RESUMEN
Bidirectional selection in rodents has been used to derive animal models of human behavior. An important question is whether selection for behavior operates on a limited number of QTL or whether the number and individual contribution of QTL varies between selection experiments. To address this question, we mapped QTL in two large F2 intercrosses (N = 815 and 821) from the four lines derived from a replicated selection experiment for open-field activity, an animal model for susceptibility to anxiety. Our analyses indicate that selection operated on the same relatively small number of loci in both crosses. Haplotype information and the direction of effect of each QTL allele were used to confirm that the QTL mapped in the two crosses lie in the same chromosomal regions, although we were unable to determine whether QTL in the two crosses represent the same genes. We conclude that the genetic architecture of the selected strains is similar and relatively simple.
Asunto(s)
Carácter Cuantitativo Heredable , Animales , Haplotipos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Ethological tests of anxiety-related behaviors, such as the open field arena and elevated plus maze, are often carried out on transgenic animals in the attempt to correlate gene function with a behavioral phenotype. However, the interpretation of such tests is problematic, as it is probable that different tests measure different aspects of behavior; indeed, anxiety may not be a unitary phenomenon. Here, we address these questions by asking whether behaviors in five ethological tests of anxiety are under the influence of a common set of genes. RESULTS: Using over 1600 F2 intercross animals, we demonstrate that separate, but overlapping, genetic effects can be detected that influence different behavioral dimensions in the open field, elevated plus maze, square maze, light-dark box, and mirror chamber. We find quantitative trait loci (QTLs) on chromosomes 1, 4, and 15 that operate in four tests of anxiety but can be differentiated by their action on behavior in threatening and nonthreatening environments and by whether habituation of the animals to an aversive environment alters their influence. QTLs on chromosomes 7, 12, 14, 18, and X influenced a subset of behavioral measures. CONCLUSIONS: The chromosome 15 QTL acts primarily on avoidance behavior, the chromosome 1 QTL influences exploration, and the QTL on chromosome 4 influences activity. However, the effects of loci on other chromosomes are not so readily reconciled with our current understanding of the psychology of anxiety. Genetic effects on behaviors in these tests are more complex than expected and may not reflect an influence on anxiety.
Asunto(s)
Ansiedad/genética , Conducta Animal , Carácter Cuantitativo Heredable , Animales , Mapeo Cromosómico , Defecación/genética , Femenino , Masculino , RatonesRESUMEN
The aim of this work was to develop new bifunctional alkylating agents which damage DNA in a selective manner. In order to extend our previously published work on conformationally restricted nitrogen mustards containing one piperidine ring, new bispiperidine derivatives were designed with varying lengths of carbon chain between the two rings and structure-activity relationships in these systems were studied. Thus samples of new bispiperidine salts 22-26 with chloromethyl groups at the 2-positions and a bridge between the two nitrogen atoms of 2-6 carbon atoms were synthesized. The analogous new bis(p-nitrophenylcarbamates) 17-21 were also prepared. The free bases were designed to be bifunctional alkylating agents via aziridinium ion formation with different distances between the two alkylating sites. The bispiperidines 22-24 were shown to alkylate guanines at the 7-position in the major groove of DNA more selectively than melphalan. The bispiperidine 22 with the shortest two carbon bridge was the most reactive but it was less cytotoxic than melphalan in a human colon carcinoma cell line (IC50 value approximately 30 microM) and in a human chronic myeloid leukaemia cell line (IC50 value approximately 12 microM). The most cytotoxic compound in the latter cell line was the carbamate 17, with an IC50 value of approximately 0.3 microM, and carbamates 17, 19 and 20 were most potent in a panel of human ovarian carcinoma cell lines. These compounds also showed circumvention of acquired cisplatin resistance in three paired cell lines. The carbamates 17-21, however, were less efficient at alkylating and cross-linking naked DNA than the bispiperidines 22-26.
