Abstract: Mimicking relevant behavioral features of the human pathology is one of the most important challenges for animal models of neurological disorders including Alzheimer disease (AD). Indeed, the most popular genetic AD mouse lines bearing mutations of the amyloid precursor protein (APP) and presenilin 1 genes (PS1), often fail to present robust cognitive deficits or show them only at very advanced ages. It is therefore crucial to identify AD-like behavioral alterations which may reliably reflect the early stages of the pathology, thus permitting tests of more efficient early therapeutic interventions. Here, we demonstrated the very early expression of noncognitive AD-like symptoms, i.e., deficits in social interest, interaction and communication, in APP and APP-PS1 transgenic mice. Conversely, other noncognitive behaviors (sensori-motor gating) as well as cognitive abilities (spontaneous alternation) were unaltered in AD transgenics. Our data suggest that social deficits precede other neuropsychiatric and cognitive AD-like symptoms and can be employed as early markers of AD pathology in genetic mouse models.
Abstract: No animal models of autism spectrum disorders (ASD) with good construct validity are currently available; using genetic models of pathologies characterized by ASD-like deficits, but with known causes, may be therefore a promising strategy. The Fmr1-KO mouse is an example of this approach, modeling Fragile X syndrome, a well-known genetic disorder presenting ASD symptoms. The Fmr1-KO is available on different genetic backgrounds (FVB versus C57BL/6), which may explain some of the conflicting results that have been obtained with these mutants up till now.
Abstract: The R6/1 mouse line is one of the most widely employed models of Huntington Disease (HD), a complex syndrome characterized by motor and non-motor deficits. Surprisingly, its behavioral phenotype during the early phases of the pathology when the motor impairments are not manifest yet has been poorly investigated. It is also not clear whether the expression of HD-like symptoms at the pre-motor stage in this mouse model differs between the two sexes.
Abstract: Acoustic startle response and its plasticity, e.g., habituation and prepulse inhibition (PPI), have been extensively investigated, being altered in several neuropsychiatric disorders. Yet, little is known about the expression of startle-related behaviors during adolescence, a critical phase in the development of a variety of major neuropsychiatric pathologies. The present study investigated for the first time startle behaviors across adolescence in male mice of the inbred strains C57BL/6J and DBA/2J. Pre-pubertal (4 weeks of age) mice displayed reduced startle reactivity and altered PPI compared to adult animals (8 weeks of age), but these effects were observed only in the C57BL/6J strain. Strain differences were also clearly detected for startle response, habituation, and PPI. All effects were modulated by the intensity of the pulse stimulus and were not confounded by differences in anxiety levels. Our data demonstrate that genetic factors and the early adolescent phase are critically important considerations in the design of mouse models of neuropsychiatric disturbances.
Abstract: Animal facilities aim to combine animal welfare with cost-efficiency and limited care staff requirements, and individually ventilated cage (IVC) systems were developed towards these goals. While IVC have great sanitary advantages both for the animals but also for the care staff, these systems involve potentially deleterious features such as high levels of air renewal, noise, and subtle vibrations of the racks because of the air filtering system used, but also reduce the frequency of stressful cage changes. It is unknown in how far these conditions may influence the animals' behavior. This issue becomes critical as many facilities are switching to IVC systems, possibly complicating replication of data or biasing ongoing studies. We investigated the effects of IVC housing in mice on different behaviors including anxiety, exploration, and learning in males and females of three common and phenotypically distant strains. Results demonstrate robust effects of IVC in multiple behavioral tests with the direction of the effect strongly dependent on strain and sex. These data should serve to alert researchers that a switch to IVC housing during the course of an experiment has the potential to bias results in a serious manner. In addition, behavioral baseline data will have to be re-established once the switch has been completed.
Abstract: Glufosinate-ammonium (GLA), the active compound of a worldwide-used herbicide, acts by inhibiting the plant glutamine synthetase (GS) leading to a lethal accumulation of ammonia. GS plays a pivotal role in the mammalian brain where it allows neurotransmitter glutamate recycling within astroglia. Clinical studies report that an acute GLA ingestion induces convulsions and memory impairment in humans. Toxicological studies performed at doses used for herbicidal activity showed that GLA is probably harmless at short or medium range periods. However, effects of low doses of GLA on chronically exposed subjects are not known. In our study, C57BL/6J mice were treated during 10 weeks three times a week with 2.5, 5 and 10mg/kg of GLA. Effects of this chronic treatment were assessed at behavioral, structural and metabolic levels by using tests of spatial memory, locomotor activity and anxiety, hippocampal magnetic resonance imaging (MRI) texture analysis, and hippocampal GS activity assay, respectively. Chronic GLA treatments have effects neither on anxiety nor on locomotor activity of mice but at 5 and 10mg/kg induce (1) mild memory impairments, (2) a modification of hippocampal texture and (3) a significant increase in hippocampal GS activity. It is suggested that these modifications may be causally linked one to another. Since glutamate is the main neurotransmitter in hippocampus where it plays a crucial role in spatial memory, hippocampal MRI texture and spatial memory alterations might be the consequences of hippocampal glutamate homeostasis modification revealed by increased GS activity in hippocampus. The present study provides the first data that show cerebral alterations after chronic exposure to GLA.
Abstract: This report analyses the genetic underpinnings of the proportions of the hippocampal terminal fields in the mouse at the midseptotemporal level. We used 5 inbred strains and all possible F(1) crosses between them (diallel cross). Broad heritabilities ranged from 11 to 53%. Additive genetic variation was present for all phenotypes analyzed. Directional dominance was found for the relative size of the suprapyramidal mossy fiber terminal field only. For the stratum lacunosum-moleculare, ambidirectional dominance emerged. These findings suggest that, in evolutionary history, directional selection has operated for a proportionally large suprapyramidal terminal field. For all other hippocampal variables (viz. the relative sizes for the strata oriens, pyramidale, radiatum, lacunosum-moleculare, CA4, intra- and infrapyramidal mossy fiber terminal field and the absolute size of the regio inferior) past stabilizing selection was inferred.
Abstract: Numerous data from human and animal studies suggest that hippocampal plasticity might be a key element in depression. However, the connection remains loose at best and further data are needed. Human studies are of necessity limited, but animal models can help providing further insight. Unpredictable chronic mild stress (UCMS) is a commonly used model because it mimics depression-like phenotypes satisfactorily. Its rationale is based on the underlying stress-induced difficulties found in many depressed patients. We therefore studied learning and hippocampal neurogenesis in mice from three different inbred strains subjected to UCMS. Learning was assessed in different hippocampus-dependent and independent tasks. The rate of survival of newly generated brain cells was determined in behaviorally-naive animals. Results demonstrated a dramatic reduction of surviving new brain cells in both the hippocampus and the subventricular zone of UCMS-treated animals. This reduction was observed both for neurons and for other cells of the hippocampus. Behavioral data demonstrated an impairment of hippocampus-dependent learning, whereas hippocampus-independent learning was spared. However, the specific results were strongly dependent on strain and sex so that there does not appear to be a direct causative relationship between the deficits in neurogenesis and behavior.
Abstract: The goal of this study was to investigate the influence of 6 months of chronic alcohol consumption on hippocampal neuroanatomy, notably the sizes of the intra- and infrapyramidal mossy fiber (IIPMF) terminal fields, and several behaviors, such as radial-maze learning, intermale aggression and anxiety-like behavior, in three inbred strains of mice (NZB, CBA/H, C57BL/6). Based upon several reports highlighting the toxicity of chronic alcohol exposure on the hippocampus, we expected a general diminution of cognitive abilities, with reduced spatial learning skills, increased aggression and anxiety; and concomitantly, a reduction in the sizes of the IIPMF. Contrary to our hypothesis, we did not find an effect of chronic alcohol exposure, neither an effect per se or in interaction with the genotype. Possible explanations for this unexpected finding include ageing effects and species differences between rats and mice.
