Stephen C. Maxson

Behavioral phenotypes of inbred mouse strains: implications and recommendations for molecular studies

Abstract Choosing the best genetic strains of mice for developing a new knockout or transgenic mouse requires extensive knowledge of the endogenous traits of inbred strains. Background genes from the parental strains may interact with the mutated gene, in a manner which could severely compromise the interpretation of the mutant phenotype. The present overview summarizes the literature on a wide variety of behavioral traits for the 129, C57BL/6, DBA/2, and many other inbred strains of mice. Strain distributions are described for open field activity, learning and memory tasks, aggression, sexual and parental behaviors, acoustic startle and prepulse inhibition, and the behavioral actions of ethanol, nicotine, cocaine, opiates, antipsychotics, and anxiolytics. Using the referenced information, molecular geneticists can choose optimal parental strains of mice, and perhaps develop new embryonic stem cell progenitors, for new knockouts and transgenics to investigate gene function, and to serve as animal models in the development of novel therapeutics for human genetic diseases.

Aggressive behavioral phenotypes in mice.

Aggressive behavior in male and female mice occurs in conflicts with intruding rivals, most often for the purpose of suppressing the reproductive success of the opponent. The behavioral repertoire of fighting is composed of intricately sequenced bursts of species-typical elements, with the resident displaying offensive and the intruder defensive acts and postures. The probability of occurrence as well as the frequency, duration, temporal and sequential patterns of aggressive behavior can be quantified with ethological methods. Classic selection and strain comparisons show the heritability of aggressive behavior, and point to the influence of several genes, including some of them on the Y chromosome. However, genetic effects on aggressive behavior critically depend upon the background strain, maternal environment and the intruder. These factors are equally important in determining changes in aggressive behavior in mice with a specific gene deletion. While changes in aggression characterize mutant mice involving a variety of genes, no pattern has emerged that links particular gene products (i.e. enzyme, peptide, receptor) to either an increase or a decrease in aggressive behavior, but rather emphasizes polygenic influences. A potentially common mechanism may be some components of the serotonin system, since alterations in 5-HT neurotransmission have been found in several of the KO mice that display unusual aggressive behavior.

Transcription of the Y chromosomal gene,Sry, in adult mouse brain

The Y chromosomal gene Sry encodes a putative transcription factor which appears to serve as a master switch initiating testicular development. Here we show that this gene is transcribed in hypothalamus, midbrain, and testis of adult male but not adult female mice. In contrast to its circular transcripts in adult testis, those in brain are linear and may be translated. We propose that Sry exerts a role in the regulation of sex differentiation of the mammalian nervous system.

Interaction of Y-chromosomal and autosomal gene(s) in the development of intermale aggression in mice.

It has been suggested that the Y chromosome of DBA/1BBg mice makes an incremental contribution to their aggressive behavior and to that of the C57BL/10 ♀×DBA/1 ♂ F1 hybrids. To test this hypothesis, a congenic stock of C57BL/10 with the DBA/1 Y chromosome was developed by the backcross system of breeding; the stock is designated C57BL/10-Y1. There were no significant differences in aggressive behavior between the congenic C57BL/10 and C57BL/10-Y1. However, the hybrid B10D1 F1 and D1B10-Y1 F1 had identical aggression scores, and both of these were more aggressive than the hybrid D1B10 F1. These findings support the hypothesis that there is an interaction between DBA/1 Y chromosomes and autosomes in the development of intermale aggression of these mice.

Chromosomal determinants of intermale aggressive behavior in inbred mice.

A behavioral genetic system has been investigated in which the Y chromosome of DBA/1/Bg mice makes an incremental contribution to the adult aggression of B10D1Ft, hybrid mice. Crosses with C57BL/10/Bg, C57BL/6/Bg, and DBA/2/Bg have identified a minimum of one incremental and one decremental (suppressor) genetic factor (in addition to the Y chromosome) which are autosomal and which affect the expression of adult intermale aggression in these strains.

SEARCHING FOR CANDIDATE GENES WITH EFFECTS ON AN AGONISTIC BEHAVIOR, OFFENSE, IN MICE

It is well established that the agonistic behavior of offense in mice is heritable. However, few genes have been identified or mapped for offense. For segments of chromosomes with effects on offense, a positional candidate strategy can be used to find such genes. This approach is illustrated for the effect of the male specific part (nonpseudoautosomal region; NPAR) of the mouse Y chromosome on offense. It is proposed that a positional candidate for this effect isSry. The Sry protein is a transcription factor. Its mRNA is expressed in fetal and adult brain. Its protein binds to response elements in the 5′ end of the aromatase and theFral genes. Each of these genes has potential effects on several brain neurotransmitter systems involved in offense. The NPAR Y chromosomes of several pairs of inbred strains have differential effects on offense. This hypothesis would be tested by sequencingSry for some of these pairs of strains.

