J. H. F. van Abeelen

Behavioral responses to novelty and structural variation of the hippocampus in mice. II: Multivariate genetic analysis

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.

Genetic control of hippocampal cholinergic and dynorphinergic mechanisms regulating novelty-induced exploratory behavior in house mice.

Neurobehavioral genetics endeavors to trace the pathways from genetic and eenvironmental determinants to neuroanatomical and neurophysiological systems and, thence, to behavior. Exploiting genetic variation as a tool, the behavioral sequelae of manipulating these neuronal systems by drugs and antisera are analyzed. Apart from research in rats, this paper deals mainly with the genetically-influenced regulation in mice of exploratory behaviors that are adaptive in novel surroundings and are hippocampally-mediated. Special attention is paid to neuropeptidergic, GABAergic, and cholinergic synaptic functions in the mouse hippocampus. The behaviorally different inbred mouse strains C57BL/6 and DBA/2 show opposite reactions (reductions and increases, respectively, in exploration rates) to peripheral and intrahippocampal injections with agents that interfere with peptidergic, cholinergic, and GABAergic neurotransmission. These findings can be explained by an interdependent over-release of opioids, arrested GABA release, and excess acetylcholine in the hippocampal neuronal network of DBA/2 mice, as compared to C57BL/6 mice where these systems are functionally well balanced. Very similar results have been obtained with the lines SRH and SRL, derived from C57BL/6 and DBA/2, and genetically selected for rearing behavior. Most probably, the opioids act to disinhibit exploratory responses. An additional genetic approach is mentioned, in which four inbred mouse strains and one derived heterogeneous stock are used for estimating genetic correlations between structural properties of the hippocampal mossy fibers and levels of hippocampal dynorphin B, on the one hand, and frequencies of exploratory responses to environmental novelty, on the other.

Behavioral responses to novelty and structural variation of the hippocampus in mice. I: Quantitative-genetic analysis of behavior in the open-field

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.

The genetic architecture of behavioural responses to novelty in mice.

The genetic architectures of 12 behavioural variables measured in adult male mice placed in a novel environment were analysed in a replicated 4×4 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.

Genetic Selection for Novelty-Induced Rearing Behavior in Mice Produces Changes in Hippocampal Mossy Fiber Distributions

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.

Effects of genotype on mouse behaviour.

Summary o 1. Behavioural differences between (i) the strains DBA/2J, C57BL/6J, and their F 1 hybrids, and (ii) homozygous and heterozygous short-ear ( se ) animals, were examined. For this purpose more than thirty stereotyped behavioural components performed by single male house mice and by pairs of males when placed into an observation cage, and avoidance behaviour in a shock escape box were taken into consideration. 2. Many strain differences not described previously were established; others generally confirmed earlier findings. Strain DBA/2J is mainly characterized by low scores for various locomotory and exploratory activities, and strain C57BL/6J by low values for feeding behaviour, defecation, grooming, and aggressiveness. There was no clear-cut difference in active avoidance learning between these strains. The B6D2F 1 hybrid showed evidence of hybrid vigour, they rated high particularly with regard to leaning postures, climbing, manipulation of bedding material, and learning performance. 3. The se locus was found to influence avoidance behaviour; mutants did less well than nonmutants. No effect upon the frequencies of fixed action patterns or upon general activity was observed.

Mouse mutants studied by means of ethological methods

In order to determine in how far some known genes will affect the behaviour of mice (Mus musculus L.) the author used the ethological method for drawing up an inventory of behavioral elements; this can be considered the phenotype to be investigated.For this purpose the behaviour was broken down into those elements presented by a solitary male (situation I), by two males placed together (situation II), and by one male and one female together (situation III). The environmental factors for the mice were kepts as uniform as was possible. In the present article an outline is given of the methods used in analysing that behaviour; in a later article it will be shown to what ends these methods can be used.

Genotype-dependent effects of scopolamine and eserine on exploratory behaviour in mice.

SummaryIn this psychopharmacogenetic study, male mice of strains C57BL/6, DBA/2, and D2B6F1 received injections with four doses of the anticholinergic scopolamine and with four doses of the anticholinesterase eserine. The frequencies of four different exploratory forms of behaviour carried out in a novel environment were subsequently measured.Both scopolamine and eserine reduced the scores of object-sniffing, leaning against the wall and rearing in the otherwise high-scoring C57BL and F1 animals. In DBA mice, which rate low when undrugged, scopolamine caused opposite effects and eserine similar effects with regard to these acts.From these observations it is concluded that there exists a cholinergic mechanism, operating efficiently in strain C57BL and less so in strain DBA, which facilitates certain exploratory behaviours and the action of which is controlled by genetic factors.

Mice selected for rearing behavior, some physiological variables.

Rearing behavior, locomotor activity, body temperature, and adrenal activity were recorded in male mice from two inbred strains and from two lines selected for rearing frequency. Significant positive correlations between rearing and locomotion indicated that loci responsible for rearing performance may act through a system which regulates the level of arousal. Although strain and line differences were found for behavior, temperature, and adrenal activity, no specific genetic relationship could be established between the behavioral and the physiological variables.

Behavioural and neuroanatomical divergence between two sublines of C57BL/6J inbred mice

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 Timms 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.