Abstract: BACKGROUND: Chromatin remodeling, including changes in histone acetylation, might play a role in the pathophysiology and treatment of depression. We investigated whether the histone deacetylase inhibitor sodium butyrate (SB) administered as single drug or in combination with the selective serotonin reuptake inhibitor (SSRI) fluoxetine exerts antidepressant-like effects in mice. METHODS: Mice (C57BL/6J) received injections of SB, fluoxetine, or a combination of both drugs either acutely or chronically for a period of 28 days and were subjected to a battery of tests to measure anxiety and behavioral despair. Histone acetylation and expression of brain-derived neurotrophic factor (BDNF) were monitored in hippocampus and frontal cortex. RESULTS: Co-treatment with SB and fluoxetine resulted in a significant 20%-40% decrease in immobility scores in the tail suspension test (TST), a measure for behavioral despair, both acutely and chronically. In contrast, decreased immobility after single drug regimens was limited either to the acute (fluoxetine) or chronic (SB) paradigm. Systemic injection of SB induced short-lasting histone hyperacetylation in hippocampus and frontal cortex. Among the four treatment paradigms that resulted in improved immobility scores in the TST, three were associated with a transient, at least 50% increase in BDNF transcript in frontal cortex, whereas changes in hippocampus were less consistent. CONCLUSIONS: The histone deacetylase inhibitor SB exerts antidepressant-like effects in the mouse. The therapeutic benefits and molecular actions of histone modifying drugs, including co-treatment with SSRIs and other newer generation antidepressant medications, warrant further exploration in experimental models.
Abstract: Mice exhibiting deficits in social behavior may provide valuable models for autistic-like behavioral problems. We tested social interactions in male mice from three inbred strains: C57BL/6J (B6), BALB/cJ (C) and DBA/2J (D2). All three strains showed gradual habituation of the number of social interactions with an ovariectomized female over four subsequent 2min sessions, returning to initial levels when presented with another stimulus mouse. Next, we studied males with a knockout mutation in the Fmr1 gene on a B6 background. KO animals showed strongly reduced levels of social interaction, which were about similar as those of habituated controls. This social behavior deficit suggests that Fmr1 KO mice could possibly be used as models for autistic behaviors.
Abstract: The widely accepted stress-diathesis hypothesis of depression postulates that genetic factors contribute to biological vulnerability. Based on this concept, the unpredictable chronic mild stress (UCMS) animal model was developed. Most effects of UCMS can be reversed by antidepressant agents, illustrating a strong predictive validity. In rodents, UCMS also has good face validity as it can elicit depression-like symptoms. While abundant for rats, the UCMS literature on mice is relatively limited. Reports sometimes are contradictory, making it difficult to establish a clear profile of stress-induced depression-like behaviors in mice. As different groups often use different strains for their experiments, differential strain susceptibility to UCMS may provide at least a partial explanation of these discrepancies. Moreover, differences in testing methodology add another level of complexity. Very little is known about the role of genetic factors and their interactions with the environment in the development of stress-induced behavioral changes relevant to depression, though recent studies unequivocally demonstrated the effects of specific gene polymorphisms on stress-induced depressive symptoms, as well as the effects of stress on gene expression. In the present study, we investigated the effects of UCMS on a battery of different tests measuring anxiety and depression-like behaviors in three behaviorally and genetically distinct inbred strains. The goals of these experiments are to obtain a clearer behavioral profile of genetically/phenotypically distant mouse strains after UCMS treatment and to evaluate the limitations and strengths of the UCMS model in mice.
Abstract: Autism is a pervasive developmental disorder appearing before the age of 3, where communication and social interactions are impaired. It also entails stereotypic behavior or restricted interests. Although this disorder was first described in 1943, little is still known about its etiology and that of related developmental disorders. Work with human patients has provided many data on neuropathological and cognitive symptoms, but our understanding of the functional defects at the cellular level and how they come about remains sketchy. To improve this situation, autism research is in need of valid animal models. However, despite a strong hereditary component, attempts to identify genes have generally failed, suggesting that many different genes are involved. As a high proportion of patients suffering from the Fragile X Syndrome show many autistic symptoms, a mouse model of this disorder could potentially also serve as a model for autism. The Fmr1 KO mouse is a valid model of the Fragile X Syndrome and many data on behavioral and sensory-motor characteristics of this model have been gathered. We present here an assessment of autistic features in this candidate model. We conclude that Fmr1 KO mice display several autistic-like features, but more work is needed to validate this model.
Abstract: Many investigators have attempted to confirm the prediction that increased levels of heterozygosity entail greater developmental stability, manifesting itself through decreased phenotypical variation. The evidence presented so far is equivocal. The predicted relationship has been found in some morphological studies, but not in others. I propose that the variability of a character should be seen as different from the character itself. For most morphological characters, natural selection promotes strong canalization of development but, to facilitate responses to environmental changes, the organism needs to retain malleability of physiological and behavioral traits. These different types of selection should lead to distinct genetic architectures for these phenotypes. I report on the results of a diallel cross between four inbred mouse strains. Qualitatively different genetic architectures were in fact revealed for variation in behaviors in the open-field. In a second study, variances of inbred and hybrid populations for hippocampal morphometry were studied. Again, hybrids were not always less variable than inbreds and sometimes even more variable. It follows that there exists no one-to-one relation between heterozygosity and developmental stability.
Abstract: BACKGROUND: The aim of this study was to investigate the effects of prenatal alcohol exposure on radial-maze learning and hippocampal neuroanatomy, particularly the sizes of the intra- and infrapyramidal mossy fiber (IIPMF) terminal fields, in three inbred strains of mice (C57BL/6J, BALB/cJ, and DBA/2J). RESULTS: Although we anticipated a modification of both learning and IIPMF sizes, no such effects were detected. Prenatal alcohol exposure did, however, interfere with reproduction in C57BL/6J animals and decrease body and brain weight (in interaction with the genotype) at adult age. CONCLUSION: Prenatal alcohol exposure influenced neither radial maze performance nor the sizes of the IIPMF terminal fields. We believe that future research should be pointed either at different targets when using mouse models for Fetal Alcohol Syndrome (e.g. more complicated behavioral paradigms, different hippocampal substructures, or other brain structures) or involve different animal models.
Abstract: Disturbances in several reproductive functions of the staggerer cerebellar mutant mouse have been observed. In this study, reproductive efficiency of staggerer mice was compared to normal mice by recording the number of pups produced and the number of oocytes occurring. It was found that staggerer mothers produced smaller litters than controls and the number of oocytes produced in their ovaries was reduced by the staggerer mutation. These results indicate a pleiotropic effect on fertility of the Rora(sg) gene underlying the cerebellar abnormalities of the staggerer mutant.
Abstract: In the present paper we review a series of experiments showing that heritable variations in the size of the hippocampal intra- and infrapyramidal mossy fiber (IIPMF) terminal fields correlate with performance in spatial, but not non-spatial radial-maze tasks. Experimental manipulation of the size of this projection by means of early postnatal hyperthyroidism produces the effects predicted from the correlations obtained with inbred mouse strains. Although the physiological mechanisms behind these correlations are unknown as yet, several lines of evidence indicate that these correlations are causal.
Abstract: In the current minireview, we focus on genetic mouse models of Alzheimer's disease (AD). Because various excellent, up-to-date reviews, special issues, and reliable websites are already dedicated to the genetics of Alzheimer's disease in general and of animal models in particular, this review is not meant to be comprehensive. Rather, we aim to steer the Alzheimer's novice through the recent mouse literature on AD. Special attention will be paid to genetic models that have been tested behaviorally.
