Genomic variants in an inbred mouse model predict mania-like behaviors.

Contemporary rodent models for bipolar disorders split the bipolar spectrum into complimentary behavioral endophenotypes representing mania and depression. Widely accepted mania models typically utilize single gene transgenics or pharmacological manipulations, but inbred rodent strains show great potential as mania models. Their acceptance is often limited by the lack of genotypic data needed to establish construct validity. In this study, we used a unique strategy to inexpensively explore and confirm population allele differences in naturally occurring candidate variants in a manic rodent strain, the Madison (MSN) mouse strain. Variants were identified using whole exome resequencing on a small population of animals. Interesting candidate variants were confirmed in a larger population with genotyping. We enriched these results with observations of locomotor behavior from a previous study. Resequencing identified 447 structural variants that are mostly fixed in the MSN strain relative to control strains. After filtering and annotation, we found 11 non-synonymous MSN variants that we believe alter protein function. The allele frequencies for 6 of these variants were consistent with explanatory variants for the Madison strain's phenotype. The variants are in the Npas2, Cp, Polr3c, Smarca4, Trpv1, and Slc5a7 genes, and many of these genes' products are in pathways implicated in human bipolar disorders. Variants in Smarca4 and Polr3c together explained over 40% of the variance in locomotor behavior in the Hsd:ICR founder strain. These results enhance the MSN strain's construct validity and implicate altered nucleosome structure and transcriptional regulation as a chief molecular system underpinning behavior.

Pinworm detection in mice with immunodeficient (NOD SCID) and immunocompetent (CD-1 and Swiss) soiled bedding sentinels in individually ventilated cage systems.

Sentinel exposure to soiled bedding is frequently used for health monitoring of mice housed in individually ventilated cage systems (IVCS). Despite its advantages, the use of soiled bedding sentinels (SBSs) is far for being a reliable method. Two studies were conducted to evaluate the sensitivity of immunodeficient SBSs NOD.CB17-Prkdc(scid)/NCrHsd (NOD SCID) against two immunocompetent outbred strains, Hsd:ICR (CD-1) and RjOr1:Swiss (Swiss) to pinworm detection in IVCS-housing. Four different diagnostic methods were used: perianal tape test, fecal flotation, plate method and histology. Positivity was considered if at least one of the techniques used was positive. In the first study NOD SCID were more sensitive than CD-1 SBSs (P < 0.05), and except for the fecal flotation test performed at week 6, all the diagnostic methods were more sensitive with NOD SCID mice (P < 0.05). In the second study differences between the Swiss and NOD SCID mice were less obvious (P = 0.08). When compared separately, the different diagnostic methods, except for the fecal flotation test, were all more sensitive in the NOD SCID mice (P < 0.05). In addition, the anal tape test in the Swiss SBSs was more sensitive at week 7 than at week 15 (P < 0.05). In conclusion, combining various diagnostic techniques and samplings at week 7 post-exposure with non-invasive methods increases the rate of pinworm detection. Immunodeficient SBSs showed higher sensitivity than immunocompetent ones. Thus, use of immunodeficient SBSs is highly recommended in health control protocols.

Spontaneous mutant ICR kuru2 might be another shaker-2 deaf mouse.

BACKGROUND: We have established a mouse model of spontaneous deafness by sib-inbreeding over 10 years. The mouse was designated as kuru(2) and has been previously reported in this Journal. MATERIALS AND METHODS: In order to identify the genetic abnormality, the mouse was back-crossed to Mus musculus castaneus (CAST), and myosine 15 or myoXV on chromosome 11 was assumed to be the responsive gene. The background abnormality was identified by gene sequencing. RESULTS: Deletion of 2446 base pairs occurred in the mouse (from 28795 to 31241 in the complete sequence of the Mus musculus unconventional myosin-15 gene; NCBI accession: AF144093). DISCUSSION: The myosin ATP-binding site is present in the deleted area. Considering the function that the affected area regulates and previous reports, hearing loss of the examined mouse is attributable to the abnormality of the myoXV gene and this mouse might be another type of shaker-2 deaf mouse.

