Gene expression in the mouse brain (indicated by the blue line) Nerve cells protruding processes

Outline During the 20th century, also called the century of science, molecular biology saw its greatest advances. It was 1944 when the essence of the gene was identified as the chemical substance DNA. In the 1970s, the establishment of basic techniques for genetic engineering led us to research our own life. The human genome project was commenced with international collaboration in the latter half of the 1980s to clarify all of the DNA sequences of man. Thanks to technological innovations for gene decoding and improvements of computer-aided analytical methods, this project is about to be completed. We have now obtained a design drawing of ourselves, which is open to the general public via the Internet in the form of about three billion sequences comprising only four different molecules that constitute DNA. It should be noted, however, that only 5% of these sequences actually serve as genes, or sources of signals for the production of particular proteins. Human DNA is believed to contain some 30,000 to 40,000 such genes, and their functional analysis represents a challenge in the post-genomic era. What will become feasible, and by what kinds of research, in the post-genomic era? First, the causes of diseases will be identified at the genetic level. This goal will be accomplished by comparing the genes of healthy individuals and those of diseased individuals to distinguish between the normal and abnormal, and identify the cause of the disease in terms of gene functions. This approach could also clarify the physiological functions of intact genes. Furthermore, animal models for analyzing gene functions have been developed proggressively using genetic manipulated techniques, including knockout mice, from which a particular gene has been deleted, and transgenic mice, which are prepared by incorporating a gene of unknown function into a normal mouse. Findings from these research activities will lead to the early diagnosis and treatment of disease, the development of drugs with a decreased prevalence of adverse reactions, and even the resolution of the mystery of biological phenomena. Based on the knowledge in molecular biology and cell biology that has been compiled to date, research activities at this department aim at elucidating mental functions recognized as the most complicated of the various functions of the human body. The higher functions of the brain, relying on a complex network of numerous nerve cells, have long been handled as a "black box." To explain this box at the molecular level in terms of the gene, we will make systematic analyses of candidate genes selected as potential causes of behavioral abnormalities in mice induced pharmacologically. To help accomplish this goal, we will establish an assay method using a nerve cell culture. We will also develop a new type of mouse model of mental illness that enables the tracking of changes in the central nervous system during its development. In addition to these activities, we will try to develop a method of quantifying mental functions. It is expected that our work will provide basic information of great significance for the creation of a sound aging society, as well as for the development of tools for the prevention and treatment of mental diseases. Research Activities With the ultimate goal of clarifying the relationship between brain functions and genes in the post-genomic era, we are investigating the challenging theme of the "molecular bases for brain functions." Thanks to the human genome project, a draft sequence of the human genome has been clarified. A draft sequence of the mouse genome is also available. The present status of genome research may be described as such that target molecules for analysis at the molecular level have been obtained. Major challenges in the post-genome era may concern functional analyses of target molecules and elucidation based on the molecular basis of combined physiological phenomena involving multiple genes including brain functions. Understanding the molecular level of higher brain functions, represented by mental functions, in particular, is a challenging goal remaining to be accomplished in the 21st century. Several years ago, the term "the mind gene" was uncommon except in mass media. However, now with the human genome sequence available, to describe mental functions in terms of the set of genes for intelligence is no longer a dream. Examining the temporal changes in the central nervous system shows that mind is formed through a long developmental process comprising the differentiation and proliferation of nerve cells, followed by apoptosis, formation of neural circuits, etc., in a good balance between the genetic program and the environment, and subsequent refinement of the neural circuits in response to the external environment. It is hypothesized that disruptions and abnormalities in these developmental events (human variations) can cause mental diseases. Research Subjects (1) A research approach from candidate genes, and the molecular cell biology of dendrites in neurons We have conducted universal and systematic analyses at the transcriptome level on genes in a mouse model of drug-induced behavioral abnormalities using the microarray method, differential display method, etc. Using molecular approaches, we will analyze the thus-obtained candidate genes. We will also make efforts to establish an in vitro assay system using a nerve cell culture. Using this system, if established, we will conduct molecular cell biological analyses of neural dendrites. (2) Approach to human neural diseases from mouse models When biological phenomena are explained in terms of molecules, genetics is robust; it is no exaggeration to say that almost all breakthroughs in the molecular basis for biological phenomena have been the fruits of genetics. We will investigate mental diseases as mental functional variants using approaches based on extensive clinical searches, and the findings of the human genome project, and will develop mouse models based on human chromosomal aberrations using the cutting-edge techniques of genetic engineering. We will also develop mouse models of conditional mental diseases that enable the monitoring of temporal changes in the central neurons system using time-controllable promoters specific to various brain regions. Being mouse mental function variants that have never existed, these mouse models will enable mouse forward genetics in mental functions. Using these mouse models, it will be feasible to understand the molecular aspects of mind, including its relation to external environments. (3) Establishment of an assay system for neural circuits using microimaging. At present, no assay systems are available to permit accurate quantitative determination of mental functions. With the aim of creating a system physiology with a molecular basis, we will make efforts to develop a genetically manipulated voltage-sensitive dye and to establish an assay system for functional circuits in the brain using microimaging, etc.