A comparative genetic analysis of the role of the brain dopaminergic systems in the regulation of behavioral elements in the "open field" test in DBA/2J and C57BL/6J mice

The effects of intraperitoneal injections of sulpiride (10 mg/kg), bromocriptine (5 mg/kg), and alaptide (1 mg/kg) on the behavior of male C57BL/6J (C57BL) and DBA/2J (DBA) mice in the open-field test were studied. In this test, C57BL mice exhibited a significantly higher horizontal locomotor activity than DBA mice, whereas DBA mice moved in place substantially longer than C57BL mice. Dopaminergic agents had different effects on the open-field behavior in different mouse strains. Alaptide increased horizontal locomotor activity in DBA, but not in C57BL mice; all the three agents decreased the duration of movement in place in DBA but not in C57BL mice; bromocriptine suppressed vertical locomotor activity and the act of looking into holes in C57BL but not in DBA mice. Thus, interstrain differences in dopaminergic functions were demonstrated. The revealed strain-specific characteristics largely contribute to the determination of open-field behavior in the studied mouse strains.     

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

Tested 15 male mice from each of 4 inbred strains (C57BL/6J, BALB/cJ, CBA/J, and DBA/2J) 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 than the 3 other low ethanol-selecting strains. Exp II with 140 Ss 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 was a much more potent depressant than 1,2 PD. Results are discussed in terms of the possible role of neural sensitivity in regulating consumption levels of the 2 alcohols. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

New flexible growth function and its application to the growth of small mammals

The effects of three putative genes which contribute to age-related hearing loss (AHL genes) were evaluated using auditory brainstem response (ABR) thresholds and post-mortem cochlear histopathology in 25 recombinant BXD inbred mouse strains, originally derived from C57BL/6J (B6) and DBA/2J (D2) progenitor strains. All BXD strains showed substantial elevation of ABR thresholds and loss of spiral ganglion cells (SGCs) during the first year of life. The findings are consistent with our genetic model in which D2 and B6 inbred strains both possess the Ahl (age-related hearing loss) gene, whereas D2 possesses two additional chromosomal loci with AHL genes (Ahl2 and Ahl3). The between-strain distribution in the severity of SGC loss and ABR threshold elevations suggests that the severity of hearing loss is determined in large part by the number of AH L genes an animal possesses and by additional genetic background effects. The present findings also demonstrate that, because BXD strains vary substantially in the rate and severity of progressive hearing loss (but are genetically closely related), they can provide powerful animal models for developmental studies of AHL.     

Female mate choice and male behaviour in domestic fowl

An F2 intercross derived from C57BL/6 and DBA/2 progenitor inbred strains was used to test for replication of quantitative trait loci (QTLs) for alcohol preference nominated by a previous study using BXD recombinant inbred (RI) strains (Rodriguez et al., Alcohol. Clin. Exp. Res. 19:367-379, 1995). Fourteen provisional QTLs were nominated in the original RI study with a p < 0.05 criterion. In the present study, a genome scan (101 microsatellite markers) was conducted on an F2 population (n = 218). Three significant QTLs were detected on chromosomes 1, 4, and 9, and three suggestive QTLs were detected on chromosomes 2, 3, and 10. Of these six QTLs, four were consistent with the previous RI nominations. The replication rate of 28.6% (4 of 14) is in agreement with the results of simulation studies performed by Belknap et al. (Behav. Genet. 26:149-160, 1996) and supports the methodological argument for a multistage research design for nominating and replicating QTLs.     

Effects of alcohol on acquisition and retention of passive-avoidance conditioning in different mouse strains.