Comparative analysis of the behavioral and biomolecular parameters of four mouse strains.

The use of mice as experimental models in pharmacological and biochemical research began over 100 years ago, during which time different mice strains with specific features were developed. Numerous studies demonstrate that the pharmacological efficacy of various compounds significantly varies among different animal strains, a factor which must be considered when analyzing experimental data. The Sabra strain, developed more than 35 years ago, is widely used for research in Israel but has an unclear origin and is not characterized as well as other strains. Comparative analyses of the molecular characteristics of Sabra and other strains should help to understand their characteristics and to enhance the validity of their experimental use. Thus, four mouse strains-outbred ICR and Sabra as well as inbred C57Bl/6J and Balb/c were compared. Animals' weight, blood corticosterone and hippocampal BDNF mRNA levels were measured, and animals' behavior was compared using the EPM, open field, FST, and hot plate tests. We found that although Sabra mice are bigger and heavier than other tested lines, this is not reflected in behavior or in biomolecular features, wherein Sabra mice lay within the diapason of other tested animals. Thus, behavioral tests of anxiety-like behavior and locomotor activity revealed that Sabra mice scored close to the mean of all tested lines. Analysis of blood corticosterone levels did not show significant differences among tested strains. We also found a correlation between general and locomotor activity of the tested strains and their hippocampal BDNF mRNA expression. In summary, we may conclude that Sabra mice have traits similar to the better known lines, and therefore they are good subjects for neuroscience research.

Comparative study of circadian variation in numbers of peripheral blood cells among mouse strains: unique feature of C3H/HeN mice.

We examined strain differences in numbers of blood cells and their circadian rhythms in male Jcl:ICR, BALB/cA, C57BL/6J and C3H/HeN mice. The total numbers of circulating white blood cells (WBCs) were increased during subjective day and night, and the peaks in the active period were common to all strains. However, the number of WBCs in C3H/HeN mice remained lower and plasma levels of corticosterone (CS) were slightly higher throughout the day compared with the other strains. The numbers of circulating red blood cells (RBC) also differed according to strain. The numbers of RBCs, hematocrit (HCT) and hemoglobin (HGB) were considerably lower in C3H/HeN mice compared with the other strains, although mean corpuscular hemoglobin (MCH) and mean corpuscular volume (MCV) were highest among the tested strains. We found that serum erythropoietin (EPO) levels were considerably higher in C3H/HeN mice than in the other three strains. The high EPO level might be related to the unique features of RBCs in C3H/HeN mice. The present observations provide basic information about the numbers of peripheral blood cells and their circadian rhythm in mouse models and also demonstrate a unique feature of C3H/HeN mice.

Putative chemical signals about sex, individuality, and genetic background in the preputial gland and urine of the house mouse (Mus musculus).

To explore whether preputial gland secretions and/or urine from the house mouse (Mus musculus) can be used for coding information about sex, individuality, and/or the genetic background of strain [ICR/albino, Kunming (KM), and C57BL/6], we compared the volatile compositions of mouse preputial glands and urine using a combination of dichloromethane extraction and gas chromatography coupled with mass spectrometry (GC-MS). Of the 40 identified compounds in preputial gland secretions, 31 were esters, 2 sesquiterpens, and 7 alcohols. We failed to find any compound unique to a specific sex, individual, or strain. However, many low molecular weight compounds between the sexes, most compounds among individuals, and several compounds among the 3 strains varied significantly in relative ratios. These quantitative differences in preputial gland volatiles (analog coding) are likely to convey information about sex, individual, and the genetic background of mouse strain. We identified 2 new main and male-elevated compounds, 1-hexadecanol (Z=3.676, P=0.000, N=19 in ICR; Z=3.576, P=0.000, N=18) and 1-hexadecanol acetate (Z=3.429, P=0.000, N=19 in ICR; Z=3.225, P=0.001, N=18), which were eluted in GC chromatogram after the 2 sesquiterpens. They might also be potential male pheromones, in addition to the well-known E-beta-farnesene and E,E-alpha-farnesene. Additionally, a few compounds including 1-hexadecanol also varied with strains and might also code for genetic information. Of the 9 identified volatile compounds in male urine, (s)-2-sec-butyl-4,5-dihydrothiazole and R,R-3,4-dehydro-exo-brevicomin are known urine-originated male pheromones from previous studies. We also detected 6-hydroxy-6-methyl-3-heptanone, a male urinary pheromonal compound, which had not been directly detected by GC-MS previously. Chemical analysis shows that the genetically more closely related ICR and KM strains had a higher similarity in the volatile compositions of preputial glands and urine than that between ICR or KM and C57BL/6. R,R-3,4-dehydro-exo-brevicomin, in particular, was sensitive to genetic shifts and differed in relative abundance among the 3 strains, whereas (s)-2-sec-butyl-4,5-dihydrothiazole differed between ICR or Km and C57BL/6. Hence, these 2 compounds might code for information about their genetic background.