Asunto(s)
Antineoplásicos Alquilantes/síntesis química , Reactivos de Enlaces Cruzados/síntesis química , ADN/metabolismo , Guanina/metabolismo , Antineoplásicos Alquilantes/farmacología , Secuencia de Bases , Reactivos de Enlaces Cruzados/farmacología , Células HT29 , Humanos , Datos de Secuencia MolecularRESUMEN
Often a single pair of lines that has been selected for high and low expression of a trait is used as an animal model to study new biobehavioral characters thought to be associated with the selected trait. Because of genetic drift at many loci, comparisons of High and Low lines on the new character will frequently produce significant line differences even when there is no association between the selected trait and the new character being studied. In the absence of replicate lines to estimate the degree of genetic drift, effect size can be used to reduce the number of false-positive associations between the original selected trait and the new character. When the heritability of the new character exceeds .40 and the inbreeding coefficient within the selected lines is moderate, High- and Low-line means on the new character will frequently differ by at least one phenotypic SD, but not often differ by more than two SDs, in the absence of any relationship between the selected trait and the new character. If the selected lines are highly inbred, drift effects are greater, resulting in more false-positive associations. Situations posing special difficulty in the absence of replicate lines include the study of characters with low heritability relative to the selected trait and cases in which the lines do not differ greatly on the original selected trait. Studies using selected lines should always report inbreeding coefficients of the generations being studies, relative to the base population from which the lines were derived.
Asunto(s)
Frecuencia de los Genes/genética , Marcadores Genéticos/genética , Modelos Genéticos , Selección Genética , Animales , Intervalos de Confianza , Expresión Génica , EndogamiaRESUMEN
Bioreducible anti-tumour agents are prodrugs which are intended to be inactive in normal cells, but are able to undergo metabolic reduction in cancer cells to produce toxic species that can damage biomolecules. A series of N-oxides of heterocyclic aliphatic amines were designed and prepared as mentioned below as bioreducible drugs based on the reported anti-cancer activity of 2,6-bis(halomethyl)piperidines. In order to study structure-activity relationships in these conformationally restricted nitrogen mustards, samples of cis- and trans-2,6-dihydroxymethyl-N-methylpiperidine were prepared and converted into a number of carbamate or halogen derivatives. The free bases were designed to be bifunctional alkylating agents via aziridinium ion formation. The corresponding N-oxides were also prepared for comparison in cytotoxicity tests. In total, 21 new compounds were synthesized plus cis-N-methyl-2,6-bis(chloromethyl)-piperidine (prepared previously but lacking spectroscopic data) and tested against two human colon carcinoma cell lines, HT 29 (high DT-diaphorase) and BE (no DT-diaphorase), under oxic and hypoxic conditions. The majority of the free bases were equally toxic against both cell lines. The most toxic compounds were cis- and trans-N-methyl-2,6-bis(bromomethyl)piperidine with oxic IC50 values between 6 and 11 microM against both cell lines. The N-oxides were relatively non-toxic under both oxic and hypoxic conditions apart from the N-oxide of trans-N-methyl-2,6-bis(bromomethyl)-piperidine. Their low toxicity suggested that the N-oxides are not reduced under hypoxic conditions. We conclude that: (i) 2,6-disubstituted N-methylpiperidine derivatives are chemically versatile cytotoxic entities that are suitable for prodrugging to enhance their therapeutic selectivity; and (ii) N-oxide prodrugs of these compounds are deactivated chemically and display reduced cytotoxicity compared to the parent amines but are apparently not reduced under hypoxic conditions. At least in the colorectal cell lines tested the latter issue would need to be addressed by modifying the redox properties in future work to progress this approach.
Asunto(s)
Antineoplásicos Alquilantes/síntesis química , Carcinoma/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Piperidinas/síntesis química , Profármacos/síntesis química , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/toxicidad , Biotransformación , Carcinoma/enzimología , Carcinoma/patología , Hipoxia de la Célula , Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/patología , Dihidrolipoamida Deshidrogenasa/metabolismo , Humanos , Proteínas de Neoplasias/metabolismo , Nitrógeno/química , Oxidación-Reducción , Óxidos/síntesis química , Óxidos/farmacología , Óxidos/toxicidad , Piperidinas/farmacología , Piperidinas/toxicidad , Profármacos/farmacología , Profármacos/toxicidad , Relación Estructura-Actividad , Células Tumorales Cultivadas/efectos de los fármacos , Células Tumorales Cultivadas/enzimologíaRESUMEN
Four hundred seventeen heterogeneous stock mice were tested for their relative sensitivity to a low dose of nicotine (0.75 mg/kg) using activity in an automated Y-maze and body temperature as response measures. A wide spectrum of individual responsiveness to nicotine, ranging from complete suppression of activity to stimulation above baseline activity, was found. Replicate measures taken 1 week later on the same animals showed the responses to nicotine to be reliable and reproducible. Activity levels and body temperatures following nicotine administration were highly correlated (r = 0.60, df = 415). From analysis of between-litter proportions of variance, the heritability of nicotine-influenced activity was estimated to be 0.12, indicating that selective breeding for differential responsiveness to nicotine would be possible. The 10 most activated and 10 most depressed male and female mice were chosen as breeders for replicate nicotine activated (NA) and nicotine depressed (ND) lines, respectively. The selection criterion was nicotine-induced activity corrected for baseline activity using regression residuals. After six generations of selective breeding a good response to selection was obtained, although the response was better for the ND than for the NA lines. Realized heritability for responsiveness to nicotine calculated from the six selected generations was found to be 0.20, or slightly greater than that estimated from the foundation population. There were no significant differences in response to selection between the replicate NA or ND lines. Nicotine-induced body temperature was measured as a correlated response to selection, and was found to remain highly correlated with nicotine-induced locomotor activity. The response was more robust for the ND lines than it was for the NA lines. In contrast to the large differences between the ND and NA lines in locomotor activity and body temperatures following nicotine administration, mean baseline activities and body temperatures remained nearly identical throughout. This indicates that selection acted specifically on nicotine-induced responses, and not on baseline measurements, as predicted for response to a selection criterion based on regression residuals.
