Let’s enjoy our research life. Students/residents/young scientists always see if senior scientists enjoy research or not. When they recognize that senior scientists are happy, they will be eager to get an independent position. Our happiness drives them to stay the science field.

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Most of psychiatric disorders have been considered to involve abnormalities in frontal and limbic brain regions and neurotransmitters of monoamine. These brain areas and monoamines play a major role in value-prediction, motivation and decision making, which are essential brain function allowing animals including human to adapt to the environment. Monoamines modulate synapses to shape value memories in frontal and limbic regions. These value-related memories in different brain regions may cooperatively and competitively regulate decision making and motivation. Recent advances in experimental techniques allow us to examine effects of physiologically-relevant monoamine signals on synapses and to associate synaptic plasticity to behaviors. The mechanical understanding of synaptic function in value-memories, decision making and motivation would be the basis for molecular description of genes related to psychiatric disease in relation to general malfunction of adapting mechanism.

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To understand and explain the symptoms of neuropsychiatric disorders from the activity of neurons and the synaptic input is one of the most important goals of the research in biological psychiatry. Recent advances in technology have made it possible to manipulate and record the activity of hundreds of selective neurons in vivo. Combining these advancements with conventional electrophysiology, which still have advantages in simplicity and temporal resolution, will help to explain the circuit pathophysiology of neuropsychiatric disorders such as epilepsy. Animal models of epilepsy show similar behavioral and electrophysiological phenotypes with humans and therefore can be compared more directly in comparison to other neuropsychiatric disorders. In this article, I would like to show how new and conventional methods for neuroscience research can be combined to clarify the pathophysiology of epileptic seizures exaggerated by the decrease of endocannabinoid signaling. Extracellular field recording, current source density analysis with multiple electrodes, in vivo whole cell recording and optogenetics were used for the experiment and the pros and cons of each method are explained.

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The deterioration of the synapses has attracted attention as the pathophysiology of neuropsychiatric disorders, and synaptic responses against the stress, such as oxidative, endoplasmic reticulum, and carbonyl stress, is now being considered as a possible causal signaling in these diseases. Thus, we develop the high throughput in vitro screening system as well as in vivo brain imaging of disease model so that quantitative measurement of the synaptic deterioration and stress-related metabolites can be performed. Together with behavioral assessment, we aim to identify a novel therapeutic target for neuropsychiatric disorders.

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Dopamine is a neurotransmitter responsible for motor function, motivation, pleasure emotion and reward related behavior, and dysfunction of dopamine is implicated in the etiology and pathology of mental disorder and neurological diseases such as Parkinson's disease, schizophrenia and depression. However, the molecular mechanism of dopamine remains still unknown. Recently, we analyzed dopaminergic intracellular signaling using phosphoproteomic approach, and found that dopamine activates Rap1 signal in medium spiny neurons of nucleus accumbens to enhance the neuronal excitability. Here, I introduce this research and discuss the role of molecular mechanism analysis for neuropsychological diseases.

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Mental disorders are complex diseases involving both genetic and environmental factors. We developed mutant DISC1 transgenic mice as a genetic model of mental disorders, which abnormality became worse by environmental stress in the prenatal or adolescent period. We also found that two distinct direct and indirect striatal pathways have the distinct roles in cognitive learning, indicating that the circuit abnormality reflects on the cognitive deficits of mental disorders. Revealing pathology of mental disorders from analysis of neural circuit functions in psychiatric disease models is expected.

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The neurodevelopmental hypothesis of schizophrenia is one of the dominant paradigms for neuropsychiatric research. Moreover, recent genetic studies have suggested a pathological overlap between schizophrenia and other neurodevelopmental disorders, such as autistic spectrum disorders and intellectual disability. These findings indicate the neurodevelopmental aspects of neuropsychiatric disorders and highlight the importance of basic studies of neurodevelopment. Here, the author presents a series of studies that were performed to clarify the pathophysiology of neuropsychiatric disorders. In these studies, we focused on neuronal migration as a fundamental step of brain development. Genetic and environmental factors that are presumed to cause neuropsychiatric disorders were shown to produce deficits of neuronal migration and abnormal cytological architecture in the neocortex of the brain. Abnormal cytological architecture has been pointed out as one of the microscopic pathological findings in the brains of patients with neuropsychiatric disorders. Further studies are required to reveal how abnormal cytological architecture contributes to the pathophysiology of neuropsychiatric disorders.

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During advances in clinical psychiatry and neurology, a part of "disorder" : an entity of functional abnormality characterized with specific symptoms and social disabilities regardless of its pathomechanism, has sometimes been re-defined as " disease" : an entity of impaired condition based upon a known etiology. These re-definitions had often been achieved by an innovation in histological, brain imaging and/or biochemical testings, and such dissection of a "disease" from a "disorder" has been accelerated by recent technological breakthrough in genome analysis, i.e. next-generation sequencing. For example, large-scale studies have discovered that ~0.1-1% of autism spectrum disorder and schizophrenia patients diagnosed with operational diagnostic criteria can be solely explained by loss-of-function mutations in CHD8 and SETD1A, respectively. In this article, findings from these studies as well as strategies to facilitate such discoveries and appropriate interpretation of genomic findings are overviewed.

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