Baseline and stress-induced plasma corticosterone concentrations of mice selectively bred for high voluntary wheel running.

The hypothalamic-pituitary-adrenal (HPA) axis is important in regulating energy metabolism and in mediating responses to stressors, including increasing energy availability during physical exercise. In addition, glucocorticoids act directly on the central nervous system and influence behavior, including locomotor activity. To explore potential changes in the HPA axis as animals evolve higher voluntary activity levels, we characterized plasma corticosterone (CORT) concentrations and adrenal mass in four replicate lines of house mice that had been selectively bred for high voluntary wheel running (HR lines) for 34 generations and in four nonselected control (C) lines. We determined CORT concentrations under baseline conditions and immediately after exposure to a novel stressor (40 min of physical restraint) in mice that were housed without access to wheels. Resting daytime CORT concentrations were approximately twice as high in HR as in C mice for both sexes. Physical restraint increased CORT to similar concentrations in HR and C mice; consequently, the proportional response to restraint was smaller in HR than in C animals. Adrenal mass did not significantly differ between HR and C mice. Females had significantly higher baseline and postrestraint CORT concentrations and significantly larger adrenal glands than males in both HR and C lines. Replicate lines showed significant variation in body mass, length, baseline CORT concentrations, and postrestraint CORT concentrations in one or both sexes. Among lines, both body mass and length were significantly negatively correlated with baseline CORT concentrations, suggesting that CORT suppresses growth. Our results suggest that selection for increased locomotor activity has caused correlated changes in the HPA axis, resulting in higher baseline CORT concentrations and, possibly, reduced stress responsiveness and a lower growth rate.

Human adenosine A(3) receptor leads to intracellular Ca(2+) mobilization but is insufficient to activate the signaling pathway via phosphoinositide 3-kinase gamma in mice.

Selective antagonists for the adenosine A(3) receptor (A3AR), a member of the G protein-coupled receptors, have been indicated as potential drugs for anti-asthma or anti-inflammation. However, potent antagonists for the rodent A3AR have not been identified. To evaluate the pharmacological effects of human A3AR antagonists in mice, we here generated A3AR-humanized mice, in which the mouse A3AR gene was replaced by its human counterpart. The expression levels of human A3AR in the A3AR-humanized mice were equivalent to those of mouse A3AR in wild-type mice. Elevation of the intracellular Ca(2+) concentration induced by an A3AR agonist was observed in bone marrow-derived mast cells from the A3AR-humanized mice and this Ca(2+) mobilization was completely antagonized by a human A3AR antagonist. However, antigen-dependent degranulation was not potentiated by the A3AR agonist in the mast cells from A3AR-humanized mice. The agonist-stimulated human A3AR did not lead to the phosphorylation of either extracellular signal-regulated kinase 1/2 or protein kinase B in A3AR-humanized mice. The rate of human A3AR internalization in the mast cells was also markedly decreased compared with that of mouse A3AR in the mast cells. These results demonstrate that the human A3AR is insufficient to activate phosphoinositide 3-kinase gamma-dependent signaling pathways in mice, probably due to the uncoupling of member(s) of the G proteins, which are capable of activating phosphoinositide 3-kinase gamma, to the human A3AR, despite the mouse G protein(s) responsible for the Ca(2+) elevation are coupled with the human A3AR.

