Attentional performance of C57BL/6 and DBA/2 mice in the 5-choice serial reaction time task.

C57BL/6 and DBA/2 were compared in the 5-choice serial reaction time task for differences in performance related to attention and impulsivity. The goal was to examine behavioural processes in mice that may relate to ADHD in humans. Groups of male mice were trained to nose-poke in response to a stimulus light presented randomly in one of five holes; correct responses were reinforced with food. During training the stimulus duration (SD) was reduced progressively from 60 to 0.5s. The C57BL/6 and DBA/2 mice did not differ during early stages of training when attentional demands were low (SD of 60, 10 or 5s). As task demands increased, strain differences emerged; C57BL/6 mice were more accurate than DBA/2 mice with stimuli of 2, 1 and 0.5s. DBA/2 mice also made more anticipatory (impulsive) responses during inter-trial intervals than C57BL/6 mice at SD of 5, 2, 1 and 0.5s. The ability to carry out the task was present in both strains of mice but they differed significantly in the levels of performance that were achieved. It is argued that the differences in accuracy and anticipatory responding were closely related and that the primary difference between the strains may be in impulsivity.

Identifying polymorphisms in the Rattus norvegicus D3 dopamine receptor gene and regulatory region.

The D(3) dopamine receptor has been implicated in several neuropsychiatric disorders, including schizophrenia, Parkinson's disease and addiction. Sequence variation in the D(3) gene can lead to subtle alteration in receptor structure or gene expression and thus to a different phenotype. In this study we examine the sequence variation in the D(3) gene in 96 rat strains and substrains. Interestingly, the analyses revealed 10 polymorphisms in the 5'flanking region and four polymorphisms in intronic regions of the gene. Moreover, two single nucleotide polymorphisms (SNPs) that result in amino acid changes were found in the last exon of the D(3) gene in the RNU/Mol strain. Additionally, bioinformatic analysis of the 5'flanking region and first intron of the gene revealed putative transcription factor binding sites that are conserved between mouse and human and are affected by the SNPs, possibly resulting in altered regulation of the subsequent transcription factor.

Genetic and environmental (inter)actions in male mouse lines selected for aggressive and nonaggressive behavior.

The purpose of this study was to investigate the effects of genetic and environmental factors, as well as their interaction, in the etiology of aggressive behavior in two mouse lines bidirectionally selected for offensive aggression. To this end, we raised the Finnish TA (aggressive) and TNA (nonagressive) selection lines either in isolation or in cohabitation with a female after weaning. At the age of 3 months we determined their aggressive behavior in three paradigms (intruder resident, neutral cage, resident intruder) against a male standard opponent. We also determined the animals' aggressive behavior against a female mouse. The results show genetic and environmental effects, as well as gene-environment interaction. We see prominent genotype effects under all conditions but each test is sensitive to a specific combination of environmental effects. A particularly noteworthy result is that variation in the unusual behavior of aggression towards a female is largely explained by the interaction of genotype with isolation. We also examined whether test experience influenced the outcome of an encounter between an experimental animal and an opponent, and found that this factor should not be underestimated, its effect size and direction depending on the type of paradigm and way of housing. These data suggest that the identification of genes underlying aggressive behavior in mice is by no means straightforward and that the result of this search will depend on the environmental design of the study (type of paradigm, housing conditions). These data also suggest that the use of 'test battery' mice might produce different results than the use of test-naïve animals.

Heritability of cortisol levels: review and simultaneous analysis of twin studies.

Cortisol has a pivotal role in physical and mental health, but relatively few studies have paid attention to individual differences in cortisol levels and the etiology of these differences, in particular their possible genetic basis. In this article we review the existing literature on the heritability of cortisol levels. Most of the studies, which have been carried out in genetically informative samples, lack methodological consistency with regard to frequency and timing of sample collection. The circadian rhythm in cortisol levels was often not taken into account. A power analysis shows that none of these studies used adequate sample sizes to distinguish genetic from shared environmental influences as a cause for familial aggregation. Results of a simultaneous analysis of 5 comparable twin studies suggest a heritability of 62%. Hence, we conclude that, to understand the contribution of genetic and (shared) environmental influences to variation in basal cortisol levels, future studies should be designed more rigorously with strict collection and sampling protocols, sufficient sample size and repeated measures across multiple days.

Apomorphine-susceptible and apomorphine-unsusceptible Wistar rats differ in their recovery from stress-induced ulcers.

