Csaba Vadasz, Program Director

Variations in behavioral traits are at least partially defined by genetic factors. However, pinpointing the individual genes that influence the expression of a complex behavioral trait has been extremely difficult; behavior, like other complex traits, is affected by numerous environmental factors such as random developmental processes, many genes, inter-genic interactions, and genotype-environment interactions ¹. Since its inception in 1983, the goal of the Neurobehavioral Genetic Research Program has been to develop strategies for the identification of individual genes that shape complex phenotypes, and to create advanced genetic animal models of neurobehavioral disorders ^2-4. In complex trait or disease research natural genetic variation analysis and mutagenesis, the two major approaches, can complement each other; however, they do not necessarily address the same question: we cannot expect induced mutagenesis to deliver into our hands the genetic variants underlying many common diseases⁵. This program has been funded by research awards from federal, and non-governmental foundations.

Ongoing Research

Genetics of the mesotelencephalic dopamine system

To circumvent some of the above-mentioned difficulties in mapping genes for complex traits one can attempt to transfer the genes onto a homogeneous genetic background. When our program was initiated, the mainstream view in genetics was that only genes of qualitatively different traits, or genes of quantitative traits with clearly bimodal distribution, could be transferred onto a background genome⁶. This is a significant limitation because it is well known that the variation in most of the complex neural and behavioral phenomena is continuous and that most of the neurobehavioral phenotypes would thus be excluded from such gene transfer. Addressing this issue of complex trait genetics, we hypothesized that unknown individual genes that control a quantitative, continuously varying trait can be transferred onto a homogeneous background and distributed in a series of recombinant quasi-congenic strains by repeated backcross-intercross cycles with concomitant selection for the extreme expression of the phenotype and fixation of the target genes ^3,4,7-10. Following this concept, we created more than 100 Recombinant Quantitative-Trait-Locus Introgression (RQI) mouse strains for the analysis of brain dopamine (DA) systems and related behaviors. In this project activity of mesencephalic tyrosine hydroxylase, the first and rate-limiting enzyme in catecholamine biosynthesis, (TH/MES), was the introgressed phenotype. However, the system can be useful for the analysis of other, "passenger" phenotypes whose expression is affected by random introgressed, or linked, genes. Our laboratory was the first to demonstrate successfully the principle of phenotypic QTL introgression ^1,3. Experiments are in progress to investigate the distribution and number of neurotransmitter-specific neurons in RQI strains. Because various aspects of the mesotelencephalic dopamine system are involved in neuropsychiatric disorders (schizophrenia, hyperactivity with attention deficit, Parkinson's disease, etc.) and in specific neurobehavioral processes (stress, memory, motor activity, brain reward circuitry, etc.), definition of genes that selectively control some components in the DA system can have far-reaching rewards in understanding the organization of these behaviors and in developing new, effective treatments for the related disorders¹¹.

This project was supported by the National Institute of Neurological Disorders and Stroke, NIH and non-governmental foundations. Contributions to the development and maintenance of the RQI system by Anthony Badalamenti, Maria Bucsek, Balint Juhasz, Peter Kabai, Gyorgy Kobor, Donald Lafrancoise (deceased), John Lafrancoise, Istvan Laszlovszky, Rui F. Mao, Peter Morena, Leelavati R. Murthy, Maria Sasvari-Szekely, Michael Serra, Istvan Sziraki, and Ilona Vadasz, at various stages of the RQI project are gratefully acknowledged.

Genetics of alcohol preference

Because dopamine neurotransmission is at the heart of the brain reward circuitry, and progenitors of our RQI strains differed greatly in their voluntary ethanol drinking, the lab is characterizing the RQI strains for ethanol preference, global gene expression in strategic brain areas, and microsatellite marker polymorphisms to locate the chromosome segments on which candidate QTLs (as differential or passenger genes) reside. It is expected that the RQI strategy will help to reduce both the genetic and environmental "noise" in alcohol preference and gene expression because homogeneity of genetic background has been ensured for RQI strains, and individuals within an inbred RQI strain are virtually identical¹². Another advantage of the RQI strategy is that a cumulative marker and phenotype database can be established for mapping diverse traits, as with the existing RI databases^13,14. It is expected that identification and functional analysis of genes that significantly influence alcohol abuse will be of help in developing new treatments^15-17.