Asunto(s)
Conducta Animal/efectos de los fármacos , Nicotina/farmacología , Animales , Temperatura Corporal/efectos de los fármacos , Cruzamiento , Femenino , Genética Conductual/efectos de los fármacos , Individualidad , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos , Actividad Motora/efectos de los fármacos , Caracteres SexualesRESUMEN
The attempt to characterize high- and low-selected lines on new variables poses serious interpretative problems when replicate lines are not available. Modest but significant line differences on new measures may be due to genetic drift totally irrelevant to the originally selected trait. Often these differences are exaggerated by inappropriate analysis using individual subject measurements rather than family means. Mean differences in high- and low-selected lines on new characters should not be ascribed to the originally selected trait unless (1) genetic drift can be estimated through the use of replicate lines, (2) the standardized mean difference exceeds 1/4 of the equivalent difference on the original selected trait, or (3) strong predictions involving multiple noncontingent measures are unconditionally supported. For most purposes of analysis, line means can be considered individual data points which can be used to compute correlations among measures. An alternative to selection with replicates--two-stage testing of commercially available inbred strains--should be considered when large genetic correlations between the characters are expected.
Asunto(s)
Ratones Endogámicos/genética , Fenotipo , Ratas Endogámicas/genética , Selección Genética , Especificidad de la Especie , Animales , Regulación de la Expresión Génica , Frecuencia de los Genes , Ratones , Actividad Motora/fisiología , RatasRESUMEN
A complete diallel cross was generated from six Jax inbred strains of Mus domesticus from diverse origins and a second 6 x 6 diallel generated from strains derived from a single wild population. During their second day of life, infants from both diallels were tested for latency to orient toward and root beneath mothers and, in a separate test, for latency to attach to mother's nipple. Rooting latency showed a significant additive maternal strain effect but little systematic effect of pup genotype. Nipple attachment latencies exhibited complete genetic dominance favoring rapid attachment, with no maternal effects. Patterns of genetic and influences obtained from the two diallels were highly similar for both behaviors, suggesting that for many traits the requirement that strains be drawn from a common base population may be relaxed.
Asunto(s)
Cruzamientos Genéticos , Ratones Endogámicos/genética , Orientación/fisiología , Fenotipo , Conducta en la Lactancia/fisiología , Animales , Animales Recién Nacidos , Femenino , Masculino , Ratones , Tiempo de Reacción/fisiología , Selección GenéticaRESUMEN
Latency to leave a lighted platform and enter a novel chamber in which other mice had received shock was measured in 2592 mice from eight inbred strains and all 56 F1 crosses. An analysis of the diallel matrix indicated a clear genetic architecture, although genetic effects accounted for only 10% of the total phenotypic variance. Dominance favoring a slight delay in chamber entry suggested a selective advantage in spending a longer time on some elements in the behavioral chain involved in avoidance-avoidance responses. Inbred strains showed greater litter variance than F1 hybrids, suggesting greater developmental buffering of heterozygotes. Both the genetic architecture and the strain rankings differ from those typically found in open field and similar tests of locomotor activity. The results illustrate the problem of interpreting behavior genetic results in terms of proportions of total phenotypic variance and difficulties in generalizing to ancestral or other populations in an attempt to interpret genetic results in an evolutionary context when reliability is low.
