed to avoid "floor effects" of antagonist treatment was not achieved in three (A/J, AKR/J, CBA/J) inbred mouse strains. Marked genetic variance in naltrexone's ability to inhibit sucrose intake was observed in the remaining strains with the greatest sensitivity observed in the C57BL/10J and C57BL/6J strains, intermediate sensitivity in BALB/cJ, C3H/HeJ, CD-1 and DBA/2J mice, and the least sensitivity in 129P3/J, SWR/J and SJL/J strains with a 7.5-36.5 fold range of greater effects in the ID(50) of naltrexone-induced inhibition in C57BL/10J relative to the three less-sensitive strains across the time course. Naltrexone primarily affected the maintenance, rather than the initiation of intake in BALB/cJ, CD-1, C3H/HeJ, DBA/2J and SJL/J mice, but significantly reduced sucrose intake at higher doses across the time course in C57BL/6J, C57BL/10J and 129P3/J mice. Whereas SWR/J mice failed to display any significant reduction in sucrose intake at any time point following any of the naltrexone doses, naltrexone's maximal magnitude of inhibitory effects was small (35-40%) in 129P3/J and SJL/J mice, moderate ( approximately 50%) in BALB/cJ, C3H/HeJ, CD-1 and DBA2/J mice, and profound (70-80%) in C57BL/6J and C57BL/10J mice. Indeed, the latter two strains displayed significantly greater percentages of naltrexone-induced inhibition of sucrose intake than virtually all other strains. These data indicate the importance of genetic variability in opioid modulation of sucrose intake.     

In vivo and in vitro glycogenic effects of methionine sulfoximine are different in two inbred strains of mice

We investigated the relationship between brain glycogen anabolism and methionine sulfoximine (MSO)-induced seizures in two inbred mouse strains that presented differential susceptibility to the convulsant. CBA/J was considered a MSO-high-reactive strain and C57BL/6J a MSO-low-reactive strain. Accordingly, the dose of MSO needed to induce seizures in CBA/J mice is lower than that in C57BL/6J mice, and CBA/J mice which had seizures, died during the first convulsion. In addition, the time--course of the MSO effect is faster in CBA/J mice than that in C57BL/6J mice. Analyses were performed in C57BL/6J and CBA/J mice after administration of 75 (subconvulsive dose) and 40 mg/kg of MSO (subconvulsive dose, not lethal dose), respectively. In the preconvulsive period, MSO induced an increase in the brain glycogen content of C57BL/6J mice only. Twenty-four hours after MSO administration, the brain glycogen content increased in both strains. The activity and expression of fructose-1,6-bisphosphatase, the last key enzyme of the gluconeogenic pathway, were increased in MSO-treated C57BL/6J mice as compared to control mice, at all experimental time points, whereas they were increased in CBA/J mice only 24 h after MSO administration. These latter results correspond to CBA/J mice that did not have seizures. Interestingly, the differences observed in vivo were consistent with results in primary cultured astrocytes from the two strains. This data suggests that the metabolism impairment, which was not a consequence of seizures, could be related to the difference in seizure susceptibility between the two strains, depending on their genetic background.     

Correlations between behaviours in the elevated plus-maze and sensitivity to unpredictable subchronic mild stress: evidence from inbred strains of mice

This study aimed at investigating the relationship between anxiety-like and depressive-like behaviour in mice. Therefore, we assessed the behaviour of mice from eight different strains (FVB/NA, BALB/c, C57BL/6, DBA/2, 129/Sv, C3H/He, CBA and BA) confronted first to anxiety models (the elevated plus-maze and the free exploratory test) and then to tests of depressive-like behaviours (forced swim test and unpredictable subchronic mild stress). In the forced swim test, mice from the DBA/2, the BA and the C3H/He strains displayed higher immobility than mice from the 129/Sv, the BALB/c, the C57BL/6 and the CBA strains. In the subchronic mild stress, mice from the C57BL/6 and the CBA strains displayed low sensitivity when compared with mice from all the others strains. A stepwise multiple regression analysis suggests that behaviour in the elevated plus-maze is associated with the time of immobility in the forced swim test (20%) and with the susceptibility to the unpredictable subchronic stress procedure (31%). The behaviour in the free exploratory paradigm is slightly associated with behaviours in the two tests of depression. These results suggest that anxiety may be a factor contributing, among others, to the susceptibility to depressive-like behaviours.     