Abstract: This note explores the effect of within-strain sample sizes on the correlations between a phenotype and a molecular-genetic marker in a battery of inbred strains. It is shown that the maximum correlation possible between a molecular marker and a behavioral or neuronal phenotype equals the additive-genetic correlation. How close the strain correlation will approach the additive-genetic correlation depends only on heritability and within-strain sample sizes. The equations derived can be used to optimize designs of studies attempting to localize Quantitative Trait Loci utilizing Recombinant Inbred Strains, provided information about the heritability of the character under study is available.
Abstract: Mice carrying engineered genetic modifications have become an indispensable tool in the study of gene functioning. The interpretation of results obtained with targeted mutants is not completely straightforward, however, because of genetic complications due to linkage and epistasis. Effects of closely linked genes flanking the targeted locus might sometimes be responsible for phenotypic changes ascribed to the null mutation. The effects of the latter might also be modified by the general genetic background. This review presents some examples and discusses some simple strategies to deal with these complications.
Abstract: The goal of the Complex Trait Consortium is to promote the development of resources that can be used to understand, treat and ultimately prevent pervasive human diseases. Existing and proposed mouse resources that are optimized to study the actions of isolated genetic loci on a fixed background are less effective for studying intact polygenic networks and interactions among genes, environments, pathogens and other factors. The Collaborative Cross will provide a common reference panel specifically designed for the integrative analysis of complex systems and will change the way we approach human health and disease.
Abstract: In this minireview, we discuss different strategies to dissect genetically the keystones of learning and memory. First, we broadly sketch the neurogenetic analysis of complex traits in mice. We then discuss two general strategies to find genes affecting learning and memory: candidate gene studies and whole genome searches. Next, we briefly review more recently developed techniques, such as microarrays and RNA interference. In addition, we focus on gene-environment interactions and endophenotypes. All sections are illustrated with examples from the learning and memory field, including a table summarizing the latest information about genes that have been shown to have effects on learning and memory.
Abstract: The active component of the acne drug Accutane is 13-cis-retinoic acid (RA), and it is highly teratogenic for the developing central nervous system. Very little is known, however, regarding the effect of this drug on the adult brain. Regions of the brain that may be susceptible to RA are those that continue to generate new neurons. In the adult mouse, neurogenesis is maintained in the hippocampus and subventricular zone. This report demonstrates that a clinical dose (1 mg/kg/day) of 13-cis-RA in mice significantly reduces cell proliferation in the hippocampus and the subventricular zone, suppresses hippocampal neurogenesis, and severely disrupts capacity to learn a spatial radial maze task. The results demonstrate that the regions of the adult brain where cell proliferation is ongoing are highly sensitive to disruption by a clinical dose of 13-cis-RA.
Abstract: This white paper by eighty members of the Complex Trait Consortium presents a community's view on the approaches and statistical analyses that are needed for the identification of genetic loci that determine quantitative traits. Quantitative trait loci (QTLs) can be identified in several ways, but is there a definitive test of whether a candidate locus actually corresponds to a specific QTL?
Abstract: A significant proportion of patients suffering from major clinical depression exhibit sudden bursts of anger often described as "panic attacks without anxiety or fear" or "irritability." We investigated aggressive behavior in mice from four different inbred strains subjected to unpredictable chronic mild stress (UCMS). Our results show that UCMS affects self-grooming behavior, as evaluated by the state of an animal's fur, with severity of symptoms differing according to genetic background. Furthermore, UCMS increased aggression both in a resident-intruder test and between cage-mates. UCMS is therefore a valuable model of the problematic aggressive behavior seen in depressive patients.
Abstract: Inducing null mutations by means of homologous recombination provides a powerful technique to investigate gene function and has found wide application in many different fields. However, it was realized some time ago that the specific way in which such knockout mutants are generated can be confounding, making it impossible to separate the effects of the induced null mutation from those of alleles originating from the embryonic stem cell donor. In addition, effects from null mutations can be altered on different genetic backgrounds. Here we present some simple breeding strategies to test for flanking gene effects that are compatible with the recommendations of the Banbury Conference on Genetic Background in Mice and with common practices of creating and maintaining mouse knockout lines.
Abstract: Previous studies showed the Fmr1 knockout (KO) mouse to be an excellent animal model for human fragile-X syndrome. The aim of this study was to further characterize the phenotype of these animals. Neuroanatomically, KO male mice were compared to wild-types (littermates) with respect to their sizes of hippocampal intra- and infrapyramidal mossy fiber (IIPMF) terminal fields. Behaviorally, they were tested in four different paradigms, each measuring different aspects of cognitive and emotional behavior: elevated plus maze (anxiety), neutral cage (aggression), open field (exploration), and radial maze (spatial memory). The results showed a diminished ability for radial maze learning associated with smaller sizes of IIPMF terminal fields. In addition, Fmr1 knockout animals exhibited increased locomotor activity, while no differences were found for aggression and anxiety. These data suggest the involvement of FMRP protein in the development of spatial learning and the sprouting of IIPMF terminal fields.
Abstract: The inbred strain FVB/N is becoming increasingly popular to generate transgenic animals. We compared animals from this strain with well-characterized C57BL/6J animals on four different behavioral tests: the elevated plus maze test of anxiety, a standard opponent aggression test, the open-field test, and spatial learning in a radial maze. Our results indicate that FVB/N animals have slightly higher levels of anxiety and aggression, are hyperactive, and have a clear learning deficit. The latter finding seems to be related to an exceptionally small intrapyramidal and infrapyramidal mossy fiber projection. It is recommended that transgenic experiments employing this strain use F1 crosses between FVB/N and C57BL/6J as much as possible for behavioral experiments intended to evaluate spatial learning.
Abstract: The convulsant methionine sulfoximine (MSO) is a byproduct of the agenized flour commonly used for feeding domestic animals decades ago. MSO is a powerful glycogenic and epileptogenic agent, and it is an irreversible inhibitor of glutamine synthetase. This latter effect was hypothesized to be responsible for the increase in the incidence of some neuropathologies in humans, such as Alzheimer's disease or Parkinson's disease. In order to test this hypothesis, we chronically administered MSO to two inbred strains of mice, C57BL/6J and BALB/cJ, and analyzed possible alterations in learning and memory features of these mice. Mice were given 20 mg/kg of MSO three times a week for 10 weeks. Spatial learning capabilities assessed with a radial maze were not affected by the long-term MSO treatment, although activity was significantly decreased in BALB/cJ mice. Thus, our data suggest that long-term administration of non-convulsive and non-glycogenic doses of MSO do not alter the spatial memory of mice. Our results do not support the hypothesis that chronic treatment with MSO influences hippocampus-dependent learning abilities in mice.
Abstract: A large variety of apparatus and procedures are being employed to measure mouse exploratory behaviour. Definitions of what constitutes exploration also vary widely. The present article reviews two studies whose results permit a genetic dissection of behaviour displayed in an open-field situation. The results agree that factors representing exploration and stress/fear underlie this type of behaviour. Both factors appear to be linked to neuroanatomical variation in the sizes of the hippocampal intra- and infrapyramidal mossy fibre terminal fields. Multivariate analysis of genetic correlations may render important insights into the structure of behaviour and its relations with neuroanatomical and neurophysiological systems.
Abstract: Mice of the inbred C57BL/6JNmg substrain carry a mutation decreasing the size of the zinc-rich hippocampal intra- and infrapyramidal mossy fibre (IIPMF) terminal fields. In the present experiment, it was investigated whether this neurological mutation has also effects on other characteristics of the brain. No morphological differences were found in two other laminated neural structures, the olfactory bulb, where the accessory granular layer is also rich in zinc terminals, and the cerebellum. However, the mutants had a somewhat inferior performance on a motor function task known to test cerebellar involvement. The present findings confirm that previously found effects of this mutation on different types of behaviour are most probably due to the IIPMF. These substrains provide a powerful tool to localise the gene involved and subsequently investigate the plausible pathways leading from gene to behaviour.