270 male Ss of the C57BL/6 and DBA/2 inbred mouse strains and of the F1 hybrid of these 2 were trained and tested in a passive-avoidance task under 0-3 gm/kg doses of ethanol. The C57 Ss performed better in acquisition at higher alcohol doses than either the DBA or hybrid Ss. The hybrids showed retention the following day at higher doses than either of the parental strains. The DBA and C57 Ss showed evidence of state-dependent learning at some alcohol doses while the hybrid mice did not. Low doses markedly disinhibited DBA mice in initial exploratory behavior, so that they became identical in this parameter to the other strains which were not so affected. (15 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Genetic analysis of the corticosterone response to ethanol in BXD recombinant inbred mice.

The genetic control over the corticosterone response to ethanol (EtOH) and its possible relationship to other EtOH-related traits was examined using BXD recombinant inbred (RI) strains derived from an F2 cross of C57BL/6J (B6) and DBA/2J (D2) progenitor strains. Quantitative trait locus (QTL) analysis of corticosterone levels 1 hr following EtOH suggested the influence of a single major gene on this trait. Two loci were predicted to account for 47% of the genetic variance in plasma corticosterone levels 6 hr following EtOH, whereas 3 loci were predicted to account for 78% of the genetic variance in corticosterone levels 7 hrs following EtOH. Markers associated with corticosterone levels 7 hrs following EtOH and corrected corticosterone levels 6 hrs post-EtOH overlapped with ones found to influence acute and chronic EtOH withdrawal severity, suggesting some degree of common genetic determination between these traits. Overall these results indicate that gene action significantly influences stress responsiveness and suggest possible chromosomal locations of these genes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Hippocampal lesions cause learning deficits in inbred mice in the Morris water maze and conditioned-fear task.

This study examined the effect of hippocampal lesions on acquisition of the Morris water maze and conditioned-fear task in inbred mice. C57BL/6J, DBA/2J, and B6D2F1 hybrid mice were given hippocampal lesions or sham surgery and then tested. The lesioned C57BL/6J and B6D2F1 mice failed to learn the Morris task relative to sham-operated controls, and no DBA group learned the task. In the contextual component of conditioned fear, lesions decreased freezing in all strains. But the lesions only affected freezing to the conditioned stimulus in the DBA/2J and B6D2F1 strains. These data demonstrate that C57BL/6J and B6D2F1 mice use the hippocampus to solve the Morris water maze and conditioned-fear task, and the DBA mice use the hippocampus, to some degree, in the conditioned-fear task. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sex-restricted non-Mendelian inheritance of mouse chromosome 11 in the offspring of crosses between C57BL/6J and (C57BL/6J x DBA/2J)F1 mice

We report on the observation of sex-restricted, non-Mendelian inheritance over a region of mouse Chromosome (Chr) 11, occurring in the offspring of crosses between two commonly used Mus musculus-derived inbred strains, C57BL/6J and DBA/2J. In the surviving backcross progeny of reciprocal matings between (C57BL/6J x DBA/2J)F1 hybrids and the C57BL/6J parental strain, we observed the preferential appearance of C57BL/6J alleles along a region of Chr 11. The deviation from Mendelian predictions was observed only in female offspring from both reciprocal backcrosses, and not in males from either cross. The sex-specificity of the observed non-Mendelian inheritance points to an explanation based on embryonic or neonatal lethality. Our data add to previously obtained evidence for a Chr 11 locus or loci with sex-specific and allele-specific effects on viability.     

Social relations and extent and severity of coronary artery disease. The Stockholm Female Coronary Risk Study