Microsatellite genotyping for genetic quality testing using sperm cells in the mouse.

We attempted to determine the number of sperm cells required for genotyping of one microsatellite marker. The crude genomic DNA extracted from about 760 or more sperm cells gave sufficient quantity of PCR product using a 20 microl-scale PCR. We also studied the effects of non-ionic detergents on extraction of crude sperm genomic DNA. PCR products amplified with the crude sperm genomic DNA extracted using the lysis buffer supplemented with non-ionic detergents showed much clear bands. In conclusion, our results suggest that a small part of the frozen sperm, which is less than 1/10 of the original volume (10 microl), provides sufficient quantity of template DNA for genetic quality testing.

Polymorphic microsatellite markers in the outbred CFW and ICR stocks for the generation of speed congenic mice on C57BL/6 background.

Reliable definition of the phenotype of particular alleles is carried out in the genetic background of inbred strains. Appearance of mutations in outbred mice therefore requires the generation of congenic mice. The aim of this study was the establishment of a list of polymorphic microsatellite markers which can be used in a polymerase chain reaction (PCR)-based marker-assisted selection protocol (MASP) to allow the use of the two common outbred stocks, CFW and ICR, as donor animals for the fast generation of congenic C57BL/6 mice. The selection of informative microsatellite markers was carried out to provide a simple evaluation of the PCR products by conventional agarose gel electrophoresis. Outbred mice from three suppliers were examined. In total, 153 microsatellite loci were analysed. Here we present 76 and 70 microsatellite markers polymorphic for the outbred ICR and CFW stocks compared to C57BL/6. At least three microsatellite loci per chromosome were chosen as informative markers for the autosomal genome, giving rise to a maximum marker distance of 58 cM. Thus, additional individual markers have to be selected for the respective outbred mouse which is chosen as a donor animal.

Sleep time following anesthesia in mouse lines selected for resistance or susceptibility to fescue toxicosis.

In previous work, a mouse line selected for resistance (R) to fescue toxicosis had higher activities of two hepatic Phase II detoxification enzymes than a mouse line selected for fescue toxicosis susceptibility (S). The primary objective of the present study was to determine whether those same lines also differed in hepatic Phase I enzyme activity, estimated from sleep time (ST) following sodium pentobarbital anesthesia. Additional objectives were to determine whether ST differences between lines were modulated by endophyte-infected fescue in the diet (with or without an enzyme inducer) and whether ST of individual mice was correlated with the effect of a toxin-containing diet on the postweaning growth of those mice. In Exp. I, 24 males from each line were randomly assigned to each of five diets: control (commercial rodent food meal); E+ (50% endophyte-infected fescue seed, 50% control); E+P (the E+ diet supplemented with 1,000 ppm phenobarbital); E- (50% endophyte-free fescue seed, 50% control); and E-P (the E- diet supplemented with 1,000 ppm phenobarbital). After 4 wk on these diets, ST was measured on all the mice. A second ST was recorded on each mouse by randomly sampling one-fourth of the population after 1, 2, 3, or 4 wk on a pelleted rodent food diet. Regardless of diet, R mice had shorter first and second ST than S mice (P < 0.01), suggesting higher hepatic Phase I microsomal enzyme activity. Mice on both phenobarbital-supplemented diets had shorter first ST than mice whose diets did not include that microsomal enzyme inducer (P < 0.01). In Exp. II, ST was measured on male and female R and S mice (n = 280) after they had been fed the E- diet for 2 wk, then the E+ diet for 2 wk, and then a pelleted rodent food diet for 2 wk. Growth response to the E+ diet was the percentage of reduction in gain on the E+ diet compared to gain on the E- diet the previous 2 wk. As in Exp. I, S mice slept longer than R mice (P < 0.01). The residual correlation between ST and gain reduction associated with the E+ diet equaled 0.04. Thus, an animal's apparent Phase I enzyme activity did not predict its growth rate depression on the toxin-containing diet. Based on these and previous studies, divergent selection for toxicosis response in mice was successful partially by causing divergence in activities of hepatic Phase I and II detoxification enzymes.