Immunochemical studies of brain glutamate decarboxylase and GABA-transaminase of six inbred strains of mice

Six different inbred strains of mice (C57BL/6J, CBA/CaJ, CE/J, DBA/2J, LP/J and RF/J) were compared in terms of specific activities and immunochemical properties of brain L-glutamate decarboxylase (GAD) and gamma-aminobutyrate transaminase (GABA-T), the enzymes responsible for the synthesis and degradation of GABA, respectively. GAD from the brains of the different strains was indistinguishable on the basis of specific activities, double diffusion tests, immunoelectrophoresis and inhibition by antibody. However, microcomplement fixation tests showed GAD from DBA and C57BL mice to be most distinctly different from GAD extracted from the Swiss mouse, from which the original antigen was prepared and that the enzyme from the CE, LP and RF also differed. Similar fixation curves were obtained for the GAD from CBA and Swiss mice. GABA-T from the different strains was indistinguishable on the basis of all the tests employed.     

Comparison of seizure phenotype and neurodegeneration induced by systemic kainic acid in inbred, outbred, and hybrid mouse strains

We assessed inbred, outbred and hybrid mouse strains for susceptibility to seizures and neurodegeneration induced by systemic administration of kainic acid (KA). Each strain showed a unique pattern of susceptibility to seizures as assessed by the dose necessary to induce continuous tonic clonic seizures, progression through six seizure levels, the number of mice that failed to satisfy seizure criteria, and seizure-induced mortality. In general, the C57BL/6, ICR, FVB/N, and BALB/c strains were resistant to seizures while the C57BL/10, DBA/2 J, and F1 C57BL/6*CBA/J strains were vulnerable. Neuronal cell death was quantified in four subfields of the hippocampus: CA3, the hilus of the dentate gyrus, CA1, and the dentate granule cell layer. Neurodegeneration was also semiquantitatively assessed in other brain regions including the neocortex, striatum, thalamus, hypothalamus and amygdala. Although there was variability in the extent of cell death within strains, there were significant differences in the amount of hippocampal cell death between strains and also different patterns of neurodegeneration in affected brain areas. In general, the C57BL/6, C57BL/10, and F1 C57BL/6*CBA/J strains were resistant to neurodegeneration while the FVB/N, ICR and DBA/2 J strains were vulnerable. The BALB/c strain was unique in that neurodegeneration was confined to the hippocampus. Consistent with previous findings, the resistant neurodegeneration phenotype was dominant in an F1 cross of resistant and vulnerable inbred strains. Our results, using a large number of mouse strains, definitively demonstrate that a mouse strain's seizure phenotype is not related to its neurodegeneration phenotype.     

Strain differences in sucrose preference and in the consequences of unpredictable chronic mild stress

Effects of unpredictable chronic mild stress (UCMS) on anhedonic-like behaviour, physical state, body weight, learning and memory were investigated in three strains of mice. These strains were chosen among 11 strains that were tested in a first experiment for their sucrose consumption and preference for sucrose solutions of different concentrations. In the second experiment, groups of mice of the CBA/H, C57BL/6 and DBA/2 strains were submitted to 7 weeks of UCMS. Measures of the sucrose consumption, the evaluation of the physical state and the measurement of body weight were weekly assessed. Following 4-week period of UCMS, sub-groups of stressed and non-stressed mice were submitted to the spontaneous alternation test in the Y-maze, and then to the water-maze test for spatial learning and memory. UCMS induced a significant decrease of the sucrose consumption in CBA/H and in C57BL/6 but not in DBA/2 mice. The UCMS effect on sucrose intake in CBA/H mice was associated with a body weight loss and a physical state degradation. Spatial learning in a water maze was not disturbed by UCMS, however, a long-term memory impairment was observed in CBA/H stressed mice during a probe test. In the Y-maze, UCMS did not modify spontaneous alternation. These results show both an anhedonic-like and an amnesic effect of UCMS in CBA/H mice. They also reveal a difference of sensitivity to UCMS according to the strain of mice.     

