This translational study will identify multiple mechanistic biotypes for mental disorders based on molecular- and cellular-level pathogenetic mechanisms. For this purpose, hierarchical multi-level databases of the human and mouse brains will be created in collaboration with the Yagishita group. These brain databases, collectively termed the Translational Psychiatry Database (TPDB), will store the data generated per standardized procedures at the participating institutions. These institutions will accelerate their psychiatric research through the use of the TPDB data.

Ultra-high-magnetic field MRI will be applied to mouse models of psychiatric diseases, and a mouse brain MRI database will be created with consideration of developmental and environmental factors. This database will be included in the TPDB, along with the human database in Subproject 3A. Identification of the translational relationship between human biotypes of psychiatric disorders and mouse brain findings will inform psychiatric pathology. Moreover, this group will support the brain MRI scanning of the subproject researchers.

Experimental cognitive tasks that require introspection, reasoning, decision-making, or other demanding mental processes will be designed to measure brain activity in humans and macaques. Functional MRI, electroencephalography (EEG), functional ultrasound imaging, and other imaging modalities will be used to measure brain activity. The obtained data will be accumulated in a database. Technical skills and expertise will be transferred to scientists both within and outside of the Core Organization.

Unique methods for brain circuit manipulation, developed through the combination of chemogenetics and imaging techniques, will be further advanced. These methods will be applied to macaque and marmoset brains to elucidate the brain dynamics involved in higher cognitive functions. Technical support will also be provided to the researchers participating in this program.

The mirror neuron system refers to the association area network that enables apprehension of the actions and intentions of others, offering great implications for human brain evolution. Calcium imaging will be used to monitor the mirror neurons in marmosets. Behavioral data will be simultaneously collected to explore the dynamics of the mirror neuron system. Technical support will also be provided to the researchers participating in this program.

The dorsolateral prefrontal cortex controls higher cognitive functions in primates but not in rodents. Its activities will be monitored using calcium imaging in marmosets undergoing cognitive tasks. Similar experiments will be conducted using marmoset models of cognitive disorders to investigate the cognitive function dynamics and abnormal mechanisms underlying such disorders. Moreover, this group will provide technical support to and collaborate with other researchers participating in this program.

The visual cortex, which occupies nearly half of the cortical surface in primates, processes input signals in a hierarchical and parallel manner. Understanding this data processing mechanism is critical for developing the digital brain model. Visual functions in many regions of the marmoset and mouse visual cortexes will be mapped at the cellular level. The resulting large-scale data will be stored in a database and used to create the digital brain model.

New models of developmental and psychiatric disorders based on genetically engineered animals (marmoset and mouse) will be generated. These and existing disease models will be analyzed for brain abnormalities. They will also be provided to the scientists participating in this program, at their request. Moreover, next-generation offspring of mutant marmosets will be established, and these mutant animal lines will be preserved through sperm cryopreservation. Mouse models that harbor the same gene mutations as the mutant marmosets will be developed. These animals will be compared to identify the phenotypes preserved across species and those specific to primates.

Rett syndrome is a neurodevelopmental disorder caused by MECP2 gene mutations. In girls, this condition is the second most common genetic cause of intellectual disability after Down syndrome. At present, no curative therapy has been established. Dr. Okano and colleagues have created MECP2-mutant marmosets that faithfully recapitulate Rett syndrome pathology. Using this primate disease model, this subproject will discover new treatments through experiments with viral gene transfection and other potential therapeutic modalities.

Mouse, marmoset, and other animal models of schizophrenia and neurodevelopmental disorders are useful for exploring the underlying pathophysiology of these conditions. However, it is also important to detect differences between diseased humans and animal models, for example in the cellular and subcellular characteristics of neurons and synapses that can be inferred from behaviors at the organismal level. This subproject will investigate the neuronal characteristics of mice, marmosets, macaques, and humans with electrophysiological techniques. Interspecies comparison of these characteristics will help deepen the knowledge of human pathophysiology.