Asunto(s)
Reacción de Prevención/fisiología , Ratones Endogámicos/genética , Ratones/genética , Animales , Cruzamientos Genéticos , Femenino , Masculino , Fenotipo , Tiempo de Reacción/fisiologíaAsunto(s)
Genotipo , Actividad Motora , Animales , Genética Conductual , Ratones , Modelos GenéticosAsunto(s)
Trastornos Mentales/genética , Trastornos del Conocimiento/genética , Enfermedades en Gemelos , Dislexia/genética , Tamización de Portadores Genéticos , Genética Conductual , Genotipo , Humanos , Inteligencia , Trastornos del Humor/genética , Desarrollo de la Personalidad , Trastornos Psicóticos/genética , Riesgo , Esquizofrenia/genética , Medio Social , Percepción VisualRESUMEN
An analysis of a juvenile hopping response from an 8 X 8 diallel cross is used to demonstrate the experimental genetic approach for testing presumed adaptive fitness of behaviors in developing organisms. In accordance with predictions, the explosive jumping behavior exhibited by 15-day mice is characterized by a pattern of genetic dominance toward high expression of the trait. Wild mice show even more vigorous responses, indicating that selection pressures maintaining high responding have been relaxed during domestication. These data suggest some applications and limitations of genetic methods for the study of behavioral evolution as related to development.
Asunto(s)
Adaptación Biológica , Ratones Endogámicos/genética , Actividad Motora , Animales , Reacción de Fuga , Genes Dominantes , Genética de Población , Ratones , Tiempo de Reacción , Selección GenéticaRESUMEN
An 8 X 8 diallel analysis of locomotor activity related to nest return in mice just prior to eye opening indicated a pattern of dominance toward high activity, with little additive genetic variance. Groups of laboratory-reared wild mice did not differ from each other or from the diallel mean, suggesting little relaxation of selection toward rapid nest return during domestication. In contrast to the nest return situation, an eight-strain triple test-cross analysis of locomotion in a test environment unlikely to be encountered by 11-day-old mice indicated only additive genetic variance, with no evidence of dominance for increased activity. When measured in an ecologically relevant environment, the nature of genetic variation appears to change with age in a manner concordant with what one would intuitively assume to be adaptive behavior at each stage of development.
Asunto(s)
Animales Recién Nacidos/fisiología , Genética Conductual , Ratones Endogámicos/genética , Actividad Motora , Envejecimiento , Animales , Conducta Animal , Femenino , Variación Genética , Genotipo , Masculino , RatonesAsunto(s)
Encéfalo , Dominancia Cerebral , Tamaño de los Órganos , Análisis de Varianza , Animales , Encéfalo/anatomía & histología , Ambiente , RatonesRESUMEN
Locomotor activity of 2,140 four-day-old inbred, hybrid, and wild mice was measured. Consonant with the prediction that high rates of locomotor activity would be maladaptive in infant mice, hybrids were less active than inbred lines. A triple test cross analysis indicated low heritability and nearly complete dominance toward low activity. Mice from wild stock were even less active than hybrids, which suggests that selection pressures for low infantile activity have relaxed during laboratory domestication. A test is described for estimating changes in selection pressures resulting from laboratory rearing.
Asunto(s)
Animales Recién Nacidos , Genes Dominantes , Actividad Motora , Animales , Animales de Laboratorio , Hibridación Genética , Conducta Materna , Ratones , Ratones Endogámicos A , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Endogámicos DBA , Ratones Endogámicos , Selección GenéticaRESUMEN
Three experiments with C57BL/10J mice examined the possible roles of cage size and simple motor practice as factors responsible for producing improved performance of animals reared in enriched environments. Neither factor was found sufficient to improve subsequent performance in a food-seeking task. Mice reared in flat environments containing a variety of objects, but designed to prevent any climbing practice, out-performed nonenriched animals on a task requiring extensive climbing activity.
Asunto(s)
Animales Recién Nacidos/crecimiento & desarrollo , Condicionamiento Operante , Ambiente , Actividad Motora , Animales , Ratones , Ratones Endogámicos C57BL , Práctica PsicológicaRESUMEN
Previous work indicates that mice of different genotypes reared in enriched environments show differential increases in performance on a food-seeking task. In this study 2 experiments examined the effects in selected mice strains of short exposures to such enrichment. Experiment 1 indicated that 48 hr of exposure to enriched cages was sufficient to produce results found previously when subjects were reared from birth in enriched cages. Experiment 2 indicated that as little as 6 hr of exposure to an enriched cage was sufficient to produce almost maximal enrichment effects in C57BL/10J mice.