One of the major goals of the Department of Physiology and Cell Biology is to elucidate the basic principles of the brain networks that are responsible for behavioral expression in rodents. Our neurophysiological research focuses mainly on the neural networks of the cerebral cortex, hippocampus, basal ganglia and thalamus that regulate particular behavioral tasks in rats; this research utilizes multichannel electrode-based multineuronal recording technology, Two-photon imaging of neural activity, optogenetics involving genetically modified animals and adeno-associated virus vectors, and theoretical analysis technologies.

Research Agenda – What do we want to know?
　In the sensory, association and motor cortices in the cerebral cortex, the excitatory pyramidal cells and inhibitory interneurons form an intracortical circuit. These brain areas, which play important roles in appropriate behavioral expression, are connected with each other and form the interareal circuit that consists of complex intercortical and subcortical connections through the hippocampus, striatum, substantia nigra and thalamus.
In the 20th century, the spike (unit) activity of single neurons in the brain that are related to behavior was actively studied using the single-unit recording technique. From a technical point of view, however, it was extremely difficult to investigate neuron subtypes and axonal connections by this method. Therefore, we developed a new experimental technique and used it to initiate a study of the basic principles whereby neural networks, particularly those in the cerebral cortex, encode behavioral information.


Research Techniques – How do we find answers?
1. Operant Learning Task
With the conventional technique of operant conditioning, it took weeks to months to train rats to obtain rewards by pushing a lever with their forelimb. Therefore, we developed a “spout-lever” by integrating a lever and a spout, and this enabled us to train rats to perform the forelimb movement task in a short period of time. This method allows for more rapid generation of rats to perform particular behavioral tasks in physiological experiments.

2. Multineuronal Recording
Multineuronal recording is a physiological technique in which spike activities of a large number of neurons are simultaneously recorded using silicon probes (multichannel electrodes). Signals recorded with electrode are distinguished by spike sorting, an analysis technique, to separate the spike (unit) activity produced by each neuron. Multineuronal recording also makes it possible to simultaneously record local field potentials and spike activities to permit the analysis of functional synchronous oscillation activities such as gamma and ripple waves.

3. Optogenetics
To understand the mechanism of information processing in neuronal networks, it is useful to demonstrate causality by optogenetically manipulating signals flowing in the networks. We are conducting experiments using gene-expressing virus vectors as well as transgenic rats that express channelrhodopsin-2, which uses blue light to depolarize membrane potentials. In addition, we are conducting research to establish a multi-linc analysis technique that identifies axonal projections of recorded neurons by combining multineuronal recording technology with optogenetics.

4. Theoretical Analysis – Simulation Modeling
In collaboration with computational neuroscientists, we are conducting sophisticated and efficient theoretical analyses of multineuronal recording data. Our goal is to fuse experiment and theory by utilizing simulation and modeling techniques.

5. Two-photon imaging of neural activity
We are constructing a two-photon microscope with the world's largest field-of-view. Using this microscope, we will record more than 100,000 neuronal activities from the brain during task execution and clarify the mechanism by which neurons cooperatively express brain functions.

6. Fiber Photometry Using Viral Vector Approach for Neuronal Activity and Neurotransmitter Release Measurement
This method involves the use of a viral vector approach for the targeted expression of genetically encoded indicators within specific neuronal populations. For assessing population-level neuronal activity, we employ calcium indicators such as GCaMP, providing a real-time measure of neuronal activity. Additionally, we utilize dLight, a dopamine-sensitive fluorescent probe, to measure local dopamine release. This probe enables the precise quantification of dopamine levels change in targeted brain regions. The viral vector method ensures that these indicators are selectively expressed in neurons of interest, allowing for the specific and localized measurement of neuronal activity or neurotransmitter release.


Research Methodologies – Pursuing Originality
　Our research targets the brain networks in rats that are responsible for behavioral expression in order to understand essential brain mechanisms. Conventional neuroscience has often explored the functional localization in the brain by “averaging” brain activities. However, brain activities dynamically change every second, and there is no doubt that it is not just single areas that play a role in information processing, but rather the whole network, which consists of multiple areas. Therefore, we aim to perform truly original research by increasing the sophistication of our methods and extending our interests to multidisciplinary research without fear of failure, from the viewpoints of “from static to dynamic states” and “from points to lines.”

see
https://researchmap.jp/yoshikazuisomura/

　The Department of Physiology and Cell Biology supports excellent next-generation researchers such as post-doctoral research fellows and graduate students through research activities that aim to elucidate the basic principles of brain networks. In principle, students define their research topics based on their future goals. One experimental setup is provided per one or two students/researchers. They receive curricula to learn a series of experimental techniques, join discussions that develop their logical thinking ability rather than simply increasing their knowledge, and receive opportunities to effectively conduct collaborative research in and out of the laboratory.
　The Department is responsible for a lecture and laboratory practice on General Physiology for medical school students. It also provides research training for students during the project semester and MD-PhD courses that aim to foster basic researchers in the early stages of their education. The field of physiology is essential for comprehensively understanding body functions and providing the foundation for doctors to treat patients. We hope that you will voluntarily and actively participate in the activities of the department to immerse yourself in physiology.

We respect each one's independence and positive attitude, and foster a sense of social cooperation and responsibility.