The aim of the present study was to investigate the effects of restraint-in-water-stress on gastric ulcerations in two fundamentally different types of animals: the apomorphine-susceptible (APO-SUS) and apomorphine-unsusceptible (APO-UNSUS) rats. APO-SUS and APO-UNSUS do not only differ in their susceptibility to the dopamine agonist apomorphine, but also in stress-induced release of mesolimbic dopamine and corticosterone. All three factors are known to either predict or be involved in gastric ulceration. The results showed that immediately after the stressor the ulcerations in APO-SUS and APO-UNSUS rats were not line-specific. On the contrary, the recovery from gastric ulceration varied between both types of rat: APO-SUS rats did not show any sign of recovery after 6 hours whereas APO-UNSUS rats significantly recovered during the period of 0-6 hr after the stressor. It is hypothesised that this difference is due to the fact that APO-UNSUS rats are characterised by a less and shorter-lasting stress-induced increase of corticosterone. This study provides evidence that the pathological effects of exposure to stressors significantly differ between APO-SUS and APO-UNSUS rats and that genetic factors may direct the process of recovering from ulcers.

Home-cage activity in heterogeneous stock (HS) mice as a model of baseline activity.

Behavioral genetic work in humans indicates that clinical hyperactivity is best viewed as the extreme end of activity levels in the population. However, current animal models of hyperactivity are not studied as quantitative traits as they are either knockout models or inbred strains. Furthermore, these animal models generally demonstrate elevated locomotion in novel environments, but not in their home-cages. This is the opposite of the symptoms seen in the human condition where childhood hyperactivity is generally more pronounced in constant, unstimulating situations. In this study we filmed an outbred population of 44 heterogeneous stock (HS) mice under red light during their active phase, to assess the reliability of individual differences in home-cage behavior and extract an index of home-cage activity (HCA) level. We then compared this measure to locomotor behavior in a novel environment--the open-field. Reliable individual differences in home-cage behaviors such as running, swinging on bars, and burrowing were found, and principal component factor analysis yielded a general activity factor, which accounted for 32% of the variance and correlated 0.90 with a subjective impression of activity level. The correlation between HCA and locomotor activity in the open-field was 0.23, which was non-significant. However, the association with HCA level appeared to increase over the five minutes of the open-field, presumably as the mice habituated. Furthermore, although mice displaying particularly high and low HCA were indistinguishable early in the open-field task, they became significantly differentiated over time. We conclude that home-cage behaviors and the open-field, after habituation, display good face and construct validity, and may provide a good model of baseline activity for quantitative trait loci (QTL) discovery and functional genomics in the HS mice.

Traceability of Equidae: a population in motion.

The accelerated speed of animal transport and the existence of complex and intricate movement systems have created an equine population in motion. This ease in the international movement of horses has an impact on the risk of introduction or spread of disease, specifically in relation to competition horses. Facilitating trade in Equidae, whilst simultaneously safeguarding the health status of the receiving country is a major challenge. To date, the international regulatory bodies are prepared to consider movement of registered horses as a relatively 'low risk' occurrence and thereby apply the least restrictive measures upon importation or re-entry. However, several outbreaks of contagious disease related to movement of horses have underlined the need to regulate identification of horses, to establish proper sanitary certification and to secure traceability of horse movement.

Differential susceptibility to periodontitis in genetically selected Wistar rat lines that differ in their behavioral and endocrinological response to stressors.

This study tests the model presented previously by Breivik et al. (1996), in which the extent of periodontitis, an inflammatory disease, is predicted from the reactivity of the HPA-axis. Briefly, the model implies that elevated plasma levels of corticosterone modulate the immune system by shifting the T-helper balance toward a more Th2 response, which, alternately, increases the sensitivity to periodontitis. To test this model, two genetically distinct types of rats that differ both behaviorally and endocrinologically in their response to stress (high corticosterone responding APO-SUS rats and low corticosterone responding APO-UNSUS rats) were compared. Periodontitis was experimentally induced through the placement of a ligature and measured as the extent of tissue (fiber and bone) loss, both histologically and radiographically. The results show that, as expected, APO-SUS animals are more sensitive to periodontitis, i.e., show more fiber and bone loss, than APO-UNSUS animals. These data are in agreement with findings in Fischer and Lewis rats, as well as with corticosterone treated and adrenalectomized animals and suggest that genetic factors underlying the variation in the reactivity of the HPA-axis (and, accordingly, their behavioral response to stress) play an important a role in the development of inflammatory diseases.

The role of genetic and early environmental factors in determining apomorphine susceptibility.