Abstract: Correlations between the densities of ionotropic glutamate, GABA(A), and serotonin binding sites in the hippocampus of seven inbred mouse strains and strain-specific learning capacities in two types of maze were studied. Binding site densities were measured with quantitative receptor autoradiography. Learning capacities were determined in a water maze task as well as in spatial and nonspatial versions of an eight-arm radial maze. The densities of most binding sites differed significantly between the strains in the subfields of Ammon's horn (CA1 and CA3) and the dentate gyrus, except for serotonin binding sites in CA1. By comparing the different strains, significant receptor-behavioral correlations between the densities of the GABA(A) receptors and the activity-dependent behavior in the water maze as well as the spatial learning in the radial maze were found. The densities of D,L-alpha-amino-3-hydroxy-5-methyl-4-isoxalone propionate (AMPA) and kainate receptors correlated positively with learning capacity in the spatial eight-arm radial maze. We conclude that hereditary variations mainly in AMPA, kainate, and GABA(A) receptor densities are involved in behavioral variations in spatial and nonspatial learning tasks.
Abstract: Spontaneous behavior patterns were assessed in eight different behavioral situations in two lines of mice, BR and BS, previously selected for their sensitivity to an anxiogenic benzodiazepine (BZ) receptor inverse agonist, Methyl beta-carboline-3-carboxylate (beta-CCM). BR is highly resistant, and BS, highly sensitive to beta-CCM-induced seizures. Tests used included an assessment of general locomotor activity, several situations classically used for measuring fear-motivated behaviors (open field, thigmotaxis, elevated plus-maze, light-dark discrimination, staircase), a test for measuring exploration (holeboard), and a test for measuring nociception (hot-plate). In the absence of beta-CCM, the results provide evidence of reduced motor activity and higher levels of anxiety in the BR line as compared to the BS line.
Abstract: Males from two substrains of C57BL/6J mice, which have been found to differ for open-field exploration, radial-maze learning, and the sizes of their hippocampal intra- and infra-pyramidal mossy fibre (IIPMF) terminal fields, were compared for offensive aggression, thermoregulatory nest-building, and their behaviour in the Light-Dark choice test. The substrain with the smaller IIPMF showed higher aggression and more nest-building behavior than the one with the larger IIPMF, whereas only tentative differences were found in the Light Dark choice test. These findings confirm and expand on previously found genetic links between the IIPMF and behaviours in mice. These substrains provide a powerful tool to localise the gene involved and subsequently investigate the pathway leading from gene to behaviour.
Abstract: The effect of the non-pseudoautosomal region of the Y chromosome on spatial learning in a radial maze task was examined in two inbred mouse strains, NZB and CBA/H, and their respective congenics for the Y(NPAR). Seven variables reflecting learning performance, learning strategy and lateralisation were measured. We found no substantial effect of the Y(NPAR) on radial maze learning, but modest influences on behavioral strategies. These findings are in agreement with previous results regarding the sizes of the intra- and infrapyramidal mossy fiber (IIPMF) terminal fields.
Abstract: Brain gamma-aminobutyric acid (GABA) levels are involved in intermale aggression in mice. It was therefore expected that animals genetically selected for their sensitivity to the convulsive effects of methyl beta-carboline-3-carboxylate (beta-CCM; BS, beta-CCM sensitive, and BR, beta-CCM resistant), a benzodiazepine (BZ) inverse agonist that specifically binds to the BZ site on the GABA-A receptor complex, would differ in their levels of aggressive behavior. Using two different aggression tests, in two independent experiments, we showed that BS mice are more aggressive than BR animals. The precise mechanisms underlying the observed line differences in beta-CCM sensitivity and aggression remain to be determined.
Abstract: Rose's Lifelines justifiably attacks the rigid genetic determinism that pervades the popular press and even some scientific writing. Genes do not equate with destiny. However, Rose's argument should not be taken too far: genes do influence behavior, in animals as well as in man.
Abstract: Mice were selectively bred according to their sensitivity or their resistance to the convulsive effects of a 4-mg/kg dose of methyl beta-carboline-3-carboxylate (beta-CCM), a benzodiazepine (BZ) receptor inverse agonist. The selection proved to be easy, with a clear separation of the two lines, convulsing with short latencies or resistant, already at the first generation of selection. Selection of a third line of animals convulsing with long latencies did not succeed. 3H-Ro 15-1788 binding analysis provided evidence for a strong decrease in Bmax in the resistant line.
Abstract: The present experiment attempted a behavior-genetic dissection of early behavioral development in laboratory mice. To this end, we used a full, replicated diallel cross to uncover the genetical architecture as well as the multivariate genetic structure underlying early behavioral ontogeny. A number of standard sensorimotor tests were administered on postnatal Days 3, 5, 8, 10, 13, 17, and 22 to a total of 622 pups from 120 litters (4-6 pups per litter) from a four times replicated complete diallel cross between five inbred mouse strains. The first day on which an animal showed adult performance was taken as its score on that test. MANOVA did not show any effects of the pup's sex on the speed of development. Hayman's analysis of variance for diallel tables indicated no or only weak additive-genetic effects. Dominance was absent in almost all cases, except for the auricular startle response, where weak directional dominance for fast development was found. These results are in accordance with an evolutionary past of directional selection for well-canalized development. Factor analyses of the phenotypic and additive-genetic correlation matrices indicate that at least two factors are necessary to describe the behavioral variation.
Abstract: Mus spretus is extensively used in interspecific mouse backcross analyses employed to generate genetic linkage maps. However, little is known about its behavior and neuroanatomy, phenotypes for which large interstrain differences have been observed in Mus musculus domesticus. Behavioral and hippocampal neuroanatomical variables were measured in adult male mice from the inbred strains C57BL/6J (Mus musculus domesticus) and SEG (Mus spretus). Clear differences were found for behavioral responses to novelty in an open field, SEG being much less active than C57BL/6J. Morphometrical analysis of hippocampal terminal fields, visualized with Timm's stain, revealed strain differences only for the size of the intra- and infrapyramidal mossy fiber terminal fields, which were about 3 x larger in C57BL/6J than in SEG. In addition, absolute left-right differences were larger in SEG for the stratum radiatum and stratum oriens. In spite of these behavioral and neuroanatomical differences, the phenotypical scores obtained for SEG do not exceed the range observed for Mus musculus domesticus inbred strains.
Abstract: The size of the intra-/infrapyramidal mossy fiber projections (IIP-MF) and their left/right asymmetry were assessed in 86 mice of either sex, including 26 animals from two mouse lines bred for strong or weak paw preference, 38 mice of a randomly bred F3 generation derived from an eight-way cross, and 22 mice with variably sized corpora callosa in which only the left hippocampus was measured. Prior to morphometry, all mice were tested for paw preference. In addition, we compared the strain means in paw preference as observed in nine inbred mouse strains with known differences in their IIP-MF distribution. Mice bred for strong paw preference had a 70% larger IIP-MF projection than weakly lateralized and dyscallosal mice; random-bred mice fell in-between the extremes. The individual scores of the strength of paw preference were positively correlated with the extent of the IIP-MF. Among the inbred strains, the extent of the IIP-MF was similarly correlated with the strength of paw preference. The acallosal mice showed a significant negative correlation between extent of the IIP-MF projection and test-retest reliability of paw use. The left-right asymmetry of the IIP-MF was significantly and positively correlated with the direction of paw preference in the entire sample. We conclude that size and asymmetry of the IIP-MF projection are some of the many factors influencing the direction of paw preference and its strength, albeit moderately. We hypothesize that mice with larger IIP-MF projections use a given paw more consistently, being perhaps more resistant to interferences, and that left-right asymmetries of the IIP-MF may bias and/or reinforce an initial choice of a paw. In addition, the data provide another example of correlations between IIP-MF variations and nonspatial behavior.