This project was supported by The National Institute on Alcohol Abuse and Alcoholism, NIH and USAMRMC. Contributions by David Pearson, Andrea Balla, Beatrix Gyetvai, Istvan Kiraly, Csaba Vadasz, II, John Lafrancoise, Mao F. Rui, Arthur Fleischer, Eva Mikics, Mariko Saito, Henry Sershen, Audrey Hashim, Istvan Szakall, Janos Piturca, Melinda Oros, Fengzhu Tan, Krisztina M. Kovacs, Ray Wang, and Danielle O'Brien to various aspects of this project are gratefully acknowledged.

References

1. Abiola, O.,...Vadasz, C.,... et al. The nature and identification of quantitative trait loci: a community's view. Nat Rev Genet 4, 911-6 (2003).
2. Vadasz, C., Kobor, G. & Lajtha, A. Genetic dissection of a mammalian behaviour pattern. Animal Behaviour 31, 1029-1036 (1983).
3. Vadasz, C. Development of congenic recombinant inbred neurological animal model lines. Mouse Genome 88, 16-18 (1990).
4. Vadasz, C. et al. Genetic determination of mesencephalic tyrosine hydroxylase activity in the mouse. Neurogenet 4, 241-52 (1987).
   
5. Vadasz, C. Analysis of complex traits: mutagenesis versus QTLs. Nat Genet 26, 395. (2000).
6. Green, E.L. Genetics and probability in animal breeding experiments, (MacMillan Publishers Ltd., London and Basingstoke, 1981).
7. Vadasz, C., Sziraki, I., Murthy, L.R. & Lajtha, A. Genetic determination of striatal tyrosine hydroxylase activity in mice. Neurochem Res 11, 1139-49 (1986).
8. Vadasz, C. et al. Transfer of brain dopamine system-specific quantitative trait loci onto a C57BL/6ByJ background. Mamm Genome 5, 735-7 (1994).
9. Vadasz, C. et al. Genomic characterization of two introgression strains (B6.Cb4i5) for the analysis of QTLs. Mamm Genome 7, 545-8 (1996).
10. Vadasz, C. et al. Analysis of the mesotelencephalic dopamine system by quantitative-trait locus introgression. Neurochem Res 23, 1337-54 (1998).
11. Zaborszky, L. & Vadasz, C. The midbrain dopaminergic system: anatomy and genetic variation in dopamine neuron number of inbred mouse strains. Behav Genet 31, 47-59. (2001).
12. Vadasz, C., Fleischer, A., LaFrancois, J. & Mao, R.F. Self-administration of ethanol: towards the location of predisposing polygenes in quasi-congenic animal models. Alcohol 3, 617-20 (1996).
13. Vadasz, C. et al. Mapping of quantitative trait loci for ethanol preference in quasi- congenic strains. Alcohol 20, 161-71 (2000).
14. Vadasz, C., Saito, M., Gyetvai, B., Mikics, E. & Vadasz, C., 2nd. Scanning of five chromosomes for alcohol consumption loci. Alcohol 22, 25-34 (2000).
15. Saito, M. et al. Mouse striatal transcriptome analysis: effects of oral alcohol self-administration. Alcohol In press (2004).
16. Saito, M. et al. Variants of kappa-opioid receptor gene and mRNA in alcohol-preferring and alcohol-avoiding mice. Alcohol 29, 39-49 (2003).
17. Saito, M., Smiley, J., Toth, R. & Vadasz, C. Microarray Analysis of Gene Expression in Rat Hippocampus after Chronic Ethanol Treatment. Neurochem Res 27, 1221-1229 (2002).