Joint Researches

Planned collaborative project


 Planned collaborative project themes are selected by NIPS, which are based on requests from researchers. Until 2007, there were two themes, “Physiological and neuroscientific studies into genetically modified model animals” and “Biomolecular sensors and physiological function.” Additional themes were added in 2008, with “Functional and morphological analyses of cells and tissues by multi-photon microscopy” and “Medical and biological applications of phase-contrast cryo-electron microscopy” (name changed to “Medical and biological applications of cutting-edge electron microscopy” in 2011), and in 2009 with “Behavioral analysis of mouse and rat”. Also, “Analysis of metabolic physiology for mouse and rat” began in 2011, while “Transfection study with primates,” “Analysis of fluctuations in function research in life science,” and “Multidisciplinary study of neural information” began in 2012. Also, “Transfection study with viral vector neurological system" was started in 2013. Furthermore, “Purification of supra-molecular complexes and analyses of their constituents by mass spectrometry” was started in 2016, “Analyses of dynamic aspects of the function and structure of membrane proteins” in 2017, “Multi-dimensional fluorescence imaging analysis with a multi-point scanning microscope” and “Elucidation of the pathology of mental/neurological disease by analysis of neural activity dynamics” in 2021, and “Visualization of white matter fiber bundles and brain microstructure by analyzing brain imaging data” and “Behavioral and neural activity analysis of macaque monkeys” in 2024. All these themes cover the most talked about scientific topics today, and are areas where NIPS is considered to be a frontrunner in Japan. We expect to receive many new proposals. Two projects, ”Analysis of fluctuations in function research in life science” and “Multidisciplinary study of neural information” were closed in 2015, due to the finish of the related NINS projects. “Behavioral analysis of mouse and rat” was closed due to the shutdown of the Section for Behavior Patterns. In 2016, NIPS performed only the collaborative experiments carried over from the prior year. “Analyses of dynamic aspects of the function and structure of membrane proteins” was closed in 2022, and “Purification of supramolecular complexes and analyses of their constituents by mass spectrometry” was closed in 2023.
 In regards to the proposed agenda, long discussions had been carried out at both faculty meetings and work meetings in 2012. The agreed requirements are as follows.
  1. Proposals should clearly state the aim and experimental design of the research project and should be completed within five years. However, depending on the state of the research, an extension period may be granted after the initial five years.
  2. Proposals should specifically state the research area of interest. Broad themes will not be accepted.
  3. There will be a limit to the number of proposals accepted. Each general collaborative research area category and research facility will accept five projects each at most, in principle.
The details of the planned collaborative research are as follows.

In accordance with the renovation and reorganization of the Animal Resource Center, starting in FY2022, the following items have been transferred to the Center's planned joint research projects.

(1) Production of advanced animal models (until FY2021, this project has been conducted as “1) Physiological and neuroscientific analysis of genetically modified model animals”, a joint research project planned by the National Institute for Physiological Sciences).
(2) Analysis of metabolic physiology for mice and rats.

Planned collaborative projects (Animal Resource Center)

Production of animal models

 Since genetically modified model animals are extremely effective for gene function analysis at the individual level, they are widely used in the field of life sciences. The recent engineering required to create such model animals has taken huge leaps forward; e.g., a new genome-editing tool (CRISPR/Cas9 system) can relatively easily cut arbitrary sequences on the genome. Section of Mammalian Transgenesis at the Center for Genetic Analysis of Behavior in Animal Resource Center has established the latest technology such as the CRISPR/Cas9 system capable of providing an endogenous genetic modification to mice and rats. Our staff familiar with not only physiology and brain science but also reproductive biotechnology, have greatly contributed to researchers all across the country by providing technology to create genetically modified model animals. We can support cooperative studies by providing the technologies to develop adoptive models such as transgenic or knock-out mice and rats. We will continue to work on the requested creation of genetically modified model animals by applying the new genome-editing tools. Fifteen projects are now scheduled for 2024.

Analysis of metabolic physiology for mice and rats

 The Section of Metabolic Physiology was set up in 2010, and the planned collaborative research project, “Metabolic physiology analysis of mice and rats,” had started in 2011. In FY2021, it was integrated with the Section of Behavioral Pattern Analysis and moved to the Section of Multilayer Physiology of the Center for Genetic Analysis of Behavior. Since then, researchers from within and outside NIPS have been looking at the following topics concerning genetically modified animals.

 (A) Evaluation of behaviors related to emotions, learning, and memories, and analyses of neural and muscular activities
(B) Non-invasive 4D cardiac function and capillary blood flow ultrasound imaging in mice
(C) Functional analysis of neuroimmune interactions in mouse models of diseases
(D) Multicellular activity measurement and manipulation in vivo
(E) Physiological measurements and analysis in vivo

 “Energy intake and expenditure in free-moving animals”, “Body temperature, heart rate, and blood pressure in free-moving animals” and “Mouse temperature preference assays with a thermal gradient ring” was closed in 2023. “Physiological measurements and analysis in vivo” was started in 2024. Sixteen projects are now scheduled in 2024.