Multifaceted strain-specific effects in a mouse model of depression and of antidepressant reversal

Etiopathogenesis of depression and the cause of insensitivity to treatment remain poorly understood, although genetic makeup has been established as a contributing factor. The isogenicity of inbred mouse strains provides a useful tool for investigating the link between genes and behavior or drug response. Hence, our aim was to identify inbred mouse strains (among A/J, BALB/c, C3H, C57BL/6, CBA, DBA and FVB) sensitive to a 9-week period of unpredictable chronic mild stress (UCMS) and, from the fifth week onward, to the reversal effect of an antidepressant (AD) (imipramine, 20 mg/kg/day i.p.) on various depression-related changes: physical, behavioral and neuroendocrine states. UCMS induced a significant deterioration of the coat state (in all the strains), blunted emotional reactivity in the novelty-suppressed feeding (NSF) test (A/J, BALB/c, C57BL/6), and changes in the level of fecal corticosterone metabolites (BALB/c, C57BL/6, DBA, FVB). Imipramine treatment reversed the UCMS-induced alterations of the coat state (BALB/c, DBA), in the NSF test (A/J, BALB/c, C57BL/6) and in fecal corticosterone metabolites (BALB/c, C57BL/6). C3H, CBA and FVB mice were irresponsive to imipramine treatment. It is noteworthy that UCMS-induced physical or behavioral changes occurred without hypothalamo–pituitary–adrenal (HPA) axis alterations in some strains (A/J, C3H, CBA), although the AD-induced reversal of these changes in BALB/c and C57BL/6 was associated with HPA axis normalization. Finally, UCMS is shown to discriminate various alterations and to replicate in a strain-dependent manner diverse profiles reminiscent of human disease subtypes. UCMS may thus enable the selection of strains suitable for investigating specific depression-related features and could be an appropriate model for identifying genetic factors associated with increased vulnerability, specific symptoms of affective disorders, and AD resistance.     

Strain-dependent behavioral alterations induced by peripheral interleukin-1 challenge in neonatal mice

Interleukin-1 (IL-1) is implicated in the pathogenesis of various psychiatric diseases. Peripheral administration of IL-1alpha to neonatal rats induces cognitive and behavioral abnormalities and, therefore, the IL-1alpha-treated animals might serve as a schizophrenia model. The present study assessed genetic influences on IL-1alpha-triggered behavioral impairments, using four different strains of neonatal mice, C3H/He, DBA/2, C57BL/6, and ddY. Neonatal treatments with IL-1alpha differentially altered adult behavioral/cognitive traits in a strain-dependent manner. IL-1alpha treatment decreased prepulse inhibition in DBA/2 and C57BL/6 mice but not in C3H/He and ddY. The treatment increased locomotor activity and startle responses in DBA/2 mice and, conversely, decreased startle responses in C3H/He mice. Behavioral alterations were most remarkable in DBA/2 mice but undetectable in ddY mice. The magnitudes of IL-1alpha actions differed between the brain and periphery and were influenced by mouse genetic background. The IL-1-triggered acute signaling, Ikappa-B degradation, was significant in the frontal cortex of DBA/2 mice and in the hypothalamus of C3H/He mice. An increase in brain p38 MAP kinase phosphorylation was also most marked in the DBA/2 strain. In contrast, subchronic influences of IL-1alpha injections failed to illustrate the strain-dependent behavioral alterations. The peripheral effects of IL-1alpha did not match the strain-dependency of the behavioral alterations, either. Acceleration of tooth eruption and eyelid opening as well as attenuation of weight gain was most marked in C3H/He mice and the induction of serum amyloid protein was the largest in ddY mice. Thus, the peripheral effects of IL-1alpha in DBA/2 mice were relatively inferior to those in the other strains. The present animal study suggests that, in early postnatal development, circulating IL-1alpha trigger brain cytokine signaling and produce distinct influences on later neurobehavioral traits, both depending on genetic background.     

Mouse strain variation in maximal electroshock seizure threshold

Maximal electroshock seizure threshold (MEST) is a classical measure of seizure sensitivity with a wide range of experimental applications. We determined MEST in nine inbred mouse strains and one congenic strain using a procedure in which mice are given one shock per day with an incremental (1 mA) current increase in each successive trial until a maximal seizure (tonic hindlimb extension) is elicited. C57BL/6J and DBA/2J mice exhibited the highest and lowest MEST, respectively, with the values of other strains falling between these two extremes. The relative rank order of MEST values by inbred strain (highest to lowest) is as follows: C57BL/6J > CBA/J = C3H/HeJ > A/J > Balb/cJ = 129/SvIMJ = 129/SvJ > AKR/J > DBA/2J. Results of experiments involving a single electroconvulsive shock given to separate groups of mice at different current intensities suggest that determination of MEST by the method used is not affected by repeated sub-maximal seizures. Overall, results document a distinctive mouse strain distribution pattern for MEST. Additionally, low within strain variability suggests that environmental factors which affect quantification of MEST are readily controlled under the conditions of this study. We conclude that MEST represents a useful tool for dissecting the multifactorial nature of seizure sensitivity in mice.     