Evolution of a small-muscle polymorphism in lines of house mice selected for high activity levels.

To study the correlated evolution of locomotor behavior and exercise physiology, we conducted an artificial selection experiment. From the outbred Hsd:ICR strain of Mus domesticus, we began eight separate lines, each consisting of 10 breeding pairs. In four of the lines, we used within-family selection to increase voluntary wheel running. The remaining four lines were random-bred (within lines) to serve as controls. Various traits have been monitored to test for correlated responses. Here, we report on organ masses, with emphasis on the triceps surae muscle complex, an important extensor of the ankle. Mice from the selected lines exhibit reduced total body mass, increased relative (mass-corrected) kidney mass, and reduced relative triceps surae mass. In addition, a discrete muscle-mass polymorphism was observed: some individuals had triceps surae that were almost 50% lighter than normal for their body mass. This small-muscle phenotype was observed in only three of the eight lines: in one control line, it has fluctuated in frequency between zero and 10%, whereas in two of the selected lines it has increased in frequency to approximately 50% by generation 22. Data from a set of parents and offspring (generations 23 and 24) are consistent with inheritance as a single autosomal recessive allele. Evidence for the adaptive significance of the small-muscle allele was obtained by fitting multiple-generation data to hierarchical models that include effects of genetic drift and/or selection. The small-muscle allele is estimated to have been present at low frequency (approximately 7%) in the base population, and analysis indicates that strong selection favors the allele in the selected but not control lines. We hypothesize that the small muscles possess functional characteristics and/or that the underlying allele causes pleiotropic effects (e.g., reduced total body mass; increased relative heart, liver, and kidney mass) that facilitate high levels of wheel running. Nevertheless, at generation 22, wheel running of affected individuals did not differ significantly from those with normal-sized muscles, and the magnitude of response to selection has been similar in all four selected lines, indicating that multiple genetic "solutions" are possible in response to selection for high activity levels.

Sleep-time variation for ethanol and the hypnotic drugs tribromoethanol, urethane, pentobarbital, and propofol within outbred ICR mice.

To evaluate the phenotypic variation within a commercial outbred mouse stock, we examined sleep-time (or duration of loss of righting reflex) of outbred ICR mice after i.p. injection of ethanol (4.0 g/kg of body weight), urethane (1.3 g), tribromoethanol (250 mg), and pentobarbital (60 mg), and after i.v. injection of propofol (30 mg). We observed high-grade individual differences in sleep-time that ranged from 0 to 179 min, 83.1 +/- 4.3 (mean and SEM of 100 mice) for ethanol; 0 to 169 min, 64.5 +/- 3.1 for pentobarbital; 0 to 160 min, 36.6 +/- 3.6 for urethane; 0 to 120 min, 21.5 +/- 2.2 for tribromoethanol; and 3 to 20.5 min, 7.1 +/- 0.3 for propofol. This extensive phenotypic variance within the outbred stock was as great as the variation reported among inbred strains or selected lines, and the varied susceptibility within the colony was inherited by Jcl:ICR-derived inbred strains IAI, ICT, IPI, and IQI. The range of sleep-time variance for ethanol, pentobarbital, urethane, tribromoethanol, and propofol within four-way cross hybrid Jcl:MCH(ICR) mice was 86.6%, 63.3%, 124%, 61.0%, and 53.1% that of outbred Jcl:ICR mice, respectively. The present study indicates that phenotypic variance within an outbred Jcl:ICR stock was at high risk for susceptibility to the drugs that depress the central nervous system and that Jcl:ICR-derived inbreds may be an excellent source of animal models for studying the anesthesia gene.