Abstract: The effects of the nonpseudoautosomal region of the Y chromosome (YNPAR) on hippocampal morphology have been investigated in the inbred mouse strains NZB/BINJ and CBA/H, using comparisons between the two parentals and their respective congenics N.H-YNPAR and H.N-YNPAR. Results obtained depend upon the hippocampal variable measured. YNPAR had no effect on the sizes of the stratum oriens, hilus, or mossy fiber terminal fields (both suprapyramidal and intra- and infrapyramidal). However, in interaction with the strain background, it affected the strata lacunosum-moleculare, radiatum, and pyramidale. Possible relationships among gene(s), mossy fiber terminal fields, and intermale aggression are discussed.
Abstract: We investigated the contribution of the septo-hippocampal cholinergic and GABAergic system to spatial and nonspatial aspects of learning and memory that had previously been found to correlate with the extent of the hippocampal intra- and infrapyramidal mossy fiber projection in different inbred mouse strains. The following cholinergic and GABAergic markers were measured in the septi and hippocampi of male mice: the number of cholinergic and parvalbumin-containing neurons in the medial septum/vertical limb of the diagonal band of Broca (MS/vDB), the number of septo-hippocampal cholinergic and GABAergic projection neurons, the density of cholinergic fibers in different hippocampal subfields, and the density of muscarinic receptors (predominantly M1 and M2) in the hippocampus. In addition, animals were behaviorally tested for spatially dependent and activity-dependent variables in a water maze and spatial and nonspatial working and reference memory in different experimental set-ups in an eight-arm radial maze. Using only those variables for which significant strain differences were obtained, we looked for covariations between behavior and neuroanatomy. The density of cholinergic fibers in the dentate gyrus was significantly correlated with activity-dependent learning in the water maze, whereas the number of septo-hippocampal cholinergic projection neurons correlated with spatial and, to a lesser extent, also with nonspatial aspects of radial maze learning. Only weak correlations were found between receptor densities and behavioral traits. From these data we conclude that variations in the septo-hippocampal cholinergic system, like variations in the mossy fiber projection, entail functional consequences for different types of maze learning in mice.
Abstract: In mice, parity and previous experience with pups may influence a mother's behavior towards her pups, thus possibly causing postnatal maternal effects on the subsequent development of the pups. The present experiment addressed the question whether parity also might have prenatal effects. We studied 622 pups from second or third litters that originated from 25 genetically different populations and had been fostered to random-bred lactating females. Development of responses was significantly delayed in mice from third litters, when compared to pups from second litters in three out of five sensorial and four out of eight motor tests. In addition, pups from second litters initially were slightly heavier than those from third litters. This difference in body weight disappeared after the 10th day postnatally. However, it should be noted that effect sizes were quite small.
Abstract: The influence of the non-pseudoautosomal region of the Y chromosome (YNPAR) on the sizes of the hippocampal intra- and infrapyramidal mossy fiber (IIPMF) terminal fields were examined in wild house mice. For this purpose selection lines for short attack latency (SAL), long attack latency (LAL), and their respective congenics for the YNPAR were used. We found an incremental effect of the (non-aggressive) LAL YNPAR, combined with an additive effect of the line background on the sizes of the IIPMF terminal fields. In contrast, only the line background affected attack latency. The implications of this finding for the previously observed correlation between the size of the IIPMF and aggression in male house mice are discussed.
Abstract: Paradise fish exhibit complex, environment-specific behavioral responses which consist of behavioral elements (motor and posture patterns) appearing in a typical, correlated manner. The genetic and environmental components underlying these phenotypical correlations have not been comprehensively investigated. Therefore, we have analyzed the behavioral elements of paradise fish from the nine populations of a 3 x 3 full diallel cross by employing a bivariate extension of the Hayman-Jinks variance-covariance analysis, demonstrating the presence of significant environmental and genetic correlations. To investigate the multivariate structure of the correlation matrices obtained, we subjected the phenotypical, environmental, additive genetic, and dominance correlations to principal-component analyses (PCAs). After rotation, the phenotypical principal factor pattern found was similar to previously obtained ones, suggesting stable underlying biological mechanisms. The environmental PCA extracted several environmental principal factors that were highly situation-specific. PCAs of the matrices of genetic correlations extracted only a small number of genetic principal factors which were not situation-specific, suggesting a relatively simple underlying genetic structure.
Abstract: Large, but non-pathological, individual differences in neuroanatomy of the brain exist in rodents, which have been shown to covary with behavioral traits. In the present review, we explore the relationship between variations in the extent of the intra- and infrapyramidal mossy fiber projection of the hippocampus and spatial and non-spatial learning capacities in mice and rats. Preliminary data concerning anatomical variation in the septo-hippocampal cholinergic system and its consequences for individual behavior are also presented. We conclude that the hippocampal intra- and infrapyramidal mossy fiber projection is intimately involved in the regulation of spatial, but not of non-spatial learning capabilities. Although lesion studies have shown that a well-functioning cholinergic system is a prerequisite for performance in spatial learning tasks, our preliminary data suggest that individual differences in the cholinergic system do not explain individual differences in learning.
Abstract: The capacity to initiate attack behavior against a passive standard opponent was measured in 140 male mice belonging to seven different inbred mouse strains. Large strain differences were found, which strongly correlated with the size of the hippocampal intra- and infrapyramidal mossy fibers terminal fields. These results, combined with those obtained from earlier experiments, point to a possible modulating role of the hippocampus in the regulation of attack behavior in male mice.
Abstract: The sizes of the hippocampal intra- and infrapyramidal mossy fiber terminal fields (IIPMF) of mice from two lines bidirectionally selected for attack latency were measured. Aggressive males possess smaller IIPMF than do non-aggressive ones. We hypothesize that both differences in aggression and sizes of the IIPMF may be mediated by perinatal testosterone.
Abstract: Compared to the parental strain C57BL/6J, male mice from the mutated substrain C57BL/6JNmg show smaller hippocampal intra- and infrapyramidal mossy fiber projections and a correlated inability to master a simple spatial radial-maze task. Possibly, these two substrains differ for only one single gene, making them a valuable model to investigate the physiological pathways leading from genotype to neurobehavioral phenotype.
Abstract: In two preceding papers we reported on two closely related inbred mouse strains, ABG and AB@Halle that display very large differences in isolation-induced intermale aggression. In the present article we investigated animals from a complete Mendelian cross between these strains to test the hypothesis that the behavioral difference is due to genetic variation at only a few loci, possibly only one. In the quantitative-genetic analysis of generation means and variances for the behavioral variables analyzed, relatively simple models were found. As epistasis was present in some cases, the monogenic hypothesis could not be confirmed. Also, the analysis of the segregating generations by means of Collins' nonparametric method revealed significant deviations of observed from expected distributions. We conclude that differences at more than only one single locus are correlated with the behavioral difference.
Abstract: The genetic-correlational approach provides a very powerful tool for the analysis of causal relationships between phenotypes. It appears to be particularly appropriate for investigating the functional organization of behavior and/or causal relationships between brain and behavior. A method for the bivariate analysis of diallel crosses that permits the estimation of correlations due to environmental effects, additive-genetic effects, and/or dominance deviations is described, together with a worked-out example stemming from a five times replicated 4 x 4 diallel cross between inbred mouse strains. The phenotypes chosen to illustrate the analysis were locomotor activity and rearing frequency in an open field. Large, positive additive-genetic and dominance correlations between these two phenotypes were obtained. This finding was replicated in another, independently executed, diallel cross.