Mouse behavioral tasks relevant to autism: phenotypes of 10 inbred strains

Three defining clinical symptoms of autism are aberrant reciprocal social interactions, deficits in social communication, and repetitive behaviors, including motor stereotypies and insistence on sameness. We developed a set of behavioral tasks designed to model components of these core symptoms in mice. Male mice from 10 inbred strains were characterized in assays for sociability, preference for social novelty, and reversal of the spatial location of the reinforcer in T-maze and Morris water maze tasks. Six strains, C57BL/6J, C57L/J, DBA/2J, FVB/NJ, C3H/HeJ, and AKR/J, showed significant levels of sociability, while A/J, BALB/cByJ, BTBR T(+)tf/J, and 129S1/SvImJ mice did not. C57BL/6J, C57L/J, DBA/2J, FVB/NJ, BALB/cByJ, and BTBR T(+)tf/J showed significant preference for social novelty, while C3H/HeJ, AKR/J, A/J, and 129S1/SvImJ did not. Normal scores on relevant control measures confirmed general health and physical abilities in all strains, ruling out artifactual explanations for social deficits. Elevated plus maze scores confirmed high anxiety-like behaviors in A/J, BALB/cByJ, and 129S1/SvImJ, which could underlie components of their low social approach. Strains that showed high levels of performance on acquisition of a T-maze task were also able to reach criterion for reversal learning. On the Morris water maze task, DBA/2J, AKR/J, BTBR T(+)tf/J, and 129S1/SvImJ failed to show significant quadrant preference during the reversal probe trial. These results highlight a dissociation between social task performance and reversal learning. BTBR T(+)tf/J is a particularly interesting strain, displaying both low social approach and resistance to change in routine on the water maze, consistent with an autism-like phenotype. Our multitask strategy for modeling symptoms of autism will be useful for investigating targeted and random gene mutations, QTLs, and microarray analyses.     

Genotypic influences on striatal dopaminergic regulation in mice

Genotypic influences on dopaminergic-induced behaviors and striatal dopaminergic receptors were evaluated in CBA/J, C57BL/6J and BALB/cJ male mice. CBA/J mice were less behaviorally sensitive to apomorphine (stereotypic behavior), but more sensitive to haloperidol (catalepsy) than C57BL/6J and BALB/cJ mice. Striatal dopaminergic receptors, assayed by binding of [³H]spiroperidol (antagonist) and [³H]ADTN (agonist), were 50% fewer in CBA/J compared to BALB/cJ mice; C57BL/6J mice had low to intermediate numbers of receptors.

Striatal dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations were similar in all strains. However, a 20% higher DOPAC/dopamine ratio in CBA/J mice suggests greater dopamine turnover. Median eminence dopamine was similar in all strains, but norepinephrine was 30% higher in BALB/cJ mice.

CBA/J mice failed to show antagonist-induced supersensitivity-type responses to chronic haloperidol treatment: enhanced stereotypic response to apomorphine and a 30% increase of dopaminergic receptors occurred in C57BL/6J and BALB/cJ mice, but not in CBA/J mice. These data suggest that CBA/J mice either cannot respond to chronic haloperidol treatment or have an elevated threshold for induction of supersensitivity response.

Chronic treatment with the dopamine agonist bromocriptine (7d) depressed apomorphine-induced stereotypic behavior in C57BL/6J mice and eliminated stereotypy in BALB/cJ mice, but caused no change in stereotypic behavior in CBA/J mice. Dopaminergic receptors were 15% lower after bromocriptine treatment in all strains.

These results suggest that some striatal dopaminergic functions are impaired in CBA/J mice relative to BALB/cJ and C57BL/6J mice. The impaired haloperidol-induced supersensitivity responses in the CBA/J mouse may be a useful model for analyzing similar impairments of supersensitivity responses in old rodents.     

N(2)O stimulates NOS enzyme activity in C57BL/6 but not DBA/2 mice

Exposure to 70% N(2)O produces a prominent antinociception in C57BL/6 mice but not DBA/2 mice. N(2)O exposure also increases conversion of [14C]L-arginine to [14C]L-citrulline in homogenates prepared from whole brains of C57BL/6 mice; there was no such increase in NOS activity in the DBA/2 whole brain. A differential N(2)O effect on brain NOS in these inbred strains might explain why the C57BL/6 but not DBA/2 mice are responsive to N(2)O antinociception.     