Genetic selection of mice for high voluntary wheel running: effect on skeletal muscle glucose uptake.

Effects of genetic selection for high wheel-running activity (17th generation) and access to running wheels on skeletal muscle glucose uptake were studied in mice with the following treatments for 8 wk: 1) access to unlocked wheels; 2) same as 1, but wheels locked 48 h before glucose uptake measurement; or 3) wheels always locked. Selected mice ran more than random-bred (nonselected) mice (8-wk mean +/- SE = 8,243 +/- 711 vs. 3,719 +/- 233 revolutions/day). Body weight was 5-13% lower for selected vs. nonselected groups. Fat pad/body weight was ~40% lower for selected vs. nonselected and unlocked vs. locked groups. Insulin-stimulated glucose uptake and fat pad/body weight were inversely correlated for isolated soleus (r = -0.333; P < 0.005) but not extensor digitorum longus (EDL) or epitrochlearis muscles. Insulin-stimulated glucose uptake was higher in EDL (P < 0.02) for selected vs. nonselected mice. Glucose uptake did not differ by wheel group, and amount of running did not correlate with glucose uptake for any muscle. Wheel running by mice did not enhance subsequent glucose uptake by isolated muscles.

Opposing pharmacological actions of cepharanthin on lipopolysaccharide-induced histidine decarboxylase activity in mice spleens.

A biscoclaurin alkaloid preparation, cepharanthin (Ceph), is reported to have opposing pharmacological effects, enhancement or depression, on several cells and tissues, although detailed mechanisms remain unclear. Previously, we reported that Ceph enhanced lipopolysaccharide (LPS)-induced histidine decarboxylase (HDC) activity in mice spleens by consecutive pre-administration. In this study, we examined the pharmacological effects on HDC activity of a single Ceph pre-administration to test the influence of the administration method. Consequently, HDC activities were decreased by a single administration 15 minutes before LPS challenge in ddY and ICR mice spleens. Moreover, to further examine this suppressing effect, we employed genetically mast cell-deficient WBB6F1 W/Wv (W/Wv) mice to avoid the influence of mast cells. In W/Wv mice, HDC activity was enhanced, but not in the congenic WBB6F1 +/+ mice. These findings suggest that mast cells influence the depressant effect on HDC activity by a Ceph single administration in mast cell sufficient mice.

Hormonal regulation of mitochondrial Tim23 gene expression in the mouse mammary gland.

Tim23, a mitochondrial inner membrane protein, is essential for cell viability. Mouse Tim23 cDNA consisted of 1142 nucleotides plus poly(A) at the 3' end. In situ hybridization showed that mammary epithelial cells expressed Tim23 mRNA during pregnancy. In order to examine the hormonal regulation of the Tim23 gene expression at lactogenesis, the quantity of Tim23 mRNA in the mammary gland was determined by the competitive RT-PCR. The level of Tim23 mRNA was low until mid-pregnancy, increased toward the end of pregnancy and was the highest on day 18 of pregnancy. On day 13 of pregnancy, Tim23 mRNA increased 2.7-fold between 8 and 16 h after ovariectomy but this increase was cancelled out by the simultaneous operation of adrenalectomy. In adreno-ovariectomized mice, the administration of cortisol increased Tim23 mRNA 2-fold but with progesterone, the stimulatory action of cortisol was no longer observed. The results indicated that the expression of the Tim23 gene became active in response to glucocorticoid.

Molecular cloning and sequence analysis of C57BL/6 mouse contrapsin cDNA.

Contrapsin is a member of the serpin superfamily and inhibits trypsin much more strongly than alpha1-antiproteinase. Mouse and rat contrapsins, however, have similarity in sequence to human alpha1- antichymotrypsin. In order to test the hypothesis that reactive site regions of contrapsin family evolved under strong selective pressure, cDNA sequence of C57BL/6 mouse contrapsin was determined and compared with that of ICR mouse. The cDNA sequence of C57BL/6 mouse contrapsin was found to contain an open reading frame encoding polypeptide consisting of 418 amino acid residues. The work reported in this paper shows that the reactive site is not hypervariable as compared with the rest of molecule.