Peak bone mass is a major determinant of risk of osteoporotic fracture. Family and twin studies have found a strong genetic component to the determination of bone mineral density (BMD). However, BMD is a complex trait whose expression is confounded by environmental influences and polygenic inheritance. The number, locations, and effects of the individual genes contributing to natural variation in this trait are all unknown. Experimental animal models provide a means to circumvent complicating environmental factors, and the development of dense genetic maps based on molecular markers now provides opportunities to resolve quantitative genetic variation into individual regions of the genome influencing a given trait (quantitative trait loci, QTL). To begin to identify the heritable determinants of BMD, we have examined genetically distinct laboratory mouse strains raised under strict environmental control. Mouse whole-body bone mineral content by dual-energy X-ray absorptiometry (DXA) correlated strongly with skeletal calcium content by ashing, and peak whole-body BMD by DXA in female mice occurred at approximately 80-90 days of age. We therefore determined mean body weight and peak whole body BMD values in 12-week-old female mice from a panel of 24 recombinant inbred (RI) BXD strains, derived from a cross between C57BL/6 and DBA/2 progenitors. The distribution of body weight and BMD values among the strains clearly indicated the presence of strong genetic influences on both of these traits, with an estimated narrow sense heritability of 60% and 35%, respectively. The patterns of differences in body weight and peak whole body BMD in the BXD strains were then integrated with a large database of genetic markers previously defined in the RI BXD strains to generate chromosome map sites for QTL. After correction for redundancy among the significant correlations, QTL analysis of the BXD RI strain series provisionally identified 10 chromosomal sites linked to peak bone mass development in the female. Several of the identified sites map near genes encoding hormones, structural proteins, and cell surface receptors that are intricately involved in skeletal homeostasis. Four QTL for body weight were also identified. One of these loci was also strongly linked to inherited variation in BMD. This finding suggests that body weight and peak BMD may be influenced by linked genes or perhaps by common genes with pleiotropic effects. Our phenotyping in the RI BXD strains has allowed us to map a number of specific genetic loci strongly related to the acquisition of peak BMD. Confirmation of these findings will likely result in the understanding of which genes control skeletal health.     

Specific anosmia in the laboratory mouse

As an approach to a general theory of olfaction, different specific anosmia phenotypes characterized by different profiles of odorant sensitivities have been proposed for humans. In the present experiments, male inbred mice were tested for relative odorant sensitivity using a conditioned aversion technique and odors classified as primary or complex for humans. C57BL/6J and C57BL/10J mice appeared to be less sensitive to the primary odorant isovaleric acid than were males of seven other inbred strains (A/J, AKR/J, BALB/cJ,C3HeB/FeJ, DBA/2J, SJL/J, and SWR/J). In comparisons of C57BL/6J and AKR/J strains, the relative insensitivity of C57 to isovaleric acid did not generalize to the musklike primary odor of pentadecalactone or to the complex odor of amyl acetate. The C57BL/6J genotype may provide an animal model of a specific anosmia as characterized among humans.     

Selection of C3 alcohols by high and low ethanol selecting mouse strains and the effects on open field activity

Mice of the high-ethanol selecting C57BL/6j strain consume significantly larger amounts of 10% solution of 1,2-propanediol and 1-propanol than the low-ethanol selecting DBA/2j strain. Both strains uniformly avoid a 10% solution of 1,3-propanediol and 2-propanol. Open field activity was tested 30 min after an IP injection of 3 different equimolar doses of each alcohol. An increase in activity was produced in the DBA/2j strain by high (0.003 ml/mg) and middle (0.0015 ml/lg) doses of 1,2-propanediol and by a low dose (0.0005 ml/mg) of 2-propanol. The C57BL/6j strain were unaffected by these doses. High doses of 2-propanol produced sleep in both strains with the DBA/2j strain sleeping significantly longer, and 1,3-propanediol produced depression in both strains. Death resulted in all animals following injections at the high (0.002 mg/gm) and medium (0.001 ml/gm) doses of 1-propanol while the low dose (0.0005 ml/gm) produced slight depression.     