Abstract: Recently, we reported on two closely related inbred mouse strains, ABG and AB//Halle, that display extreme differences in isolation-induced intermale aggression. In the present article we investigated the influence of both maternal and social postnatal environmental influences. No effects were found of the postnatal maternal environment. Likewise, whether animals after weaning were housed together in same-strain or mixed-strain groups did not influence their subsequent aggressive behavior. We conclude that the aggressive behavior of ABG and AB//Halle is rather robust with regard to postnatal environmental modification and that the difference between the two strains is most likely due to only few genetic factors.
Abstract: Male mice from nine inbred mouse strains were tested at the age of 3 months in either a spatial or a non-spatial version of the radial maze. Only four out of eight arms contained food rewards, permitting simultaneous assessment of working and reference memory in both situations. Other animals from the same strains were processed histologically to estimate the strain-specific extents of the mossy fibre projections. No significant between-task correlations were obtained for either working or reference memory. However, measures of working and reference memory correlated with each other within tasks. This suggests that these concepts may perhaps not be validly used in the mouse. Large, positive correlations of the size of the intra- and infrapyramidal mossy fibre projection with both working and reference memory were obtained in the spatial radial maze task, but not in the non-spatial one. We conclude that heritable variations of the hippocampal intra- and infrapyramidal mossy fibre projection influence processes related to spatial learning capabilities in radial mazes.
Abstract: Behavioral responses to novelty in an open field and spatial learning in a radial maze with four arms out of eight reinforced were tested in male and female CFY and Long-Evans rats. Subsequently, the sizes of the total hippocampi and of various hippocampal cell layers and terminal fields at the midseptotemporal level were measured in Timm-stained sections. No strain differences were found in the open field (except for defecation). In the radial maze, Long-Evans rats showed better spatial reference memory capabilities than rats of the CFY strain. The relative sizes of the intra- and infrapyramidal mossy fiber (IIP-MF) projections did not differ between the strains. Within the more variable CFY strain, a positive correlation between the size of the IIP-MF projection and radial maze performance was found. The absolute sizes of the entire hippocampi and all hippocampal layers at the midseptotemporal level were larger in the CFY strain. The size of the suprapyramidal mossy fiber projection was related to the number of granule cells and to the ratio between granule and CA3 pyramidal cells. In contrast, the size of the IIP-MF projection did not correlate with either of these variables. The results indicate that the size of the mossy fiber projection may be determined mainly by the available postsynaptic surface on the dendrites of CA3 pyramidal neurons. Furthermore, an increased number of granule cells and their larger projection to the apical dendrites of pyramidal neurons does not appear to result in physiological changes with behavioral consequences.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Heritable variation of mossy fiber synapses in hippocampal region CA3 was studied in the two inbred mouse strains C3H and CPB-K. Previous Timm studies had shown a larger mossy fiber projection in C3H mice. In contrast, synaptic boutons of CPB-K mice were larger in size and perimeter and were contacted by more dendritic spines than in C3H mice. These results point to an inverse relationship between the size of the mossy fiber projection and the number of spine synapses formed by an individual mossy fiber bouton. Thus, the fiber density of a projection may be crucial for the actual morphology of the synaptic contacts formed.
Abstract: Previously, we have demonstrated that hippocampal mossy fibers, containing the opioid peptide dynorphin B, are functionally connected with the gene-dependent exploratory behavior of mice. In order to seek further evidence of causal relationships between dynorphin B action and exploration, a quantitative-genetic method was chosen. For this purpose, mice from the inbred strains C57BL/6, DBA/2, BLN, and CPB-K were used. By means of radioimmunoassay, the hippocampal level of dynorphin B was monitored in mice that had been exposed to environmental novelty, as compared to naive animals. Clear evidence was obtained that novelty induces the release of hippocampal dynorphin B. Furthermore, low tissue content was found to be causally connected with high exploratory scores.
Abstract: Our previous work provided evidence that hippocampal opioid peptides form an important neurochemical substrate underlying the gene-dependent exploratory behavior of mice. A prominent hippocampal opioid is dynorphin B, which resides in the mossy fibers exclusively. In order to seek support for causal relationships between dynorphinergic hippocampal mechanisms and exploration, a quantitative-genetic method was chosen. For this purpose, mice from the inbred strains C57BL/6, DBA/2, BLN, and CPB-K were used. Their hippocampal mossy fiber projections were visualized by means of immunohistochemistry, using a highly specific anti-dynorphin B antiserum. The additive-genetic correlations that were estimated suggest pleiotropic gene effects on locomotion, rearing-up, wall-leaning, and several intra- and infrapyramidal mossy fiber (iipMF) variables. Long iipMF, in particular, were found to be associated with high exploratory activity.
Abstract: Ten male mice from each one of nine inbred strains were tested for spontaneous alternation in a T-maze, which was placed in a spatially richly structured room. Each test consisted of two trials, the first choice to be made was forced, the second one free. By turning the maze 180 degrees between choices during 8 of the 16 tests, 3 variables could be measured: total alternation, spatial alternation, and non-spatial alternation. After Timm's staining, the sizes of the intra- and infrapyramidal mossy fibre terminal fields (iip-MF) were measured. Significant strain differences were found for all variables, but none of the behavioural variables correlated with hippocampal variation. These results disagree with earlier experiments, where large correlations between the iip-MF and spatial working memory were found. Some hypotheses to explain this discrepancy are presented.
Abstract: Male mice of strains C57BL/6J and DBA/2J differ reproducibly in a number of behaviours displayed in an open-field. In particular, C57BL/6J mice show a higher rearing-up frequency than do DBA/2J animals. Recently, a marked drop occurred in the frequency with which this behaviour is displayed by the C57BL/6J//Nmg (N) subline, that has been separated from the original C57BL/6J line over 62 generations. Comparison of our animals with the C57BL/6J//Kun(K) subline, separated from the Jackson parent over at least 40 generations, showed a significant strain difference for rearing. Since both a positive additive-genetic correlation between rearing and the size of the intra- and infrapyramidal mossy fibre terminal field (iipMF) and a correlated response in the size of the iipMF to selection for rearing have been found previously, we expected to find smaller iipMF in N, as compared with K. After processing for Timm's stain, this predicted difference was indeed found. Skin grafting demonstrated that the two sublines were still completely histocompatible, excluding a possible genetic contamination of N. This provides very strong support for the hypothesis that both the behavioural and the neuroanatomical differences between these sublines are caused by a single spontaneous mutation in the N line and strengthens the idea of a functional relationship between the structural and the behavioural variable.
Abstract: Newborn male pups of the inbred mouse strain DBA/2J were injected with a buffered solution of L-thyroxine, known to induce a hyperplasia of the intra- and infrapyramidal mossy fiber terminal fields (iip-MF). Because previous studies have shown that the size of the iip-MF correlates positively with both reference memory and working memory in a spatial radial maze task, we expected improved performance on such a task in the treated animals. Such an improvement was in fact found for both reference and working memory. We conclude that the iip-MF are functionally involved in the regulation of spatial learning and memory in mice.