Linkage mapping of the mouse nephrosis (nep) gene to chromosome 15.

ICGN is a partially inbred strain of mice with nephrotic syndrome caused by spontaneous glomerular lesion. It has been reported that the albuminuria in ICGN mouse was controlled by at least a single autosomal recessive gene (nep). In this study, we mapped the nep locus by linkage analysis of backcross progeny between ICGN and MSM mice using DNA pooling method. The linkage analysis revealed that the nep locus was localized on the distal part of chromosome 15.

Differential effects of MK-801 on cerebrocortical neuronal injury in C57BL/6J, NSA, and ICR mice.

1. Antagonists of the N-methyl-D-aspartate (NMDA) glutamate (Glu) receptor, including [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate], dizocilpine maleate (MK-801), injure pyramidal neurons in the posterior cingulate/retrosplenial (PC/RS) cortex when administered systemically to adult rats and mice. 2. These results have, to our knowledge, only been reported previously in Harlan Sprague Dawley albino rats and International Cancer Research (ICR) mice, an outbred albino strain. 3. Male Non-Swiss Albino (NSA) mice, an albino outbred strain, and male C57BL/6J (B6) mice, a pigmented inbred strain, were injected systemically with 1 mg/kg of MK-801 in the first experiment. This dose of MK-801 reliably produces cytoplasmic vacuoles in neurons in layers III and IV of the PC/RS cortex in 100% of ICR mice treated 4. There was a significant difference in the number of vacuolated neurons in B6 and NSA mice, as assessed by ANOVA. The NSA were not significantly different than previously examined ICR mice, but the B6 had fewer vacuolated neurons than either of the two outbred strains. 5. In the second experiment, male NSA, ICR, and B6 mice were injected systemically with a high dose, 10 mg/kg, of MK-801. This dose has been demonstrated to result in necrosis in the same population of neurons injured by lower doses of MK-801. 6. An ANOVA indicated that there was a significant difference among the three strains of mice, and a Fisher's protected t revealed that the B6 mice were significantly different from both the NSA and ICR, but that, with our test, those two strains were indistinguishable. 7. Male ICR, NSA, and B6 mice were tested in the holeboard food search task 5 hours after 1 mg/kg of MK-801. There were significant differences between the strains in performance both pre and posttreatment. The effect of the drug was not statistically significant. 8. These results suggest that there may be a genetically mediated difference in the reaction to NMDA receptor antagonists, a finding which may be important given the NMDA receptor hypofunction hypothesis for the etiology of schizophrenic symptoms.

Differential longevity in mouse stocks selected for early life growth trajectory.

Small body size is associated with superior longevity in several intraspecies comparisons, including dogs bred for specific forms of work, mice and rats fed diets low in calories, rats fed diets low in methionine, and mutant mice whose levels of growth hormone and thyroid hormone are atypically low. To further investigate the interactions among body size, genetic endowment, and longevity, we measured the life span of female mice selectively bred from Institute for Cancer Research stock for differences in rate of body weight gain. These mice were selected for differential rates of growth either early (0-10 days) or later (26-56 days) in the first 2 months of life. The data show a good correlation between the average weight of the stock and its mean longevity, with low body size associated, as predicted, with longer life span. Weight at 3, 6, and 12 months, and weight at peak body weight, are all significant predictors of longevity (among stocks) in univariate regressions; weight at 6 months has the strongest association in stepwise multiple regression. There is no significant correlation between the life span for the stock and the proportion of deaths attributable to neoplasia in this group of mice. The data provide support for the hypothesis that genetic factors that influence early life growth trajectories can have a strong influence on life span. These size-selected mice provide useful tools for analysis of the genetic factors that influence life history parameters, including maturation and aging rates.