Modeling behavior: the quest to link mechanisms to function

The ‘developmental pathway’ of a new scientific society can follow one of two paths. It can either follow very specific research themes, which with time may form a forum of converted specialists in closely related fields, and where a non-specialist newcomer, be it a student or researcher with interest in other areas may feel slightly lost, if not intimidated. On the other hand, a young society has a chance (the chance not being good most of the time) to become a magnet for people working in various, often non-overlapping fields, who want to exchange thoughts and ideas with both specialist and non-specialist alike. The fifth annual meeting of the International Behavioural and Neural Genetics Society (IBANGS), which was held at a picturesque venue in Tours in the Loire Valley of France, proved that IBANGS has become the latter. While in its infancy IBANGS meetings attracted predominantly ‘mouse people’, the recent meeting in Tours (organized splendidly by Catherine Belzung together with Sabine Richard and Christian Andres as part of a local organizing committee) covered topics ranging from modeling human neurodegenerative diseases through the use of genetic and pharmacological interventions to explain the mechanisms of behavior, to studies on the genetic and physiological mechanisms of stress in Japanese quail with clear implications for husbandry and animal welfare. It would be difficult, if not impossible, to discuss fully all the presentations, not only due to the limitation of space, but also from an inability to do them justice by presenting the results ‘second hand’. One simple solution is to join the society (it is as easy as a ‘mouse handling’, just click on the IBANGS web site: http://www.ibngs.org/), and experience future meetings ‘first hand’ as well as obtaining a complimentary subscription to Genes, Brain and Behavior. The first day of the meeting included a poster session which, although it lasted only one hour, provided a forum for discussions that continued until late in the evening during a splendid conference banquet in an old French farm. Constraints of space do not allow us to describe all the posters, so we will only highlight the main themes that dominated the session. A number of posters addressed the issue of strain differences in various behavioral tests. Richard Brown and co-workers (Halifax, Canada) presented interesting results on differences in the rotarod performance between C57BL/6J, 129S1, Molf/Ei, A/J, BALB/cByJ, and HS strains of mice. Apart from striking strain and sex differences, Brown also convincingly demonstrated that in most cases the differences were confounded by body weight. A large interstrain variability (eight different mouse strains were tested) in mouse models of anxiety was presented by Ducottet and Belzung (Tours, France). Mice were tested in the elevated plus maze and free exploration tests which were followed by subchronic unpredictable mild stress (SCUMS). Sucrose preference was scored before and after SCUMS. Cluster analysis revealed two groups: one highly anxious which deteriorated physically after SCUMS (129/SvJ and C3H/HeJ strains), another low and mildly anxious group of strains which were physically not changed. However, some strains were more resistant to procedural manipulations (C57BL /6J and CBA /J), while others deteriorated physically after stress (FVB/NA, BALB/cByJ, and C3H/HeJ). Claudia Plappert and colleagues (Tuebingen, Germany) presented a study on prepulse inhibition (PPI) and prepulse facilitation (PPF) of the acoustic startle response in several mouse strains (C57BL/6J, 129/SvHsd, AKR/OlaHsd and a hybrid NMRI × wild type mouse). These studies concluded that the genotype of mice affects both PPI and PPF which are likely genetically determined independent processes. Two posters, one by Arabo et al. and the other by Arguel et al. (Rouen, France) presented results on the characterization of lupus prone mice. These mice suffer from auto-immune pathological changes similar to human Systemic Lupus Erythematosus. In this model, the males were found to have severe deficits in spatial cognition as tested in the water maze. Females, however, were not affected (Arabo et al.). Lupic males carry the autoimmune accelerator (Yaa) gene which leads to an early onset and greater severity of the autoimmune response. The females, who lack this gene, are protected for a longer time. The study of trait anxiety, like locomotor exploration and discrimination abilities, found no differences between males and females, but the males were more affected than females in state-anxiety measures (exploration of an open-field and elevated + maze). These results indicate possible relationships between state anxiety, hippocampal function, and auto-immunity. Recently, human research identifying brain mechanisms that are correlated genetically with cognitive ability have shown that individual differences in brain volume are highly heritable and that genetic factors explain about 16% of variation between the brain volume and general cognitive abilities. Paya-Cano and co-workers (London, UK) attempted to use similar correlational analysis on genetic mediation of brain weight and behavior in mice. Consistent with human data, total brain, cerebellum and hippocampus weights resulted in high positive sibling correlations in mice. Also, general ‘cognitive’ abilities extracted from various cognitive tests yielded a positive significant sibling correlation. However, the brain weight did not predict the ‘cognitive’ abilities of the mice, thus, unlike the human data, the brain weight does not contribute to the explanation of the individual differences in mice. An attempt to identify a common trait underlying the phenotype of anxiety in mice was presented in the poster of Liu and co-workers (London, UK). Using data from a battery of anxiety tests, the authors identified two major factors accounting for 25% and 18% of the total variance. Principal component factor analysis indicated that exploratory activity measures are loaded on the first factor, and classical anxiety measures on the second. Taking into account sibling interactions with the above factors, the authors concluded that there was a strong familial basis for the phenotypic data. A symposium on Drosophila behavioral neurogenetics, which was organized by Gert Pflugfelder, highlighted the power of molecular genetics and the single gene mutant approach for dissection of behavior. In the first presentation, Alberto Ferrus described the use of gigas mutant flies as a genetic tool to investigate the relationship between neuronal cell size, synapse number, and neuronal function. The gigas mutation results in dramatic increases in cell size (due to increased ‘endoreplication’), but apparently has little or no effect on ‘wiring’ of the nervous system (at least on a gross level). Ferrus was thus able to use the genetic toolbox of the fly to manipulate cell size and (as a result) synapse number in the sensory systems (olfactory and visual). Using genetic mosaics, for instance, Ferrus was able to increase the size of the antennae without altering the number of antennal sensory neurons or their projections to the antennal lobe. The dramatic increases in cell size, however, resulted in a more than twofold increase in synapse number. Surprisingly, these mutant animals have normal electro-antennograms and have remarkably ‘normal’ olfaction. Intriguingly, however, the mutants were more sensitive to low concentrations of odors such as ethyl-acetate. Moreover, the magnitude of behavioral responses (attraction/repulsion) was increased. In the second talk of the Drosophila neurogenetics symposium, Jean-Rene Martin used the palette of genetic tools in the fly to investigate sexually dimorphic neuroendocrine control of locomotion. In a ‘shuttle box’ activity monitor, male and female flies exhibit different patterns of locomotion. While both males and females tend to have the same over-all levels of locomotion, females exhibit higher movement frequency (start/stop behavior), and longer movement duration. In contrast, male flies move with a higher velocity. Using the Gal4/UAS transgenic expression system and the wealth of knowledge of the genetics of sex determination, Martin was able to dissect the neuroanatomy of this sexually dimorphic behavior. By spatially restricting expression of the transformer-2 gene in males, Martin was able to selectively ‘feminize’ specific brain regions in order to map anatomical foci underlying female specific locomotion patterns. This anatomical dissection rapidly focused attention on the Pars Intercerebralis (PI), a small region of the fly brain involved in neuroendocrine control. Direct support for a role of PI in female-specific locomotion patterns came from transplantation of female PI neurons into males. This manipulation resulted in the feminization of locomotor behavior (as did pharmacological manipulation of juvenile hormone levels). Martin also was able to provide a potential genetic link between feeding and locomotor activity because males with a mutation in a gene called takeout, which encodes a JH-binding protein that is induced by starvation, exhibit female levels of movement frequency. These first two talks in the Drosophila symposium clearly illustrate the potential offered by behavior-genetic investigation for dissection of sensory systems and locomotion. The next three presentations by Henrike Scholz, Kevin O'Dell and Gert Pflugfelder, demonstrated that fruit flies also can be manipulated to inform our understanding of the human condition. Banking on the remarkable conservation of the behavioral, pharmacological, and genetic properties of the responses to addictive drugs, for example, Scholz used flies to identify genetic and neuroanatomical substrates of ethanol tolerance. In a dramatic illustration of the potential of molecular genetics for dissection of complex behaviors, Scholz used the Gal4/UAS system to spatially restrict expression of tetanus toxin. In this way she was able to map neuroanatomical loci underlying responses to ethanol. Kevin O'Dell similarly has established Drosophila as a genetic model system for mitochondrial deafness. In humans, up to 2% of early deafness and 10% of adult deafness are due to mitochondrial dysfunction – apparently because of the high metabolic requirements of the inner ear. Individuals suffering from this type of disorder also characteristically exhibit short stature and antibiotic sensitivity. Remarkably, mutations in technical knockout (tko), a nuclear encoded mitochondrial ribosomal component in flies, result in Doxycyclin sensitivity and slower larval growth. Moreover tko mutants appear to have hearing deficits, measured behaviorally by exposing male flies to male courtship song. In wild type males, courtship song elicits male:male courting. In contrast, tko males do not respond, suggesting that they are unable to hear the ‘music’. Thus mitochondrial dysfunction in flies appears to mimic ‘clinical’ effects seen in humans! A final presentation in the Drosophila symposium by Pflugfelder demonstrated the potential of flies for modeling polygutamine (PolyG) expansion related neurodegenerative disease. Using the Gal4/UAS system to spatially restrict expression of a truncated ataxin3 containing polyG expansions, Pflugfelder was able to demonstrate neurodegenerative effects measured behaviorally (by locomotion and phototaxis assays) as well as anatomically (by observation of glial degeneration and the presence of nuclear inclusions). In flies, as in vertebrates, the time-course of clinical symptoms is correlated with PolyG expansion length, suggesting mechanistic similarities. With these assays in hand, the ease of genetic screening in Drosophila promises to bring a powerful tool to bear on characterization of genetic components underlying neurodegeneration. The focal point of the symposium organized by Catherine Belzung (Tours, France) was to bridge pharmacological and genetic approaches in the study of behavioral mechanisms. The symposium was opened by Florence Crestani (Zurich, Switzerland) who presented an elegant study on the differentiation of functions of GABAA receptor subtypes in mutant mice. Point mutations (His > Arg) introduced into mouse α1, α2, α3 and α5 subunit genes rendered the respective GABAA receptor subtypes insensitive to diazepam. Behavioral evaluation of the mice revealed that the sedative action and the anterograde memory impairment caused by diazepam is mediated by α1 receptors, while its anxiolytic-like action, determined in the light–dark choice and the elevated + maze tests, was mediated by α2 receptors. On the other hand, the muscle relaxing propensities of diazepam involved α2-, α3- and α5-GABAA receptors. In conclusion, the fact that the behavioral effect of a drug could be the result of the activation of specific receptor subtypes in distinct neuronal circuits should be of importance for drug design and should be taken into account during the interpretation of behavioral results after pharmacological intervention. Catherine Belzung (Tours, France) presented an interesting example of research on the function of the antidepressant effects of fluoxetine, a serotonin (5-HT) reuptake inhibitor. To evaluate fluoxetine antidepressant action on 5-HT1a receptors, Belzung, in the first experiment, used pharmacological blockade of the 5-HT1a receptor (injecting the 5-HT1a antagonist) in normal, wild type mice. 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