RATIONALE: There is ample evidence that rats show large individual differences in their response to dopaminergic drugs, such as apomorphine. OBJECTIVE: The aim of the present study was to investigate the role of genetic and (early) environmental factors in determining the adult susceptibility to apomorphine. Four experiments were performed: In experiment 1, the original selective breeding of rats for apomorphine susceptibility (leading to APO-SUS and APO-UNSUS rats) was extended and replicated in an independent group of Wistar rats. In experiment 2, APO-SUS males were cross-bred with APO-UNSUS females and vice versa. In experiment 3 APO-SUS litters were cross-fostered to APO-UNSUS mothers or infostered to unknown APO-SUS mothers and vice versa. In experiment 4 APO-SUS and APO-UNSUS rats were maternally deprived on postnatal day 9, for a single 24-h period. METHODS: Adult rats were subcutaneously injected with 1.5 mg/kg apomorphine and their gnawing response was automatically recorded in a gnawing box for 45 min. RESULTS: In experiment 1, the original breeding was extended up to generation 24, leading to a strong and consistent difference in gnawing scores. The replication experiment also succeeded in differentiating APO-SUS and APO-UNSUS. The cross breeding experiments showed that the APO-SUS/UNSUS offspring showed gnawing scores in between the original selection lines. Cross-fostering APO-SUS with APO-UNSUS significantly reduced the gnawing response in the offspring, whereas it did not affect the gnawing score in the APO-UNSUS animals. Maternal deprivation had the opposite effect: increase in gnawing response in APO-UNSUS, with no effect in APO-SUS. CONCLUSION: The results show a clear-cut contribution of both genetic and early environmental factors to the susceptibility of apomorphine.

Genetic, sex, and early environmental effects on the voluntary alcohol intake in Wistar rats.

The aim of this study was to investigate the effects of genetic, sex, and early environmental factors on the voluntary alcohol intake in Wistar rats. Genetic correlates were examined by comparing animals pharmacogenetically selected for high susceptibility to apomorphine (APO-SUS) with animals selected for low susceptibility (APO-UNSUS). Early environmental factors were investigated through postnatal manipulations (cross-fostering in APO-SUS and maternal deprivation in APO-UNSUS). Voluntary alcohol intake was measured using a two-bottle, free-choice protocol, in which animals could choose either water or an ascending series of alcohol concentrations every second day. Genetic correlates were only observed in male rats, with APO-UNSUS animals consuming more alcohol than APO-SUS animals. No effect of the early postnatal manipulations was detected: neither cross-fostering nor maternal deprivation influenced the voluntary alcohol intake. As for the influence of gender on ethanol self-administration, APO-SUS females consume more alcohol than APO-SUS males, while no sex differences were observed in APO-UNSUS animals.

Behavioral profiles of genetically selected aggressive and nonaggressive male wild house mice in two anxiety tests.

Artificially selected aggressive (SAL) and non-aggressive (LAL) male house mice were tested in a hexagonal tunnel maze and light-dark preference (LD) box to determine if the bidirectional selection for aggressive behavior leads to a coselection for different levels of trait anxiety. The tunnel maze consists of an open, brightly lit central arena surrounded by a complex system of interconnecting tunnels. As in the LD box, animals which spend less time and are less active in the brightly illuminated section of the maze are considered to have higher anxiety levels. In the tunnel maze, the LAL mice showed more exploration and spent more time in the central arena than the SAL animals, but only during the final 2 min of the 6-min test. This reduced preference for the central arena was not due to general inactivity or a failure of the SAL to find the central arena and indicates a higher level of state anxiety in the aggressive animals. In contrast, no "anxiety-like" differences were found in the LD box, either for the percentage of time spent in the light compartment or for the number of crossings. SAL males actually showed higher levels of moving and rearing, and lower levels of freezing, than did LAL males.

Genetics of testosterone and the aggression-hostility-anger (AHA) syndrome: a study of middle-aged male twins.

The aim of this study was to determine the genetic contribution to the variation in testosterone and the aggression-hostility-anger (AHA) syndrome in middle-aged twins. Moreover, the relation between testosterone and this syndrome, and possible common genetic mechanisms were investigated. Towards this end, blood samples were collected at two time points; the AHA syndrome was measured using three questionnaires: the Buss-Durkee Hostility Inventory with seven subscales, the Jenkins Activity Survey and the Spielberger State-Trait Anger Scale. The results showed substantial heritabilities for testosterone (approximately 60%) and moderate to fair heritabilities for the nine measures of the AHA syndrome (23-53%). The best fitting model for testosterone at two time points included a small age component and additive genetic and unique environmental factors, while a multivariate analysis of the nine AHA subscales resulted in an independent pathway model with two common additive genetic and two common unique environmental factors. No correlation between the common genetic factor influencing testosterone and the AHA subscales was found. We did, however, detect a negative correlation between the common environmental factor underlying testosterone and both common environmental factors influencing the nine AHA subscales, which may reflect a tendency for testosterone levels to rise and hostility to drop (or vice versa) after repeatedly experiencing success (or failure).

