Stress predisposes the morbidity of the psychiatric disorders such as depression. To address the mechanism underlying stress susceptibility, recent progress in neural circuit regulating it was overviewed. In particular, based on a central role of hypothalamus‐pituitary‐adrenal axis in the mammalian stress response, modulatory effect of the hippocampus and prefrontal cortex interacting with monoaminergic system was discussed. While recent genetic approach manipulating the neural activity in a pathway‐specific or cell type‐specific manner enables identification of the neural circuits responsible for stress susceptibility, it remains elusive how those neural circuits interact with each other. Theoretical analysis of the neural activity recorded simultaneously in multiple brain regions needs to be done to construct an integrated model for the neural system regulating stress susceptibility.

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Exposure to chronic stress can be differently perceived by individuals and can have persistent sequelae depending on the level of stress, resilience, or vulnerability of the individual. While stress vulnerability may influence depression, the molecular and neural mechanisms underlying the susceptibility and resilience to chronic stress within the brain are poorly understood. Recent studies including our works suggest that stress‐induced changes in epigenetic mechanisms and subsequent synaptic and structural plasticity may be key underlying mechanisms of stress resilience and susceptibility. Indeed, disruptions in transcription occur in various brain areas in preclinical models of depression and in patients with depression. Recent studies have suggested that histone deacetylases (HDACs) ‐mediated gene transcription has important roles in the pathophysiology and the treatment of depression. Here, we review information regarding current understanding of HDACs‐mediated pathways that may impact depression susceptibility and resilience. These novel mechanisms of action may lead to new therapeutic strategies for treating major depression.

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The hippocampus is a brain region that is highly responsive to various stimuli and an important therapeutic target for depression. Electroconvulsive therapy is a highly effective and fast‐acting treatment for depression. However, its mechanism of action remains largely unclear. Using electroconvulsive stimulation (ECS) as a model of electroconvulsive therapy, we have focused on phenotypic changes in mature neurons of hippocampal dentate gyrus and cellular changes in neurogenesis in the dentate gyrus. In addition, using an antidepressant treatment resistant model, we suggested that impaired neuromodulation and monoaminergic signaling in the hippocampus are among factors contributing to antidepressant treatment resistance. These findings suggest that phenotypic changes in the hippocampal neurons induce changes in excitability and responsiveness, and these may be important for recovery from depression.

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Circadian rhythms are the fundamental phenomena in almost all of the living organisms. In mammals, these rhythms are associated with not only physiological systems and behaviors, but also mental health. Several disorders such as cancer, metabolic syndrome and sleep disorders are known to be triggered by circadian dysfunctions. Understanding the circadian responses and functions of these disorders probably contribute to development for therapeutic strategy. Recently, several works have indicated the relationship between chronotypes and mood disorders that morning person of chronotype is tended to stress resilience. Therefore, recent attempt to analyse the chronobiological aspects of mood disorders and stress responses is getting more attention. In this review, we introduce the recent advances between mammalian circadian rhythms and mood disorders such as stress, depression and bipolar disorders including our data that the mice with a clock ASPS variant are resilient to chronic stress.

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Biological research that is being actively conducted from various directions is rapidly elucidating the pathophysiology of psychiatric diseases. Many postmortem brain studies have recently been performed to verify the findings of the above studies. For such postmortem brain researches, a systematic psychiatric brain bank that can provide brain samples suitable for study is essential. Since 1997 we have managed the systematic postmortem brain bank on psychiatric diseases specializes in schizophrenia for the first time in Japan in order to understand and cure psychiatric diseases and currently maintains 62 brain tissue resources. Since 2016, Japan Brain Bank Net (JBBN) has been organized, and brain banks in Japan are being networked nationwide in order to meet the wishes of nationwide pre‐registered donors. In this article, we show the practices of psychiatric postmortem brain bank in Japan and the outlines the current status of psychiatric disease studies using postmortem brain samples.

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Protein expression studies in postmortem brain are necessary for investigating molecular mechanisms underlying the pathogenesis of neuropsychiatric disorders including schizophrenia. Since there are a number of confounding factors originated from various conditions other than pathological conditions in postmortem brain studies, so it is vital that evaluate and control them carefully. We have investigated the relationship between the expression level of candidate proteins in the postmortem brain of schizophrenia as an intermediate phenotype and their association with single nucleotide polymorphism (SNPs) . These studies have conducted using the postmortem brain samples with mainly psychiatric diseases preserved at Fukushima Brain Bank and them with healthy controls preserved at Brain Research Institute, Niigata University. In this article, we show the investigation whether differences between two different brain banks had any effect on protein expression in postmortem brain samples, and the study of Aldehyde dehydrogenase 4 family member A1 (ALDH4A1) expression levels in postmortem brains of patients with schizophrenia and their association with SNPs.

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Dietary sugar in humans has increased dramatically in the modern era. However, it is unclear whether and how high sugar diets affect the pathogenesis of psychiatric disorders. Here we first investigated causal relationship between excess sugar intake and development of psychiatric disorders using mice. We demonstrate that a high sugar diet induces expression of schizophrenia and bipolar disorder‐associated phenotypes in mice deficient for glyoxalase‐1, an enzyme associated with psychiatric disorders and involved in the detoxification reaction in glycation processes. We found that a high sugar diet increased nondiabetic vascular damage in glyoxalase‐1 mutant mice, and reduced glucose uptake into the brain parenchyma. Chronic aspirin treatment protected vascular damage, increased glucose uptake into the brain, and prevented development of several psychiatric‐associated phenotypes. Postmortem analysis of brains from patients with schizophrenia and bipolar disorder revealed similar vascular damage to what we observe in our mutant mice. Our results indicate that schizophrenia is associated with vascular damage likely caused by metabolic dysfunction.

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Spatial transcriptomics was selected as the “Method of the Year” by the journal Nature Methods this year. In single‐cell analysis, RNA sequencing is performed for each individual cell, while in spatial transcriptomics, RNA sequencing is performed in conjunction with spatial information. Since the human brain is large and has a spatially complex shape, it is desirable to analyze gene expression profiles with spatial information when analyzing postmortem brains for the study of neuropsychiatric disorders. At present, Visium by 10x Genomics and GeoMX Digital Spatial Profiler (DSP) by nanoString are the representative methods. I will focus on these methods and give an overview of spatial transcriptomics.

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