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2018 Neuroscience Prize

Okihide Hikosaka

Okihide Hikosaka developed his interest in science while growing up in Japan during the 1950s and 1960s. “I was originally interested in physics, but I wasn’t sure about my mathematics ability,” Hikosaka recalls. So, when he went off to the University of Tokyo, he decided to focus on biology instead. Hikosaka completed his MD in 1973 and his PhD in 1978, after working in the laboratory of neurobiologist Hiroshi Shimazu on the basic brain stem mechanisms of the vestibule-oculomotor system, a basic sensory-motor network in the brain that helps maintain visual stability during head movements. “I found inhibitory burst neurons that control the quick eye movements, and I thought that would be useful for understanding saccadic movements, which turned out to be true,” Hikosaka recalls. “Later, though, I found that many other brain areas are involved, some voluntary and some automatic.”

After spending a year on the faculty of the Toho University School of Medicine in Tokyo, Hikosaka traveled to the United States to do postdoctoral research with neuroscientist Robert Wurtz at the National Institutes of Health’s National Eye Institute (NEI) in Bethesda, Maryland. There he worked on the role of the substantia nigra pars reticulata (SNr) in the control of saccadic eye movements. They found the relationship with reward systems several years later. The SNr is an output of the basal ganglia, clusters of neurons situated at the base of the forebrain. “Not many people were working on the neuromechanisms of basal ganglia at that time,” says Hikosaka. In their studies, Hikosaka and Wurtz discovered that SNr neurons have key connections to the superior colliculus, a brain structure that transforms sensory input into movement output, including saccadic, or voluntary, eye movements. That finding has had important implications for both health and disease. “It turns out that if that mechanism is disrupted — for example, because of the involuntary movements that happen in many diseases, like Parkinson’s disease — then it’s very difficult to initiate voluntary eye behavior,” Hikosaka explains.

Hikosaka returned to Japan where he continued his research, first at Toho University (1983-1988), then at the National Institute of Physiological Sciences in Okazaki (1988-1993), and next at Juntendo University School of Medicine in Tokyo (1993-2002), before returning to NEI’s Laboratory of Sensorimotor Research in 2002. At each institution, Hikosaka made groundbreaking discoveries that have transformed our understanding of the physiology of the basal ganglia and its importance not only to motor behavior, but also to memory and reward. He showed, for example, that monkeys made eye movements toward a location on a screen that they have been trained to associate with a reward more quickly than to other locations, and that these eye movements were the result of tonic neural inhibition and a quick release of the inhibition in an area of the basal ganglia known as the caudate nucleus. He also discovered that a distinct type of dopamine neurons was involved in this process, and that dopamine neurons function differently in different areas of the basal ganglia — findings that have transformed the existing view of the role of dopamine neurons in emotion and motivation.

In other important studies, Hikosaka demonstrated the motivational functions of a brain structure called the lateral habenula, which receives input from the basal ganglia. He showed that neurons in the lateral habenula were activated when animals expecting a reward (fruit juice) were either not rewarded or “punished” with an air puff to the face. These findings have opened up promising new avenues of research not just for the study of motivation, but also for research on psychiatric disorders, including depression, schizophrenia and drug addiction. In other animal studies, Hikosaka demonstrated — for the first time — how the formation of a habit (skill) is mediated by neurons in the caudate and sustained by neurons in the substantia nigra pars reticulata, which plays an important role in motor behavior. These neural processes are likely the result of memories of the value of objects, and thus allow the animals to make quick, efficient decisions — actions essential for survival.

Hikosaka has received numerous honors and awards for his research, including membership in the American Academy of Arts and Science. He lives in Bethesda, Maryland, with his wife, Naeko Hikosaka, who is a visual artist. They have two grown children, a son, Tomo, and a daughter, Mona.