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An organism is finely controlled by various systems. Among them, the brain has been called as “the most complex system in the universe." In this laboratory, we consider mental and neurological disorders as a "system failure in the brain" and aim at clarifying the mechanisms underlying these disorders and developing prevention and treatment methods by performing studies on animal models that represent a disease. These animals, including genetically modified mice, are subjected to advanced analytic methods ranging from molecular to behavioral levels.

1. Studies to understand the mechanisms and control methods in intermediate phenotypes of psychiatric disorders (the immature brain)

Psychiatric disorders, such as schizophrenia and mood disorders are considered brain diseases. With an aim to clarify the relationship between genes, behavior, and psychiatric disorders, we discovered that there are genetically modified mice with significant behavioral abnormalities resembling those of patients with psychiatric disorders, by clarifying their behavioral changes in our laboratory. Among them, the phenomenon of immature dentate gyrus (iDG), a pseudo-immature state of the granule cells (neurons) in the hippocampal dentate gyrus, has been found out for the first time in various kinds of mice that demonstrated schizophrenia-like behavioral abnormalities (Yamasaki et al., Mol. Brain, 2008; Takao et al., Neuropsychopharmacol., 2013)(Fig.1.).

Fig. 1. In the dentate gyrus of Shn2 KO mouse, a mouse model for schizophrenia, the mature granule cell marker, calbindin, is remarkably decreased. Green, calbindin (mature granule cell marker); red, cell nucleus.

A similar state also has been observed in the brain of patients with schizophrenia or bipolar disorder (Walton et al., Transl. Psychiatry, 2012; Hagihara et al., Mol. Brain, 2014). In addition, various artificial manipulations, such as electrical stimulation and drugs, have been shown to convert the mature neurons of the dentate gyrus to the pseudo-immature state (dematuration) in adult brains of wild-type animals (Kobayashi et al., PNAS, 2010; Shin et al., Bipolar Disord., 2013). It has also been reported that such “dematuration” occurs in parvalbumin-positive interneurons in the amygdala, an emotion-related brain structure, when animals are treated with antidepressants (Karpova et al., Science, 2011), and that certain types of interneurons are in the pseudo-immature state in the cortex of patients with schizophrenia (Gandal et al., PLoS ONE, 2012) and the cortex of rodents (Powell et al., Neuropharmacol., 2012). Swiss researchers have also found that specific cells demonstrate dematuration in the hippocampus of mice performing a learning task, and that it returns to the mature state when the learning has been established (Donato et al., Nature, 2013). From the above results, it can be assumed that some brain cells repeatedly undergo rejuvenation and maturation in responses to changes in the external environment, and that bidirectional changes of cellular maturity in the brain play an important role in the maintenance of homeostatic mechanisms and their failure at the cellular level.
In this research, we aim to 1) clarify the molecular mechanisms and functional significance of maturity changes in various brain cells, including neurons in the hippocampal dentate gyrus, and 2) establish the methods by which brain cell maturity is controlled, using advanced and comprehensive analysis technologies. We believe that this research may significantly contribute to the establishment of prevention, diagnosis, and treatment strategies for psychiatric disorders, such as schizophrenia and depression, as well as for the elucidation of mechanisms underlying the aging brain.

2. Development of brain function phenotype database by using model mice

Along with the developments of genomic science, one-dimensional information of all genes has brought about a revolutionary change in the advancement of life sciences. This has allowed for the use of a comprehensive method to study all genes as targets when we analyze a certain biological phenomenon. In order to clarify the relationship between genes and brain functions, many strains of genetically modified mice are produced in the world, and studies have reported the brain functional phenotypes of those mice. However, only fragmentary knowledge has been accumulated due to the use of non-standardized experimental techniques. Accordingly, comprehensive and systematic bioinformatics analyses cannot be applied, and an understanding of the overall picture that connects brain function and genomic information becomes difficult. In light of these points, we developed a mouse behavioral experimental facilities in our research group in 2003, which has enabled the analysis of mouse behavioral phenotypes, the development of behavioral test experimental control and analysis software, total automation of behavioral experiments, standardization of data acquisition techniques, and the development, maintenance, and publication of databases. Then, we have successfully established a comprehensive behavioral analysis system that allows a high throughput screening of mouse behavioral phenotypes. Thus far, we have also conducted behavioral analyses for more than 160 strains of genetically engineered mice both within and outside the country. Consequently, we have succeeded in identifying various mouse models of mental and neurological disorders (Miyakawa et al., PNAS, 2003; Powell & Miyakawa, Biol. Psychiatry, 2006; Arron et al., Nature, 2006; Nakatani et al., Cell, 2009; Yamada et al., Nature Med., 2009; Ohno et al., Nature Neurosci., 2009; Koshimizu et al., Mol. Brain, 2012; Takao et al., Neuropsychopharmacol., 2013; Ohira et al., Mol. Brain, 2013).
We have created a database ( the experimental control and analysissoftware for behavioral experiments and the behavioral experimental data obtained from previous studies. In addition, the mouse brains and plasma used in our behavioral experiments were collected after the study and cryopreserved in the laboratory, thereby allowing these mouse samples with existing behavioral data to be studied further by using various methods.
Currently, we offer assistances on the behavioral analyses of genetically modified mice (systematic brain function behavioral analysis) as part of the resources and technical support of the Scientific Research on Innovative Areas (Comprehensive Brain Science Network, the Japan Science and Technology Agency) in our department. Contact us if you are interested.