Changes in hepatic enzyme activities related to ethanol metabolism in mice following chronic ethanol administration

Male mice of three strains, C57BL, DBA and C3H/He, were fed on commercial food with 10% (v/v) ethanol solution as drinking liquid ad libitum for eighty days, and the changes in the activities of enzymes in the metabolic pathway of ethanol in the liver were examined. C57BL and C3H/He mice showed a preference for drinking the 10% (v/v) ethanol solution, while DBA mice did not. The ethanol intake g/g of body weight of C3H/He mice showed the highest value among all three strains and that of C57BL mice tended to show higher value than that of DBA mice. The liver weights of C57BL and C3H/He mice increased significantly following chronic ethanol administration, but that of DBA did not. The cytosolic enzyme alcohol dehydrogenase (ADH) showed no changes in any of the strains following chronic ethanol administration. The microsomal ethanol-oxidizing system (MEOS) of C57BL mice exhibited approximately 2-fold higher activity compared to that of DBA and C3H/He mice but did not increase in any strain following chronic ethanol administration. However, the microsomal aniline hydroxylase activity in the liver increased significantly in C57BL and C3H/He mice following chronic administration of ethanol. The microsomal cytochrome P-450 content also tended to slightly increase in the same strains of mice. It seemed that cytochrome P-450IIE1 was induced in the liver microsomes of these strains. Total aldehyde dehydrogenase (ALDH) activities together with high-Km ALDH activity increased markedly in the microsomes of C57BL mice and tended to increase in C3H/He mice, while it did not change in DBA mice following chronic ethanol administration. In the mitochondria of C57BL, total ALDH activities increased slightly and high-Km ALDH activities tended to increase. These mitochondrial ALDH activities of C3H/He and DBA mice tended to increase following chronic ethanol administration. The cytosolic ALDH activity showed no changes in any strain of mice following chronic ethanol administration. It seemed that in the microsomes, the activities of enzymes related to oxidation of ethanol increased in C57BL and C3H/He mice, which tended to consume a large amount of ethanol, and did not in DBA mice which tended to consume a small amount of it. It seemed that the increases in activities of enzymes related to oxidation of acetaldehyde in the microsomes and in the mitochondria were responsible for the strain difference.     

Characteristics of women choosing birth center care

Certain strains of mice, designated V beta a, have a deletion of the gene segments encoding the beta chain of the T-cell receptor variable region. These mice do not express 40 to 50% of the T-cell receptor V beta chains. In this study, we examined the influence of this deletion on susceptibility to Histoplasma capsulatum. In addition, H. capsulatum-injected V beta a mice were tested for their capacity to generate T-cell dependent responses to H. capsulatum antigens. Susceptibility profiles of V beta a mice, SWR/J (H-2q), SJL/J (H-2s) and C57L-(H-2b), were compared to V beta b strains, C57BL/6 (H-2b) and DBA/l (H-2q), following intravenous (IV) injection of sublethal and lethal inocula of H. capsulatum yeast cells. One week after injection of 6 x 10(5) yeast cells, the spleens of SWR/J, SJL/J and C57L mice contained 5- to 7-fold fewer colony forming units (CFU) than spleens of C57BL/6 mice. Approximately 50% fewer CFU of H. capsulatum were recovered from the spleens of DBA/l mice compared to those from C57BL/6 animals. Subsequently, groups of mice were challenged IV with either 1.5 x 10(7) or 7.5 x 10(6) yeast cells and observed for 30 days. Survival of SWR/J,SJL/J, C57L and DBA/l mice was significantly prolonged compared to C57BL/6 mice. V beta a and DBA/l mice injected with viable H. capsulatum yeast cells mounted a delayed-type hypersensitivity response to an extract from the cell wall and cell membrane of yeast cells and to HIS-62, a purified antigen derived therefrom.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mice: Progesterone and the regulation of strain differences in pregnancy-induced nest building.