Mouse strain differences in locomotor,sensitisation and rewarding effect of heroin; association with alterations in MOP‐r activation and dopamine transporter binding

There is growing agreement that genetic factors play an important role in the risk to develop heroin addiction, and comparisons of heroin addiction vulnerability in inbred strains of mice could provide useful information on the question of individual vulnerability to heroin addiction. This study examined the rewarding and locomotor‐stimulating effects of heroin in male C57BL/6J and DBA/2J mice. Heroin induced locomotion and sensitisation in C57BL/6J but not in DBA/2J mice. C57BL/6J mice developed conditioned place preference (CPP) to the highest doses of heroin, while DBA/2J showed CPP to only the lowest heroin doses, indicating a higher sensitivity of DBA/2J mice to the rewarding properties of heroin vs C57BL/6J mice. In order to investigate the neurobiological substrate underlying some of these differences, the effect of chronic ‘intermittent’ escalating dose heroin administration on the opioid, dopaminergic and stress systems was explored. Twofold higher μ‐opioid receptor (MOP‐r)‐stimulated [³⁵S]GTPγS binding was observed in the nucleus accumbens and caudate of saline‐treated C57BL/6J mice compared with DBA/2J. Heroin decreased MOP‐r density in brain regions of C57BL/6J mice, but not in DBA/2J. A higher density of dopamine transporters (DAT) was observed in nucleus accumbens shell and caudate of heroin‐treated DBA/2J mice compared with heroin‐treated C57BL/6J. There were no effects on D₁ and D₂ binding. Chronic heroin administration decreased corticosterone levels in both strains with no effect of strain. These results suggest that genetic differences in MOP‐r activation and DAT expression may be responsible for individual differences in vulnerability to heroin addiction.     

Social approach-avoidance behavior of inbred mouse strains towards DBA/2 mice

Little is known about the genetics of social approach-avoidance behaviors. We measured social approach-avoidance of prepubescent female C57BL/6J, DBA/2J, FVB/NJ, AKR/J, A/J, and BALB/cJ mice towards prepubescent DBA/2J female mice. C57BL/6J mice showed the greatest predominance of approach, while BALB/cJ mice showed the greatest predominance of avoidance. Thus, this phenotype is affected by spontaneous genetic variation in mice and can be measured in an assay useful for future neurogenetic studies.     

Mouse brain IgG-like immunoreactivity: strain-specific occurrence in microglia and biochemical identification of IgG

Unlike the brains of most mammals, the mouse brain appears unique in the massive appearance of cells showing IgG-like immunoreactivity, which has repeatedly been shown via immunohistochemistry. In the present study, we first examined possible species differences in IgG-like immunohistochemical staining in the brains of various rodents, including mice. In four of six mouse strains examined (ICR, Balb/c, C57BL/6, and AKR/J), antibodies against mouse IgG revealed positive staining in many brain microglia. However, no such positive staining was detected in brains of the rat, hamster, guinea pig, or two other mouse strains (CBA/N and CBA/J). We purified IgG-like-immunoreactive molecule(s) biochemically from brain of the ICR mouse as a representative mouse strain. Our amino-acid-sequence analysis proved that the purified protein was identical to serum IgG. The possibility of IgG synthesis by brain microglia in the ICR mouse was denied by our RT-PCR experiments and in situ hybridization histochemistry. In addition, Fcgamma-receptor-deficient double-knockout mice of the C57BL/6 genetic background contained no IgG-immunoreactive microglia in the brain. These results clearly indicate that microglial IgG staining is due to the uptake of serum IgG through Fcgamma receptors. However, the strain-specific mechanisms resulting in microglial IgG uptake remain to be elucidated, in that Fcgamma receptors are omnipresent in microglia of all rodents examined here.     

