I am deeply honored to receive the Tokizane Toshihiko Memorial Award, a prestigious award from the Japan Neuroscience Society. As someone who spent my graduate and assistant years in the laboratory established by Professor Tokizane (Department of Neurophysiology, the Institute for Brain Research, Faculty of Medicine, University of Tokyo), I feel an exceptional sense of gratitude.

During my time as a medical student, I happened to encounter a physiology experiment and was instantly captivated by it. This led me to pursue further studies in graduate school. In graduate school, during my study abroad in Sweden, and upon returning to Japan as an assistant professor, I conducted research using classical electrophysiology, neuroanatomy, and lesion studies to analyze motor control mechanisms via the brainstem and spinal cord, using cats—a standard model from the 1950s to 1970s.

However, the 1980s and 1990s marked an explosive advancement in new research paradigms, including molecular neurobiology, higher brain function studies using primates, non-invasive brain imaging in humans, and computational neuroscience. Recognizing the need to expand my field, I transferred to Gunma University and shifted to studying the molecular physiology of glutamate receptors. At the time, this was one of the most competitive areas of research, and I struggled to keep up with leading labs in Europe and the U.S.

It was during this period that I was given the opportunity to establish my own lab at the National Institute for Physiological Sciences. The faculty there believed that, although molecular biology was at its peak, a time would come when it would be used to unravel brain systems—and I was chosen to contribute to that vision. At the time, I didn’t yet have a clear idea of how to use molecular biology to study brain systems, but research progressed rapidly beyond expectations. The era of optogenetics and chemogenetics arrived, and we succeeded in developing pathway-selective functional manipulation methods in primates. Using these, we were able to elucidate the normal functions of specific circuits in the sensorimotor system and their roles in functional recovery following brain and spinal cord injury.

Nine years ago, I moved to the Graduate School of Medicine at Kyoto University, which expanded our collaborative network and allowed us to explore higher-level decision-making and neuropsychiatric disease models in primates. In this way, I have been able to lead a research field that truly uses molecular biology to elucidate brain systems in primates.

Specifically, it was believed that dexterous hand movements in primates required the direct pathway from the corticospinal tract (originating in the motor cortex) to hand/finger motor neurons. However, we demonstrated that, even in monkeys, there is also an indirect pathway involving propriospinal neurons (PNs) in the mid-cervical spinal cord. Moreover, we showed that even with complete transection of the corticospinal tract at the cervical level, dexterous hand movements could recover almost fully within a few weeks. To prove the involvement of PNs in this functional recovery, we developed a method to selectively block PNs. This method involved injecting a retrograde virus vector into the projection target region, and a second virus vector into the neuronal soma region, to enable reversible suppression of synaptic transmission in double-infected neurons.

This kind of intersectional pathway-selective blocking method is widely used today, but at the time, not even mouse researchers had adopted it—we were the first to develop it in primates. Using this method, we clarified that the indirect pathway via PNs plays a role in the recovery of fine motor skills after corticospinal tract injury.

We also used non-invasive brain imaging with PET to show that, during the recovery process, initially the ipsilesional motor cortex contributes, followed by the premotor cortex in the stable recovery phase. This revealed that brain regions not normally used are sequentially recruited. Furthermore, using large-scale data analysis and mathematical modeling, we proposed that input from the contralesional motor cortex is important for this activation. Combining double-viral vector infection with the DREADDs method, we demonstrated the involvement of interhemispheric pathways via the corpus callosum. At a higher level, we also found that the nucleus accumbens, a key region for motivational control, activates the motor cortex in the early recovery phase, thereby promoting recovery.

Until then, most research on recovery from spinal cord injury had focused on reconnecting the damaged spinal cord using rodent models. In contrast, we proposed a paradigm shift: viewing functional recovery as a form of motor learning, where undamaged neural systems compensate for function at the level of the entire brain.

Next, in humans, there are cases where patients with damage to the primary visual cortex can, without conscious visual awareness, still orient their gaze or reach accurately toward visual stimuli in the impaired visual field. This phenomenon is known as blindsight and has been widely debated. Using monkeys with primary visual cortex lesions, we demonstrated—using circuit manipulation with double-viral vectors, PET imaging, and pharmacological inhibition—that both the evolutionarily older visual pathway (from the retina to the superior colliculus and pulvinar to higher visual and parietal areas) and a pathway from the retina via the lateral geniculate nucleus (LGN) to the same higher areas enable visual cognition after primary visual cortex damage.

Moreover, even in this blindsight state, we found that many visual cognitive functions remain intact: subjects can still experience a vague sense of presence, hold short-term memory, reflexively gaze at salient stimuli, and perform associative learning that links stimuli to rewards.

More recently, we have been investigating the role of the midbrain dopaminergic system in flexible decision-making. Specifically, regarding high-risk/high-reward (HH) versus low-risk/low-reward (LL) choices, we expressed the red-light-sensitive membrane protein ChrimsonR in dopamine neurons of the ventral tegmental area (VTA) using viral vectors. By shining red light on the VTA–6VV (ventral part of Brodmann area 6) pathway in the frontal cortex, we selectively activated it and observed an increased preference for HH choices. In contrast, activating the slightly more dorsal 6VD pathway led to a decrease in HH preference.

Repeated stimulation caused lasting effects—continued activation of the 6VV pathway led to a chronic increase in HH preference, while continued stimulation of the 6VD pathway maintained a low HH preference. These results show that risk preferences in decision-making are determined by the balance of activation between dopamine pathways from the midbrain to subregions of the prefrontal cortex, and that sustained activation of a particular pathway can chronically alter decision-making styles in monkeys.

These findings may help in understanding and treating addiction-related disorders, such as gambling disorders. At present, we believe our research represents the most sophisticated use of optogenetics to manipulate specific pathways in primates and causally demonstrate their involvement in higher cognitive functions.

Looking ahead, we hope to apply these techniques to primate models of neuropsychiatric disorders to uncover pathophysiological mechanisms and develop new treatments.