Mice selected for differences in sensitivity to a benzodiazepine receptor inverse agonist vary in intermale aggression.

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.

Y chromosomal and sex effects on the behavioral stress response in the defensive burying test in wild house mice.

Genetically selected short attack latency (SAL) and long attack latency (LAL) male wild house mice behave differently in the defensive burying test. When challenged, SAL males respond actively with more time spent on defensive burying, whereas LAL males are more passive with more time remaining immobile. The first aim of this study was to find out whether the nonpairing part of the Y chromosome (Y(NPAR)) affects the behavioral stress response in this paradigm. Second, to determine if the differential behavioral profile found in males is also present in females, SAL and LAL females were tested. Third, nonattacking and attacking LAL males were compared. Five behavioral elements were recorded: defensive burying, immobility, rearing, grooming, and exploration. Males were first tested for attack latency. The results show that the Y(NPAR) influences defensive burying. However, the size of this effect is overshadowed by the background of the mice. Furthermore, although females differed from males, they tended to demonstrate the same behavioral profile as males. Nongenetic factors may also play a role, as attacking LAL males showed more defensive burying than nonattacking LAL males.

Radial maze learning in two inbred mouse strains and their reciprocal congenics for the non-pseudoautosomal region of the Y chromosome.

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.

Further phenotypical characterisation of two substrains of C57BL/6J inbred mice differing by a spontaneous single-gene mutation.

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.

Behavioural genetics: An introduction.

Behavioural genetics is the study of the hereditary influence on behaviour, and can therefore be regarded as the intersection between behavioural sciences and genetics. As with most other fields of research it is difficult to exactly pinpoint when behavioural genetics started. In fact, one might say that the notion behavioural traits can be inherited may have appeared in human thought as early at 8000 BC, when the domestication of the dog began. The scientific era of behavioural genetics is generally considered to start with Charles Darwin. In his famous book On the Origin of Species by Means of natural Selection, or the Preservation of favoured Races in the Struggle for Life, published in 1859 (and sold out the first day), he devoted an entire chapter on instinctive behavioural patterns. Some years later, in his book The Descent of Man and Selection in Relation to Sex, he clearly stated that the difference between the mind of a human being and the mind of an animal 'is certainly one of degree and not of kind'. Moreover he gave considerable thought that mental powers (and insanity) are heritable aspects.

No evidence for a Y chromosomal effect on alternative behavioral strategies in mice.

This study takes the first step toward testing a Y chromosomal effect on both aggression and thermoregulatory nest-building behavior in mouse lines either bidirectionally selected for short (SAL) and long (LAL) attack latency or high (HIGH) and low (LOW) nest-building behavior. Using reciprocal crosses between SAL and LAL, and between HIGH and LOW, we found no indications for Y chromosomal effects on thermoregulatory nest-building behavior. As for aggression, we confirmed earlier studies on SAL and LAL, i.e., the origin of the Y chromosome influences attack latency, i.e., aggression. However, we did not find indications for a Y chromosomal effect on aggression in the HIGH and LOW lines. Since aggression and nest-building behavior have been shown to be characteristic parameters of two fundamentally different behavioral strategies, the present data underline the improbability of Y chromosomal genes underlying the genetic architecture of alternative behavioral strategies.

Enhanced 5-HT1A receptor expression in forebrain regions of aggressive house mice.

The brain 5-HT1A receptor system in male wild house mice selected for high and low offensive aggression was investigated by autoradiographic analysis of in situ hybridization and radioligand binding. In high-aggressive mice, characterized by a short attack latency, the rise in plasma corticosterone concentration during the early dark phase was reduced. At that time the level of 5-HT1A mRNA in the dorsal hippocampus (dentate gyrus and CA1) was twice the amount measured in low-aggressive mice that had long attack latency and high plasma corticosterone level. Increased postsynaptic 5-HT1A receptor radioligand binding was found in dentate gyrus, CA1, lateral septum, and frontal cortex. No difference in ligand binding was found for the 5-HT1A autoreceptor on cell bodies in the dorsal raphe nucleus. In conclusion, genetic selection for high offensive aggression co-selects for reduced (circadian peak) level in plasma corticosterone and increased postsynaptic 5-HT1A receptor number in limbic and cortical regions.