Abstract: Inbred mice show strain-specific differences in the hippocampal mossy fiber projection. These differences are most pronounced in the portion of the projection that forms synaptic connections with the basal dendrites of the CA3 pyramidal neurons [intra- and infrapyramidal mossy fiber (IIP-MF) projection]. We have previously demonstrated that the extent of the IIP-MF subfield is positively correlated with the capacity to perform a spatial radial-maze task and that an experimentally induced enlargement of the IIP-MFs, by means of postnatal thyroxine treatment, predicted the ability of adult two-way avoidance learning. In the present study, we tested whether this treatment would also influence radial-maze performance. Forty-five male mouse pups from the inbred strain DBA/2 (chosen because of scanty IIP-MF projection and poor radial-maze learning) were divided into three groups that received daily injections of either 2 micrograms L-thyroxine, an alkaline vehicle solution, or physiological saline. Treatment lasted from postnatal days 0 to 11. At the age of 3 months, these animals were tested in an eight-arm radial maze. The extent of their IIP-MF projections was measured by means of planimetry on Timm-stained sections. Thyroxine-treated animals made significantly fewer errors and had larger IIP-MF projections as compared to both control groups. Within each group, the individual variability of the IIP-MF projection was significantly and positively correlated with performance. We conclude that experimentally modified IIP-MF projections mediate processes underlying spatial working memory. It would appear that the hippocampal circuitry alterations induced by postnatal hyperthyroidism can counteract a hereditary lack of talent, albeit only partially and in selected populations.
Abstract: We investigated hippocampal anatomy in artificially-produced chimeras derived by the aggregation of embryos from two widely-studied inbred mouse strains, C57BL/6J and BALB/cJ. Contrary to expectations, the chimeras were not always intermediate between the parental strains. For a number of characters, the chimeras exceeded qualitatively as well as quantitatively the phenotypical range displayed by both inbred parental strains. These findings imply that if only one parent is available for comparison, for instance, in studies involving a normally inviable genotype, separating effects of this genotype from idiosyncratic effects inherent to the chimeric model will be very difficult, if not impossible.
Abstract: Species-specific elements of the paradise fish's ethogram were recorded in one familiar and three different unfamiliar environments, which were designed to model certain features of this species' natural habitat: (1) a densely vegetated home range, (2) a novel open field, (3) a small novel place, and (4) a small novel place with a predator. The inheritance of the behavioral elements was investigated employing a five-times-replicated diallel cross among three inbred strains. A detailed Hayman analysis of variance and a variance-covariance analysis were performed to uncover the genetic architectures of these phenotypes. Additive genetic effects and/or ambidirectional dominance was found to be characteristic of most species-specific behavioral elements studied, suggesting an evolutionary history of stabilizing selection.
Abstract: Two reference memory tasks were tested in a T-maze, which was placed in a spatially richly structured environment and turned 180 degrees between trials following a semi-random schedule. Male mice from 9 different inbred strains were either trained always to go to the same place (spatial task) or always to make the same turn (non-spatial task). Animals were subsequently processed for Timm's stain and the sizes of their intra- and infrahippocampal mossy fibre terminal fields (ipp-MF) were measured. Significant strain differences were found for this variable and in both learning tasks, but learning and hippocampal variation did not correlate. This disagrees with earlier findings in a radial maze, where significant correlations between the iipMF and spatial reference memory were obtained. Two hypotheses are brought forward to explain this discrepancy. First, in radial mazes (multiple choices) different memory capabilities might be used than in T-mazes (only two choices). Second, a considerable amount of stress appeared to be present in our subjects, possibly induced by the large size of the T-maze. This might have interfered negatively with acquisition. Further experiments will be needed to test these hypotheses.
Abstract: The high incidence of the fra (X) syndrome (about 1:2000 male newborns) requires an explanation in view of the low fitness of mentally retarded hemizygous males and heterozygous females. In the past, it has been proposed that the mutation rate may be unusually high, and that mutations occur exclusively in male germ cells. According to an alternative hypothesis, a moderately high mutation rate might combine with a selective advantage of clinically unaffected heterozygotes. In earlier studies, such a combined hypothesis was shown to lead to plausible implications regarding mutation rate and fitness. Moreover, a mutation rate in male germ cells of the magnitude required by the exclusive mutation hypothesis was excluded by studies on comprehensive pedigree data. In this third study in the series, an increased fitness of heterozygous females is demonstrated directly by a comparison of the reproductive performance of heterozygotes with that of adequate controls (mothers and grandparents of Down's syndrome patients). Since, average numbers of children have decreased during recent decades in populations of industrialized countries, heterozygotes (mothers of affected probands and their female relatives in their own generation) were subdivided into those born before and after 1940. Moreover, sibship sizes of probands' mothers and fathers were analyzed separately for family branches in which the fra (X) trait segregated (mostly the maternal branch), or did not segregate (in most instances the paternal branch). In all four categories reproductive performance in heterozygotes was found to be higher than in the controls. This difference was significant statistically for two of the four groups; it was small and nonsignificant only for the parental family branch in which the fra (X) mutant did not segregate and for mothers born after 1940. Fitness estimates ranged between 1.11 and 1.36. A higher incidence of dizygotic twinning suggests a biological component for this increased fertility. On the other hand, fra (X) families have a significantly lower social status than the controls. This suggests a socio-psychological component of their higher fertility. Apparently, both components contribute to their fertility; at present, their relative importance cannot be assessed.
Abstract: One hundred and eight male mice from nine different inbred strains were tested for two aspects of learning in an eight-arm radial maze. In the first experimental arrangement of the maze, measuring spatial working memory, clear strain differences were found on the fifth day of training. Furthermore, this type of learning showed a high positive correlation with the size of the intra- and infrapyramidal hippocampal mossy fiber terminal field as revealed with Timm's staining. In the second experiment, in which non-spatial reference memory was tested, significant strain differences were found for the learning variables, but there were no significant covariations with the sizes of the intra- and infrapyramidal mossy fiber terminal fields. These results, combined with previous data, suggest that heritable variations of the hippocampal intra- and infrapyramidal mossy fiber projection influence processes determining spatial learning capabilities in mice.
Abstract: Unilateral cataracts were investigated in 750 day-old BALB/c, C57BL/6 and DBA/2 mice, and the six reciprocal crosses between these strains. This abnormality of the lens appears to be inherited additively in the cross DBA/2xBALB/c (with incomplete penetrance in DBA/2 and F1 mice) but as a completely recessive character in the cross DBA/2xC57BL/6. The mode of inheritance may depend on the genetic background against which this phenotype is expressed, unless this abnormality is inherited as a threshold character. Aged DBA/2 mice may constitute a useful model for senile unilateral cataract, probably caused by early uveitis.
Abstract: Large differences in hippocampal lamination have been found between several inbred strains of mice. These variations are thought to be caused by differences in developmental processes. We produced aggregation chimaeras between the inbred strains BALB/c and C57BL/6 and studied the lamination patterns in these animals. Next to some intermediate patterns, several patterns not occurring in the donor strains were obtained. These patterns differed also from those found in F1 hybrids. Thus, although the genetic information from both parental strains is present in both F1 and chimaeric mice, different processes occur during development.
Abstract: Previous investigations in mice revealed the existence of a set of genes that influence variations in hippocampal anatomy as well as variations in behavioral responses to novelty. In particular, a positive genetic correlation was found between the size of the intra- and infrapyramidal mossy fiber (iip-MF) projection and rearing frequency in an open-field. On the basis of these findings, we hypothesized that genetic selection for rearing would entail correlated changes in hippocampal morphology. This was tested in the inbred selection lines SRH (selection for rearing: high) and SRL (selection for rearing: low). As expected, the SRH mice appeared to possess iip-MF terminal fields that were larger than those of the SRL mice. Because the behavioral difference between the two lines is most probably caused by a single genetic unit, these animals represent valuable material for molecular-genetic investigations into the mechanisms that control behavioral and neuroanatomical variation.
Abstract: As a first step towards a multivariate quantitative-genetic analysis of covariations between heritable variation in hippocampal structure and mouse behavior, a univariate analysis of the genetic architecture of behavioral responses to novelty is presented. For several components of exploratory behavior considerable amounts of genetic variation were found and an evolutionary history of stabilizing selection for intermediate levels of exploration was inferred. Comparison of these results with those from a previous study indicated that even a relatively small diallel cross, involving 4-5 inbred strains, may provide useful genetic information on a specific sample of animals. Larger numbers of strains are needed to provide precise estimates of genetic parameters in a population.
