Lab overview

Pharmacology research aimed at elucidating the biological basis that controls stress and aging of brain function and resilience toward therapeutic drug development

Pharmacology is a discipline that elucidates the molecular mechanism responsible for the interaction between drugs and living organisms and the pathophysiology of diseases and contributes to drug treatment and drug discovery. We study stress and brain aging related to mental and physical health and illnesses from the pharmacology viewpoint.

Stress due to adverse environments and demanding conditions causes diverse effects on mental and physical functions. For example, acute and controllable stress promotes adaptive responses to cope with stress, increasing habituation and resilience to stress. On the other hand, chronic and uncontrollable stress induces depression, elevated anxiety, and cognitive dysfunction, increasing the risks for mental and physical illnesses, such as depression. In addition, chronic and uncontrollable stress does not necessarily cause depression and elevated anxiety in all individuals, and there is considerable individual variability in stress susceptibility, suggesting the presence of stress resilience. However, stress and resilience mechanisms remain poorly understood, and therapeutic drug development targeting stress is not established.

To address this issue, we have been conducting biological studies using mouse stress models, such as social defeat stress. We demonstrated that the impacts of stress on brain structures and functions and behaviors vary depending on stress conditions. Thus, acute stress causes dendrite growth of neurons in the medial prefrontal cortex via the neurotransmitter molecule dopamine, augmenting stress resilience. By contrast, chronic stress induces emotional disturbances along with dendrite shrinkage of neurons in the medial prefrontal cortex via inflammatory molecules derived from microglia, inflammation-related cells in the brain. In addition, it is becoming clear that chronic stress causes leukocyte mobilization from the bone marrow and infiltration into the brain, contributing to emotional disturbances.

Thus, the biological basis of stress-induced emotional disturbances is molecular and cellular changes of neurons and glia in the brain, cooperating with leukocytes that infiltrate from the periphery into the brain. These interactions alter the activity patterns of local and distributed neuronal networks, leading to emotional disturbances.

Besides, brain aging is also associated with motivation and cognitive decline. Neuroinflammation derived from dendritic shrinkage of neurons and microglial activation is implicated in brain aging. Individual variability in brain aging suggests the presence of resilience to it. However, what and how brain aging occurs remains elusive.

In this laboratory, we aim to elucidate the biological basis that underlies stress-induced mental and physical alterations, aging of brain function, and resilience to stress and aging toward developing innovative therapeutic drugs for mental and physical illnesses such as depression.

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