We aim to elucidate neural circuits and their functions that continuously change throughout life from development to aging, focusing on plasticity in development and learning, as well as degeneration and functional recovery in neurological diseases. Using multifaceted approaches including electrophysiology, neural circuit tracing, imaging, molecular biology, and behavioral analysis, we strive for an integrative understanding of brain function from the molecular and synaptic levels to the individual level. If you are interested in our research, please feel free to contact us.
Operational Principles of Neural Circuits Underlying Higher Brain Functions and Pathophysiology of Neurodegenerative Diseases
The arrangement and connectivity patterns of neurons, the basic units of brain information processing, contain mechanisms that link brain structure and function. Through neuropsychological methods and functional MRI studies at the regional level, as well as single-unit recording methods at the neuronal level, the essential regions and fundamental information processing for various higher brain functions are becoming clearer. Most of these findings represent averages or typical patterns obtained from examining numerous samples.
However, individual diversity is a fundamental aspect of human nature, as people feel, think, and behave differently even under identical circumstances. Furthermore, in our current super-aged society, there is growing interest in the "prodromal" state—the transition from healthy aging to disease. To understand the neural basis of this diversity, we focus on: (1) the effects of multi-layer connectivity patterns and intra- and inter-layer synchronous activity on higher brain functions, and (2) the effects of synchronous activity on brain microenvironment homeostasis.
Effects of Multi-layer Connectivity Patterns and Intra- and Inter-layer Synchronous Activity on Higher Brain Functions
Regarding neural connectivity and synchrony, it is known that neurons handling similar information tend to synchronize their activity at various levels—from micro/mesoscopic levels such as cortical "columns" or hand regions in the motor cortex, to macroscopic levels such as "visual" and "motor" global networks. Furthermore, it has become clear that achieving certain higher functions requires not only activity in the core regions identified by conventional functional MRI or single-unit recording methods, but also synchrony of activity within or between global networks. We aim to understand how the neural basis of higher brain functions can be expressed not only in terms of neural activity strength or firing frequency, but also in terms of network activity dynamics.
Basic Research and Methodological Development of Functional MRI
We have pioneered the development of functional MRI for monkeys (Hayashi et al., 1999; Miyashita and Hayashi, 2000), comparative fMRI studies between humans and monkeys (Nakahara, et al., 2002; Morita, et al., 2004), and resting-state functional MRI in monkeys (Hayashi, et al., 2007), working on elucidating the neural basis of frontal lobe function and motor learning, as well as clinical applications to Alzheimer's disease. We are currently conducting collaborative research on motor learning functional MRI in monkeys with the University of Pittsburgh Brain Institute.
We have also worked on elucidating the mechanisms of BOLD and synchrony signals using high-field MRI (Hayashi, et al, 2005, 2007). Using multi-unit recording, wide-field microscopy neural activity measurements, and functional MRI, we aim to elucidate the origins and functions of synchronous activity at various levels from cortical columns to global networks.
Pathophysiology of Neurodegenerative Diseases
We aim to elucidate the pathophysiology of neurodegenerative diseases such as Alzheimer's and Parkinson's disease, and to develop early diagnostic and therapeutic methods. While this is a theme pursued by researchers worldwide, our laboratory focuses on the modulation of synchronous activity in global neural networks and the disruption of brain microenvironment homeostasis. Our research is centered around members with extensive clinical experience as neurology specialists, and we aim to link experiments using cultured cells and model animals with clinical research.
- Effects of Diffuse Projection Systems on Brain Environment
- Surrogate Marker Search and Pathophysiology of Cognitive Decline and Behavioral and Psychological Symptoms (BPSD) in Parkinson's Disease
- Pathophysiology of Exosome Transport Exosomes function as intercellular communication tools, transporting signaling molecules and maintaining environmental homeostasis while being involved in the onset and progression of various diseases. In neurons, exosomes are known to be secreted in an activity-dependent manner. In our laboratory, we focus on the function of exosomes that contribute to the onset and progression of neurodegenerative diseases such as Alzheimer's and Parkinson's disease by mediating the propagation of pathogenic proteins in the brain. Through a multi-level approach from the molecular to cellular and individual levels, we analyze the properties and intra- and extracellular dynamics of exosomes, aiming to elucidate their transport mechanisms and contribute to the search for disease-specific biomarkers and the development of novel therapeutic approaches.
Alzheimer's disease is characterized by two major molecular pathologies: amyloid pathology and tau pathology. Clarifying their relationship is an important step toward understanding the onset mechanisms of Alzheimer's disease. The relationship between diffuse projection systems and Alzheimer's disease has been extensively studied based on the cholinergic hypothesis, leading to the realization of treatment with acetylcholinesterase inhibitors. Focusing on the locus coeruleus noradrenergic system, one of the earliest sites where tau pathology appears, we aim to modulate the locus coeruleus noradrenergic system activity in model mice to alter cortical synchronous activity and brain environment, thereby clarifying the impact of the noradrenergic system's brain homeostasis maintenance function on Alzheimer's disease pathology and amyloid pathology. We also aim to explore the potential of therapeutic approaches through functional modulation of the locus coeruleus noradrenergic system.
Treatment for the motor symptoms of Parkinson's disease (PD) has improved with the availability of many drugs with different pharmacological effects. However, with the increase in elderly patients, the complication rate of dementia and behavioral and psychological symptoms (BPSD) is increasing, and these complications directly lead to poor prognosis including decline in instrumental activities of daily living (iADL), making early diagnosis and intervention important. Using data from PPMI, a longitudinal cohort study of PD, we aim to extract characteristic biomarker patterns and neural activity dynamics of cognitive decline and BPSD, and to develop a model that serves as a surrogate marker for prediction, while elucidating the pathophysiology of BPSD. We also serve as the psychology lead for J-PPMI, Japan's prodromal Parkinson's disease cohort.