Imagine the ability to monitor brain activity at the molecular level in real-time! The possible scientific and medical applications are endless. Recent advancements in neuroscience have achieved this milestone, but current strategies still require some polishing. This can be attributed to several shortcomings of existing techniques—high light scattering, narrow field of observation, surgically invasive manipulations to set up imaging, among others, which could potentially disrupt the molecular system under observation.
In this regard, a group of scientists led by Dr. Makoto Higuchi, Head of the Department of Functional Brain Imaging at the National Institutes for Quantum Science and Technology (QST), Japan, and senior researcher Dr. Masafumi Shimojo of the same department appear to have identified a blanket solution to all these neuroimaging problems. They have developed a positron emission tomography (PET)-based neuroimaging technique that uses the bacterial enzyme, dihydrofolate reductase (ecDHFR), and its unique antagonist, trimethoprim (TMP) to facilitate in vivo imaging in the brain. Their breakthrough findings have been published as a research article in The EMBO Journal (DOI: https://doi.org/10.15252/embj.2021107757).
Accordingly, the PET-based neuroimaging technique allows the live visualization of brain circuitry at the molecular level, without the disruption of the blood-brain barrier (BBB). The team of scientists, which in addition to Drs. Higuchi and Shimojo also comprised Dr. Ming-Rong Zhang of Department of Radiopharmaceuticals Development, QST, Dr. Yutaka Tomita of Department of Neurology, Keio University School of Medicine, and Dr. Anton Maximov of Department of Neuroscience, The Scripps Research Institute, La Jolla, among others, meticulously determined the components required for successful live brain imaging.
Firstly, they genetically manipulated neuronal cells in brains of living mice to express ecDHFR. Parallelly, they prepared a concoction of TMP tagged with a fluorophore (a fluorescent chemical that emits light upon excitation with light) called HEX, and radioisotope labeled TMP derivative, [18F]fluoroethoxy-TMP. Then, they intravenously injected the concoction into the living mice, and allowed it to penetrate the BBB. Finally, they performed live imaging of brain regions using two-photon microscopy to confirm their results.
Though their study is a success, Dr. Shimojo believes there is scope for further perfecting the technique. In this regard, he says, “At this stage, substantial continuous effort will still be necessary to overcome the challenges in terms of safety, cost-effectiveness, and ethics, although recent advances in the design of viral tools for non-invasive gene delivery will make it feasible to eventually apply these reporters to biomedical PET imaging of human brains.” Currently, they are hard at work addressing all the possible issues.
However, the results are still exciting. Particularly, the finding that this technique allows visualization of undetectable tau protein assemblies, the hallmark of neurodegenerative diseases like Alzheimer’s, during the early stages of their aggregation could be invaluable for neurodegenerative disease research. Speaking about the clinical potential of their findings, Dr. Higuchi explains, not without excitement, ”Along with the recent advances in gene therapy and regenerative medicine, genetic reporter imaging could become a principal pillar of future biomedical applications. In a few studies, HSV1-tk reporter imaging was indeed tested to track a tumor or infused cytolytic CD8+ T cells in human patients, highlighting the feasibility and advantage of genetic reporter imaging for future clinical applications.”
Indeed, these findings do create hope for illuminated probing of the intricacies of the enigmatic brain and may herald a paradigm shift in neuroscience research.
About National Institutes for Quantum Science and Technology, Japan
The National Institutes for Quantum Science and Technology (QST) was established in April 2016 to promote quantum science and technology in a comprehensive and integrated manner. The new organization was formed from the merger of the National Institute of Radiological Sciences (NIRS) with certain operations that were previously undertaken by the Japan Atomic Energy Agency (JAEA).
QST’s mission is to raise the level of quantum and radiological sciences and technologies through its commitment to research and development into quantum science and technology, the effect of radiation on humans, radiation emergency medicine, and the medical use of radiation.
To ensure that research and development delivers significant academic, social and economic impacts, and to maximize benefits from global innovation, QST is striving to establish world-leading research and development platforms, explore new fields, and serve as a center for radiation protection and radiation emergency medicine.
About Dr. Makoto Higuchi from National Institutes for Quantum Science and Technology, Japan
Dr. Makoto Higuchi is the Deputy Director of the Department of Functional Brain Imaging, at the National Institutes for Quantum Science and Technology, Japan. He also serves as the Group Leader, Brain Disorder Translation Research Group of the Institute. He has a license in Medicine and a PhD in Medicine from Tohoku University, and over two decades of research experience in neuroscience, physiology, neuroimaging, brain function, and translational neuroscience. He has authored over 370 research articles in national and international journals of repute and cited over 11,000 times.
About Dr. Masafumi Shimojo from National Institutes for Quantum Science and Technology, Japan
Dr. Masafumi Shimojo is a senior researcher at the Department of Functional Brain Imaging, at the National Institutes for Quantum Science and Technology, Japan. Dr. Shimojo has over 7 years of experience in the field of neuroimaging. His primary research interests include molecular and cellular neuroscience, physiology, neuroimaging, brain function, and translational neuroscience. He has authored over 20 research publications in journals of international reputation.
This study was financially supported in part by JST CREST Grant Number JPMJCR1652; AMED Grant Number JP19dm0207072, and JP19dm0107146; and JSPS KAKENHI Grant Number 18H04752 and 18K07777.
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The EMBO Journal
A genetically targeted reporter for PET imaging of deep neuronal circuits in mammalian brains