Electroencephalographic correlates of the audiogenic seizure response of inbred mice.

Abstract The cortical EEG of 5 inbred strains of mice susceptible to audiogenic seizures and of 3 inbred strains resistant to them as well as 3 accoustically primed inbred strains was recorded before, during, and after exposure to intense noise once a day for 4 consecutive days beginning at 29 or 30 days of age. None of the resistant mice had a convulsion and all of the susceptible mice had at least one convulsion. Before, during, and after the audiogenic seizure, there was no evidence of spike waves or paroxysmal activity in the trace from the bipolar cortical electrodes. Rather, there might be a slight amplification and acceleration of the trace at the stimulus onset with no further changes during wild circling activity, but with a diminution of the trace during clonic or clonic-tonic convulsions. This pattern was observed for all 5 genetically susceptible strains and for all 3 acoustically primed groups. However, during chemoconvulsive seizures with picrotoxin or thiosemicarbazide, these same mice as well as resistant mice show spike waves and paroxysmal activity of the cortex. It is suggested on the basis of these data that the neural mechanism for the expression of audiogenic seizures and chemoconvulsive seizures is different, that all audiogenic seizures have a common mechanism for expression but not for development of this phenotype, and that the audiogenic seizure is a type of brain stem epilepsy.

GENOTYPE-DEPENDENT SEX DIFFERENTIATION OF DOPAMINERGIC NEURONS IN PRIMARY CULTURES OF EMBRYONIC MOUSE BRAIN

In order to investigate genetic factors that interfere with hormone-mediated sex differentiation of dopaminergic neurons, we raised sex-specific primary cultures from embryonic day 13 diencephalon (D) or mesencephalon (M) of three different strains of mice, NMRI, CBA/J, and BALBc/J. Part of the cultures were maintained for 6 or 13 days in vitro (DIV) in medium containing 17 beta-estradiol or testosterone. The cultures were analyzed for sex differences in numbers of tyrosine hydroxylase-immunoreactive neurons, endogenous dopamine (DA) levels, and specific uptake of [3H]DA. Previous results obtained with cultures of embryonic Sprague-Dawley rats had shown that these parameters develop sex-specific characteristics in the absence of sex differences in hormone environment. Similar steroid-independent sex differences as they occur in the rat were found in M cultures of NMRI but not in CBA and BALBc mice. Long-term sex steroid treatment did not affect any of the above parameters in any strain. It is concluded that cell-autonomous realization of the genetic sex of dopaminergic neurons depends on the genetic background.

The Y chromosome, social signals, and offense in mice.

Offense is one type of aggression in mice (Mus musculus/Mus domesticus). Offense was measured in a panel of testers design for two congenic strains of mice. The two congenic strains were DBA1Bg and DBA1. C57BL10-YBg. These differ in the Y chromosome. Offense was measured for the following dyadic pairs: Group 1 (DBA1 tested against a DBA1 opponent); Group 2 (DBA1 tested against a DBA1.C57BL10-Y opponent); Group 3 (DBA1.C57BL10-Y tested against a DBA1.C57BL10-Y opponent); and Group 4 (DBA1.C57BL10-Y tested against a DBA1 opponent). Group 1 was more aggressive than Group 3, whereas Group 2 was no more aggressive than Group 4. Thus, when the experimental and opponent pairs have the same Y chromosome, the congenics differ in offense, whereas when the experimental and opponent pairs have different Y chromosomes, the congenics do not differ in offense. These findings are consistent with the hypothesis that these Y chromosomes affect the display of and response to social or other stimuli for offense of mice. These stimuli may be individual recognition chemosignals in urine.

Correlated effects of the y-chromosome of mice on developmental changes in testosterone levels and intermale aggression.

Abstract Serum testosterone (T) was studied developmentally in DBA/1/Bg and C57BL/10/Bg inbred mice, as well as in their reciprocal F1 hybrids. Testosterone determinations were made using a radioimmunoassay. At 35 and 40 days post partum , DBA/1/Bg mice had higher levels of T than C57BL/10/Bg males. Comparison of the regression coefficients for the serum T values over days 30, 35, 40, and 50 also indicated statistical differences in the two curves of developmental changes in T. The pubertal rise in B10D1F1 but not D1B10F1 males was found to be steeper in slope over days 30, 35, 40, and 50 than that of C57BL/10/Bg males. These data suggest that during the pubertal period there may be a more rapid increase in serum T titer associated with the DBA/1 Y-chromosome. However, the developmental curves of T for the two reciprocal hybrids were not statistically different from each other or from that of the DBA/1/Bg males. These findings are suggestive of a Y-chromosome effect on developmental changes in T and of a genetic correlation with intermale aggression.