Main Research Themes

Elucidation of stress-induced cellular changes in the brain and their significance

Stress-induced changes in structures and functions of neurons and glia in the brain are crucial for cognitive and emotional disturbances and mental illnesses. However, the changes in subcellular organelles and their mechanisms remain unknown. We aim to elucidate stress-induced cellular changes in the brain and their significance using histological analyses with volume electron microscopy and expansion microscopy, multi-omics analyses, brain region- and cell type-specific molecular manipulations with recombinant viruses, and mouse behavior experiments, partly through collaborations.

Elucidation of stress-induced transcriptional and epigenetic regulations in the brain and their significance

Since neuronal and glial responses to stress are altered with chronic stress, these changes may involve transcriptional and epigenetic regulations, which remain unknown. We aim to elucidate stress-induced transcriptional and epigenetic regulations in respective cell types in the brain and their significance using brain region- and cell type-specific gene expression, transcriptional and epigenetic analyses, single-cell omics analyses with cell sorting from respective brain regions, brain region- and cell type-specific molecular manipulations with recombinant viruses, and mouse behavior experiments, partly through collaborations.

Elucidation of neural circuits and their information coding that underlie stress susceptibility and resilience

Stress-induced molecular and cellular changes in the brain lead to emotional disturbances through changes in the activity patterns of neural circuits composed of multiple brain regions. The importance of the medial prefrontal cortex, the nucleus accumbens, and the monoaminergic projections to these brain regions has been established. However, the entire neural circuits that control stress susceptibility and resilience and their information coding remain unknown. We aim to elucidate neural circuits that control stress sensitivity and resilience and the activity patterns of these neuronal circuits by whole-brain neural activity mapping, electrophysiological recording, and brain region- and neuronal projection-specific manipulation of neuronal activities, partly through collaborations.

Elucidation of stress-induced inflammatory responses and their significance

We and others demonstrated crucial roles of neuroinflammation mediated by various inflammation-related molecules such as bioactive lipids and cytokines for stress-induced emotional disturbances and mental illnesses. Stress also induces systemic inflammation manifested by the production of inflammation-related molecules and the mobilization of leukocytes in the blood, which may contribute to functional changes in the brain and peripheral organs and their interplay. We aim to elucidate stress-induced inflammatory responses in the brain and periphery and their significance using comprehensive analyses of bioactive lipids and cytokines, flow cytometry analyses of leukocytes, single-cell omics analyses, tissue- and cell type-specific genetically modified mice, and mouse behavioral experiments, partly through collaborations.

Elucidation of the biological basis of brain aging

We will evaluate altered brain functions, such as motivation and cognitive decline, in aged mice in multiple dimensions using various cognitive tasks, including stimulus discrimination task and attention set shift task, besides conventional emotional tests. We will then elucidate the mechanisms responsible for respective cognitive and emotional alterations associated with aging using multi-omics analyses, histological analyses, and molecular and neuronal activity manipulations, partly through collaborations.

Research outlook

We will promote basic research using mouse stress models and aged mice, and if necessary, conduct clinical research using specimens of healthy subjects and patients, partly through collaborations. We aim to biologically address the fundamental problems about stress, brain aging, and resilience and develop innovative therapeutic drugs that overcome mental and physical illnesses, including neuropsychiatric disorders.

• How is stress generated, amplified, and maintained in the brain?
• How are susceptibility and resilience to stress and aging controlled?
• How does individual variability in stress and brain aging occur?
• How are neural and bodily changes due to stress and aging related?
• How are stress and aging related to mental and physical illnesses?
• How can mental and physical dysfunctions with stress and aging be restored?

Research methods (including those performed in collaboration)

Mouse behavior experiments (P1A/P2A), generation of genetically modified mice, brain stereotactic surgery, generation of mice inoculated with recombinant viruses, implantation with a cannula for intracerebral administration, implantation with osmotic pumps, optogenetic/chemogenetic manipulation, in vivo imaging of neuronal activities, slice electrophysiology, cell sorting, flow cytometry, immunohistochemistry, laser confocal microscopic observation, volume electron microscopic analysis, expansion microscopic analysis, automated image analysis, comprehensive gene expression analysis (RNA-seq), comprehensive epigenome analysis (chromatin immunoprecipitation and ATAC sequencing), comprehensive lipid analysis (LC-MS/MS), comprehensive cytokine analysis, primary cultured neurons and glia, cell transfection, biochemical slice experiments, HPLC-ECD, plasmid construction, generation of recombinant viruses, quantitative RT-PCR