Four experiments with 113 C57BL/6J and 80 DBA/2J female mice showed that pregnant DBA/2J Ss built significantly larger and more completely enclosed nests than did pregnant C57BL/6J Ss. This strain difference was restricted to the last half of gestation and was not observed during either the virgin state or lactation. Genotype-based differences in pregnancy-induced nest building were not related to circulating levels of progesterone (P), core temperature, or body weight. Exposure to supplemental P (100, 200, or 400 μg, sc) during pregnancy elevated nest building exhibited by pregnant C57BL Ss but did not induce DBA-like levels of the behavior. Also, virgin DBA Ss built larger nests in response to P than did C57BL Ss. Findings suggest that differences in the sensitivity of central neural tissue to steroid hormones may account for genotypically determined variation in patterns of pregnancy-induced nest building. (27 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Stereospecific, high affinity binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin by hepatic cytosol. Evidence that the binding species is receptor for induction of aryl hydrocarbon hydroxylase

We previously hypothesized that the genetic trait of aromatic hydrocarbon nonresponsiveness (the failure in certain inbred strains of mice of polycyclic hydrocarbons to induce aryl hydrocarbon hydroxylase activity, and the diminished sensitivity to the more potent inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is due to mutation which results in an induction receptor with a diminished affinity for the inducing compound. Following the intraperitoneal administration of [14C]TCDD (6 nmol/kg), hepatic accumulation of the radiolabel was greatest in C57BL/6J mice, intermediate in the hybrid B6D2F1/J mice, and least in DBA/2J mice, a pattern which mirrors the strain sensitivity to hydroxylase induction by TCDD (C57BL/6J greater than B6D2F1/J greater than DBA/2J). These data are compatible with receptor mutation theory and suggested that the hepatic uptake of TCDD is determined by the affinity of the receptor. In vitro experiments on the binding of [3H]TCDD to hepatic cytosol from C57BL/6J mice revealed a small pool of high affinity sites which stereospecifically and reversibly bind TCDD. The specific binding of [3H]TCDD to hepatic cytosol had an equilibrium dissociation constant KD of 0.27 nM and a maximum binding capacity of 84 fmol/mg of cytosol protein. Much less high affinity specific binding of [3H]TCDD was observed in hepatic cytosol from DBA/2J mice, but the KD was not estimated because of the limited aqueous solubility of the ligand. The binding affinity of 23 halogenated dibenzo-p-dioxins and dibenzofurans for this hepatic cytosol-binding species closely correlated with the potencies of these compounds as inducers of hepatic aryl hydrocarbon hydroxylase activity. The polycyclic hydrocarbons that induce hepatic hydroxylase activity competed with [3H]TCDD for hepatic cytosol binding, but phenobarbital, pregnenolone-16alpha-carbonitrile, and the steroid hormones had no specific binding. The data suggest that the hepatic cytosol species which binds TCDD is the receptor for the induction of hepatic aryl hydrocarbon hydroxylase activity, and that the mutation in nonresponsive mice results in an altered receptor with a diminished affinity for inducing compounds.     

Passive-avoidance conditioning in inbred mice: Effects of shock intensity, age, and genotype.

Observed the performance of 8 groups (n = 336) of DBA/2J, 8 groups (n = 320) of C57BL/6J, and 4 groups (n = 160) of B6D2F1 mice in passive-avoidance conditioning under conditions of distributed practice. Ss' age and the footshock intensity were varied systematically. DBA/2J Ss performed best when they were 5-mo-old and the footshock level was at least 1 ma. C57BL/6J Ss performed very poorly under these conditions. The best performance by C57BL/6J Ss was observed at .1-ma footshock. The performance of B6D2F1 Ss was almost identical to that of the C57BL/6J parental type. Footshock intensity was the major determinant of the performance of DBA/2J Ss, while footshock intensity and age were major determinants of the performance of C57BL/6J and B6D2F1 mice. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Fear conditioning in inbred mouse strains: An analysis of the time course of memory.