Behavioral and neural activity analysis of macaque monkeys

 Using macaque monkeys as model animals, we will mainly evaluate social behavior and measure and analyze social-related neural activity. One project is now scheduled in 2024.

Planned collaborative projects (National Institute for Physiological Sciences)

Ultrastructure analysis of biological specimens by cutting-edge electron microscopy

 One cryo-electron microscope (cryo-TEM) and two serial block-face scanning electron microscopes (SBF-SEMs) are mainly used for this joint research program. Cryo-TEM shows the best performance when combined with a rapid-freezing sample preparation method. Under this condition, it is possible to study three-dimensional structures of unstained biological specimens, including isolated proteins, viruses, bacteria, cultured cells, and tissues, to more or less their true state with higher resolution. On the other hand, SBF-SEMs are used for the studies of ultrastructural analysis of thick biological specimens, like brain tissue. The specimens embedded in the plastic resin are sliced by a diamond knife and imaged by SEM continuously. Finally, the three-dimensional ultrastructure of the specimens is rebuilt at dozens of nanometer resolutions. The program support studies by using these states of the art electron microscopes. Twentyfour projects are now scheduled in 2024.

Functional and morphological analyses of cells and tissues by multi-photon excitation microscopy

 A two-photon excitation fluorescence microscope is a less invasive method for studying the microscopic structure and functions of cells in deep tissues of biological organisms. Currently, our institute has three upright two-photon excitation microscopes, and these allow us to observe the structure in the depth of one millimeter with a spatial resolution of a micrometer. Since the maintenance of a two-photon microscope is complicated, NIPS is the only institute that can provide the opportunity for collaborative research with a high-quality experience. Furthermore, we recently build the two-photon fluorescence lifetime microscope system which enables us to observe the intermolecular interactions and the activity of signaling protein in a living cell in the deep tissue. We are also working on single-molecule imaging using quantum dots in a combination of a fluorescence microscope. Using these "cutting-edge methods," we have conducted collaborative research. Recent successes are particularly in vivo Ca2+ imaging, and long-term imaging of neurons in living mice. Two planned collaborative projects are scheduled in 2024.

Development and supply of viral vectors and gene-transfer to primates

 Advances in technology to control molecular functions or change neural activity by inserting certain genes into primate brains using virus vectors can lead to major possibilities. Getting to do such research, however, requires a long list of equipment and facilities to enable researchers to develop do things such as develop vectors, or insert vectors. A planned collaborative research project “Transfection study with primates” was launched in 2012 so that researchers could share their resources, and work together to unravel mysteries about higher brain functions and pathological conditions. In 2013, five projects were carried out, and five projects were carried out in 2014.
 The key point of the experiments is the development of suitable viral vectors. Also, viral vectors are useful, not only for primates but also for other animals. Thus, a planned collaborative project “Gene transfer into the nervous system using viral vectors” was started in 2013. In Section of Viral Vector Development, we promote collaboration with many laboratories by providing various serotypes of AAV vectors, conventional lentiviral vectors, and highly efficient retrograde gene transfer vectors. Moreover, we proceed with the collaboration to exploit the more advantageous viral vectors. Up to 2014, we provided more than 100 viral vectors for other laboratories and performed two planned collaborative research in 2013, and 4 in 2014. At present, very intriguing research results are being obtained. In 2015, the two projects were merged as “Development and supply of viral vectors and gene-transfer to primates.” The three examples of the achievements are as follows. 1) Virus vectors helped to identify system circuits that compensated motor functions after spinal cord injury in macaque monkeys. 2) Virus vectors revealed the property of subnetwork composed of excitatory and inhibitory neurons in layer 5 of the rat frontal cortex. 3) Virus vectors identified a specific subset of neurons commanding the dietary preference for carbohydrate over fat in mice. Fifteen projects are now scheduled in 2024.

Multidimensional fluorescence imaging analysis by multipoint scanning microscopy

We conduct joint-use research based on our originally developed multipoint scanning confocal and two-photon microscopy method. In particular, quantitative visualization analysis of cellular physiological functions, including biological rhythms, will be performed by high-speed 3D, ultra-long term, multi-color, and super-resolution observation. Four projects are scheduled in 2024.

Elucidation of the pathology of mental/neurological disease by analysis of neural activity dynamics

 To study the relationship between human and animal neural activity dynamics and the pathology of various mental and neurological diseases by combining unit recording, local field potentials (LFPs), electrocorticography (ECoG), scalp electroencephalography (scalp EEG), functional magnetic resonance imaging (fMRI), and magnetoencephalography (MEG) are utilized in a multi-layered manner. In particular, we analyze neural activity dynamics such as vibration, synchronization, and fluctuation. Seven projects are now scheduled in 2024.

Visualization of white matter fiber bundles and brain microstructure by analyzing brain imaging data

 We conduct collaborative research to visualize microstructures in white matter fiber bundles, cortical gray matter regions, and neuronal nuclei by analyzing human or animal brain tructural images acquired using MRI and other techniques. Four projects are now scheduled in 2024.