Abstract: Genetically-defined rodent strains permit the identification of hippocampal traits which are of functional relevance for the performance of two-way avoidance behavior. This is exemplified here by analyzing the relationship between infrapyramidal mossy fibers (a tiny projection terminating upon the basal dendrites of hippocampal pyramidal neurons) and two-way avoidance learning in about 800 animals. The necessary steps include 1) identification of structural traits sensitive to selective breeding for extremes in two-way avoidance, 2) testing the robustness of the associations found by studying individual and genetical correlations between hippocampal traits and behavior, 3) establishing causal relationships by Mendelian crossing of strains with extreme structural traits and studying the behavioral consequences of such structural 'randomization', 4) confirming causal relationships by manipulating the structural variable in inbred (isogenic) strains, thereby eliminating the possibility of genetic linkage, and 5) ruling out the possibility of spurious associations by studying the correlations between the hippocampal trait and other behaviors known to depend on hippocampal functioning. In comparison with the classical lesion approach for identifying relationships between brain and behavior, the present procedure appears to be superior in two aspects: it is non-invasive, and it focuses automatically on those brain traits which are used by natural selection to shape behaviorally-defined animal populations, i.e., it reveals the natural regulators of behavior.
Abstract: On the basis of results from lesion studies in rodents, covariations are expected to exist between naturally-occurring heritable variations in hippocampal morphology and exploratory behavior elicited by novel surroundings. For this reason, we set up a full diallel cross between five inbred mouse strains and analyzed the behavioral and the hippocampal anatomical variation in male animals from this cross. Employing a bivariate extension of the diallel-cross analysis, estimates were obtained for the phenotypical, environmental, and genetical correlations between the phenotypes studied. A factor analysis performed on the matrix of additive-genetic correlations revealed that variations in the size of the intra- and infrapyramidal mossy fiber terminal fields (iip-MF) are negatively related to open-field exploration and novelty-induced fear. These results indicate that having larger iip-MF projections promotes the collection and processing of information about a novel environment, entailing lower levels of exploration and fear.
Abstract: From a four-way cross between unrelated inbred strains of mice, a random-breeding line was developed that segregated at two coat-color loci and carried Y chromosomes from different sources. Adult males were used for measurements of black-white discrimination learning and 7-day response retention in a water maze, body weight, brain weight, and left- and right-side hippocampus weight. Clear evidence was obtained of Y-linked influences on response acquisition, body weight, right-side hippocampus weight, and hippocampal asymmetry, whereas direct effects of autosome 9 were indicated with regard to right-side hippocampus weight only. However, epistatic interactions of the Y chromosome with autosome 9 were found for response acquisition and body weight and with autosome 4 for hippocampal asymmetry.
Abstract: The postnatal development of the hippocampus of the inbred mice strains BALB/c, C57BL/6, and DBA/2 was studied in organotypic explant cultures using the roller-tube technique. In vivo, mice exhibit strain-specific mossy fiber distribution patterns. As a main result we found, that after cultivation of 3-4 weeks, similar strain-specific patterns became apparent in vitro, as visualized by a modified Timm staining. From this experiment we can conclude that a postnatal extrinsic influence cannot be the cause of the strain-specific hippocampal features.
Abstract: Twenty-four male mice, belonging to 8 different inbred strains, were tested in an 8-arm radial maze. Clear strain differences were found for performance on the third day of training, which correlated very strongly with the size of the hippocampal intra- and infrapy ramidal mossy fibre (iip-MF) terminal fields. These results, combined with those from earlier experiments, indicate that genetic variations of the iip-MF projection influence processes that determine behavioural abilities of mice.
Abstract: Adult male mice were made anosmic by intranasal flushing with a 5% zinc sulfate solution. Twelve behavioral variables were measured in treated as well as saline-irrigated control animals placed in a novel environment. The genetic underpinnings and the genotype-treatment interactions with regard to these behaviors were analyzed in a classical Mendelian cross between the inbred strains C57BL/6 and DBA/2 and in a full 4 X 4 diallel cross, replicated five times, between these strains and strains C3H/St an CPB-K. Based on the hypothesis of an evolutionary history of directional selection for a well-balanced information-processing system, one might expect directional dominance for decrease in exploration after anosmization. Although decreases were found for several behavioral phenotypes, only few and relatively unimportant genotype-treatment interactions were present. This absence of any kind of genetic variation for behavioral change after anosmization points to an extremely strong directional selection which has eliminated all less favorable alleles. The findings support the hypothesis of directional selection for an efficient olfactory information-processing system.
Abstract: We studied the sizes of the hippocampal intra- and infrapyramidal mossy fiber (iip-MF) terminal fields and habituation to a new environment (open-field) in 25 genetically different groups of mice. Based on previous findings and theoretical considerations, a positive relationship between the size of the iip-MF terminal fields and the extent of behavioral change between two subsequent exposures to the open-field was expected. In fact, such a relationship was revealed by a factor analysis. Our results indicate that mice possessing large iip-MF terminal fields are more efficient in the processing of spatial information.
Abstract: The genetic architectures of 12 behavioural variables measured in adult male mice placed in a novel environment were analysed in a replicated 4 X 4 diallel cross. The results were combined with those obtained in a classical cross involving two of the four strains. Based on the hypothesis of an evolutionary history of stabilising selection for mouse exploratory behaviour, we expected additive genetic effects and ambidirectional dominance. Such genetic architectures were actually found for those exploratory behaviours where epistatic effects were of minor importance. Similar findings emerged for some non-exploratory phenotypes. All behaviours analysed appeared to be polygenically controlled.
Abstract: This report analyses the genetic underpinnings of the proportions of the hippocampal terminal fields in the mouse at the midseptotemporal level. We used 5 inbred strains and all possible F1 crosses between them (diallel cross). Broad heritabilities ranged from 11 to 53%. Additive genetic variation was present for all phenotypes analyzed. Directional dominance was found for the relative size of the suprapyramidal mossy fiber terminal field only. For the stratum lacunosum-moleculare, ambidirectional dominance emerged. These findings suggest that, in evolutionary history, directional selection has operated for a proportionally large suprapyramidal terminal field. For all other hippocampal variables (viz. the relative sizes for the strata oriens, pyramidale, radiatum, lacunosum-moleculare, CA4, intra- and infrapyramidal mossy fiber terminal field and the absolute size of the regio inferior) past stabilizing selection was inferred.
Abstract: The genetic architectures of 12 behavioural variables measured in adult male mice placed in a novel environment were analysed in a replicated 4 X 4 diallel cross. The results were combined with those obtained in a classical cross involving two of the four strains. Based on the hypothesis of an evolutionary history of stabilising selection for mouse exploratory behaviour, we expected additive genetic effects and ambidirectional dominance. Such genetic architectures were actually found for those exploratory behaviours where epistatic effects were of minor importance. Similar findings emerged for some non-exploratory phenotypes. All behaviours analysed appeared to be polygenically controlled.
Abstract: A classical cross-breeding study involving the inbred mouse strains DBA/2 and C3H/HeJ revealed a rather complex mode of inheritance for the following hippocampal variables: size of stratum pyramidale, number of supra-, intra- and infrapyramidal mossy fiber synapses, and the size of terminal fields receiving entorhinal input. A polygenic mode of inheritance was inferred for these phenotypes. For the size of the regio inferior a model containing additive genetic effects only was sufficient to explain the variation between generations. The strain difference may be caused by one genetic factor only. In agreement with previous experiments a strong negative correlation between the number of intra- and infrapyramidal mossy fiber synapses and shuttle-box avoidance performance was found in the genetically heterogeneous F2 population.
