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Research

Genetic/Genomic Research
Psychological Research
Reseach of Brain Images
Animal Model Research
Cell Biology

Genetic/Genomic Research

Our research is supported by patients and healthy volunteers who agreed to donate their blood plasma for research purposes. We attempt to understand the genetic variations specific to patients with mental disorders by analyzing their genetic information along with environmental factors of patients, using clinical data gathered by mental health practitioners and clinical psychologists. DNA samples of patients and healthy volunteers are used to conduct genotyping, including several whole genome-wide association studies, in order to obtain information of genetic polymorphisms (SNPs and CNVs) specific to individuals with mental disorders. We also focus on RNA expression levels and proteome in patients with mental disorders. Our goal is to find biomarkers of psychiatric diseases, with strong hope that the markers will provide us with further understanding of pathophysiology of diseases, better knowledge on mechanisms of drug action, thereby leading to advancement of therapeutic criteria of complex mental disorders.

SNPs Genotyping Assay
Genetic variations associated with psychiatric disorders.

SNPs distribution on a chromosome
Results from a genome wide association study.

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Psychological Research

Various psychological and physiological assessments are conducted by a team of psychologists to quantify cognitive and behavioral characteristics of subjects recruited for research. First, all volunteers are interviewed using M.I.N.I. (Mini iInternational Neuropsychiatric Interview) by experienced psychiatrists for the evaluation of general mental status. For subjects who showed indications of psychiatric disorders in the interview, clinical rating scales, such as HAM-D and PANSS, are applied by psychiatrists to evaluate the severity. WAIS-R is used to measure IQ, and WMS-R (Revised version of Wechsler Memory Scale) to assess memory functions in individuals. Tests called BACS (Brief Assessment of Cognition in Schizophrenia) and PPI (prepulse inhibition) are used to examine their validity as methods for screening of schizophrenia. The data obtained are employed in a variety of studies genomic and imaging researches to examine the association between biological factors and psychological traits.

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Reseach of Brain Images

Our research focus is on the elucidation of the pathophysiology, enabling of early diagnosis and the assessment technique for medication of psychiatric diseases, e.g., schizophrenia, bipolar disorder, and depression, using magnetic resonance imaging (MRI). Further, we challenge to build up the database of human brain mapping using these tools. MRI technique enables us to measure the structure of brain, fiber tract image (diffusion tensor imaging), function of neuroactivity (fMRI), and cerebral blood flow (arterial spin labeling) in humans. These studies using MRI with cognitive, characteristic and grading scale for clinical severity allow the investigation of regional neural function. The aim of our research work is the establishment of bio-markers for early diagnosis and evaluation of treatment from various perspectives.

1.5T MRI (Siemens)

3-dimensional T1-weighted image

Tract fiber that run through the frontal region.

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Animal Model Research

Due to the nature of psychiatric disorders, behavioral, neurobiological, and pharmacological analyses using model animals are of great importance in elucidating the pathophysiology and developing putative therapies. Both genetic and environmental factors are likely to play roles in the onset and the progress of the diseases. Therefore, manipulation of genes (e.g. genetically modified mice) as well as environments (e.g. housing, hormone, and intrauterine growth retardation conditioning) are used in the investigations. Our studies focus on the factors that function in the neuronal development and plasticity, such as genes related to brain-derived neurotrophic factor. Tests for depression/anxiety-like behaviors and cognitive functioning such as learning and memory are performed for evaluation. The sensory motor gating is assessed by the prepulse inhibition test, which is known to be associated with schizophrenia. Histological investigations, biochemical approaches such as in vivo microdialysis, and gene/protein-expression analyses are also performed.

Open Field Test

Elevated Plus Maze Test

Model Mouse

   

Tissue slice of hippocampus

   

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Cell Biology

Summary

Neurons communicate with each other in many ways including neurotransmission and neurosecretion. Brain-derived neurotrophic factor (BDNF), one of the most important proteins secreted by neurons, plays an irreplaceable role in neuronal survival, neurite outgrowth and activity-dependent forms of synaptic plasticity. Because of its various functions in the central nervous system, dysfunction of BDNF is believed to contribute to the pathogenesis of complex psychiatric disorders such as mood disorders and schizophrenia.

Our goal is to clarify the mechanism of BDNF dysfunction in neurons, which may lead to symptom onsets of psychiatric disorders.

Stress-related hormones affects neuronal function
Our focus is to determine the effects of stress-related hormones, psychomimetic and antipsychotic drugs (e.g. glucocorticoids, phencyclidine and imipramine) on neurons on cellular/molecular levels. As an example, we have found the interaction between glucocorticoid receptor (GR) and BDNF receptor (TrkB) in cortical neurons (Numakawa et. al. 2009 PNAS ), and that the interaction regulates BDNF function in neurotransmission. Stress-induced glucocorticoid decreases the interaction and results in lower neuronal activity. It is possible that BDNF dysfunction caused by glucocorticoid is one of the pathogenetic mechanism of depression.

Basic properties of BDNF trafficking and secretion
Unveiling the intracellular behavior of BDNF is another research interest of our team. Though BDNF exerts its biological functions via binding to BDNF receptor (trkB) after secreted from neurons, basic properties of BDNF inside neurons is not ignorable. To know the intracellular traffick ing and the secretion mechanisms of BDNF might lead to a breakthrough on understanding of molecular mechanisms underlying the pathophisiology of psychiatric disorders. Our world-class level cellular biological technology provides Fluorescent-tagged BDNF that enables us to observe the intracellular behavior of BDNF!

If you are interested in joining us to share the excitement of researching the relationship between protein functions and psychiatric disorders, contact us!

 

Genetically-modified neuron was visualized by GFP

Intracellular trafficking of BDNF-GFP

Activation of intracellular signaling molecules (ERK).

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