Three mouse strains were examined for short- and long-term memory for Pavlovian fear conditioning measured 1 hr and 24 hr after conditioning. Both DBA/2J and CBA/J mice exhibit reduced long-term memory for contextual fear conditioning compared with C57BL/6J mice. In cued fear conditioning, however, DBA/2J mice show reduced short- and long-term memory compared with C57BL/6J mice, whereas CBA/J mice exhibit reductions only in short-term memory. These results underscore the importance of examining the time course of memory retention, and they suggest that inbred mouse strains may provide a diversity of phenotypes. The results also suggest that the processes of short- and long-term memory storage as well as contextual and cued fear conditioning are dissociable and are mediated by genetically distinct neurobiological mechanisms. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Segregation analysis of the testis-determining autosomal trait, Tda, that differs between the C57Bl/6J and DBA/2J mouse strains suggests a multigenic threshold model

The testis-determining autosomal trait (Tda) of the mouse was uncovered when the Y chromosome of the poschiavinus variety of Mus musculus domesticus was introduced into the C57BL/6J laboratory strain background. Testis development is normal in the F1 generation but, in the backcross and subsequent crosses to C57BL/6J females, XY individuals with the poschiavinus Y chromosome expressed bilateral ovaries or various combinations of an ovotestis with a contralateral ovary or testis or bilateral ovotestes and few had testes bilaterally. In other strain backgrounds, such as DBA/2J, XY individuals with the poschiavinus Y chromosome always expressed normal testes bilaterally. The first breeding analysis of this difference in the interaction of strain background with the poschiavinus Y chromosome suggested that the Tda trait was due to a single gene, but attempts to map it failed. We constructed two strains of C57BL/6J and DBA/2J that are consomic for the poschiavinus Y chromosome in order to conduct a segregation analysis of the Tda trait. In the C57BL/6J.Y-POS consomic strain, liability to express incomplete testis development is normally distributed and thresholds in development specify the probability of different classes of ovary, ovotestis, and testis combinations. Testis development is complete in the DBA/2J.Y-POS consomic strain. We demonstrated previously that the Tda trait of C57BL/6J is recessive to that of DBA/2J and the segregating first backcross generation of embryos rejected the single-gene model. We have extended our analysis to a F2 generation of embryos that also rejects a single-gene model. We also report a test mating analysis of the first backcross generation. It was initiated to provide an independent assessment of the single-gene model, but the analysis of the distribution of test mating results suggests that the difference in the Tda trait between C57BL/6J and DBA/2J may be due to a small number of loci, possibly four or five, and that the phenotypic effect between loci may be additive.     

Genotype-dependent effects of septal lesions on different types of learning in the mouse.

Tested 80 C57BL/6J, DBA/2J, and SEC/1ReJ mice with septal or control lesions for exploratory behavior, shuttle-box avoidance learning, discriminated avoidance, and maze-learning ability. Control DBA and SEC Ss normally displayed low levels of exploratory behavior and efficient avoidance and maze learning. High exploratory activity and low avoidance and maze learning were characteristically shown by C57 controls. All strains with septal lesions increased levels of exploratory and avoidance behaviors. In contrast, following septal lesions the 3 strains performed more poorly in discriminated-avoidance and maze learning. It is concluded that differences in septal function-e.g., in level of response inhibition-do not substantially account for the learning differences evident between these strains. (19 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A major influence of sex-specific loci on alcohol preference in C57Bl/6 and DBA/2 inbred mice

C57Bl/6 mice reproducibly prefer to ingest more 10% ethanol in a two-bottle choice paradigm than do DBA/2J mice. In this paper we report the identification of two new sex-specific alcohol preference (Alcp) loci. Melo and associates (1996) identified two loci: Alcp1, a male-specific locus on Chromosome (Chr) 2, and Alcp2, a female- and cross-specific locus on Chr 11. We have additionally identified Alcp3, a male-specific locus on Chr 3, and Alcp4, a female-specific locus on Chr 1. We have also performed a statistical analysis to exclude the possibility of undiscovered major alcohol preference loci that are not sex-specific in our backcross paradigm. Our results indicate that alcohol preference in C57BL/6 mice, as measured in our backcross, is largely controlled in a sex-specific manner.