Inbred mouse strain differences in the establishment of long-term fear memory

Studies describing variations in fear-related memory in inbred mouse strains typically focus upon 24 h retention. As a consequence, little is known about strain differences in the establishment of longer lasting memories of aversive events. In the present study, male mice from the strains A/Ibg, AKR/J, BALB/cByJ, CBA/J, C3H/HeIbg, C57BL/6J, DBA/2J, LP/J, SJL/J and 129/SvevTac were tested 24 h, 14, or 60 days after contextual and auditory-cued fear conditioning. Consistent with previous data, 24 h after conditioning these strains exhibited substantial variation in levels of memory for the context and the auditory cue as measured by freezing scores. Sixty days after training, most strains exhibited some forgetting of the context and auditory cue, and again there was significant strain variation. Strain rankings at 60-day retention were similar to that at 24 h with a significant genetic correlation between freezing values for the two time periods. Fourteen days following training, nearly all strains exhibited generalized freezing, a behavioral phenotype originally observed in C57BL/6 but not DBA/2 mice. These data confirm that cognitive differences exist between several popular inbred mouse strains during 24 h contextual fear recall. In addition, they extend these differences into retention time frames longer than those typically used and reveal several unique learning profiles of mouse strains that may be useful in furthering our understanding of how memories are formed. Emotionally arousing situations are often recalled a great deal of time after an event. Therefore, a more complete picture of the biochemical and genetic underpinnings of learning and memory will benefit from studies using time points that assess time points beyond 24 h retention. The utility of the 14-day hyper responsiveness phenotype as a potential model for fear-related psychopathology is also discussed.     

FOS and FOSB expression in the medial preoptic nucleus pars compacta of maternally active C57BL/6J and DBA/2J mice

C57BL/6J and DBA/2J inbred mice differ in aspects of maternal behavior and in the morphology of the medial preoptic nucleus (MPO), suggesting a possible association. DBA/2J mice have a compact subnucleus in the MPO, the MPOpc, that is sexually dimorphic and absent in C57BL/6J mice. To determine whether MPOpc cells are activated by maternal behavior, FOS and FOSB immunohistochemistry was performed on brain sections of C57BL/6J and DBA/2J mothers following the return of their pups after a separation of 2 days. In both light and dark phases of the daily cycle, stimulation of DBA/2J mothers evoked an increase in FOS- and FOSB-immunoreactivity in the MPOpc. Stimulated C57BL/6J mice, which lack the MPOpc, did not show an increase in cellular activity in the corresponding MPO region. Cells immediately lateral to the MPOpc were activated by pup stimulation, in both strains. These results suggest that MPOpc cells are active during maternal behavior, and that strain differences in maternal behavior are related to anatomical differences in the MPO.     

Genotypic variation in striatal calmodulin content

CBA/J and BALB/cJ mice have quantitative differences in the nigrostriatal projection. The number of nigral tyrosine hydroxylase reactive neurons, nigral and striatal tyrosine hydroxylase activity and the density of striatal D-2 dopamine receptors are all less in the CBA/J compared to the BALB/cJ mouse. An unrelated strain, the C57BL/6J, has a striatal D-2 dopamine receptor density that is intermediate to that of CBA/J and BALB/cJ mice. CBA/J mice also show deficits in the ability of brain monoaminergic receptor systems to develop supersensitivity. Calmodulin may participate in several striatal dopaminergic receptor mechanisms. Thus, striatal calmodulin was examined in CBA/J, C57BL/6J and BALB/cJ mice. Striatal calmodulin was greater in CBA/J mice than in C57BL/6J or BALB/cJ. In all three strains, cerebral cortical calmodulin was similar. The percent distribution of total striatal calmodulin between soluble and particulate fractions was similar in the three strains. Calcium redistributed soluble striatal calmodulin into the particulate fraction and EGTA shifted calmodulin from the particulate into the soluble fraction. The percent of total striatal calmodulin redistributed by either treatment was similar in all three strains. Gel filtration chromatography of heat-treated soluble extracts from CBA/J and BALB/cJ striatum was similar in elution pattern, although more calmodulin was observed in extracts from the CBA/J. Possible mechanisms for the strain differences in calmodulin are discussed along with their relationship to strain differences in striatal dopamine receptor subtypes.     

Influence of non-major histocompatibility complex differences on the severity of lymphocytic choriomeningitis

The role of the non-major histocompatibility complex (MHC) genetic background in the development of lymphocytic choriomeningitis (LCM) was examined for a range of mouse strains of the H-2k haplotype. The onset of meningitis relative to the time of injection of LCM virus was delayed and the maximal level of cellular extravasation into cerebrospinal fluid was lower in C3H/HeJ and CBA/H compared with AKR/J, B10.Br and BALB/c.H-2k mice. Adoptive transfer experiments indicated that the C3H mice are genuine low responders, but immune spleen cells from the CBA/H were as potent on a cell-for-cell basis as those from the AKR/J. Further analysis with CBA/H, AKR/J and (CBA/H x AKR/J)F1 mice showed that the pattern of high response for the AKR/J was dominant, with the differential kinetics of the development of meningitis correlating with the cellularity of the cervical lymph nodes. Thus, the generation of the LCM inflammatory process is not dictated solely by the MHC phenotype.