2015: Hikosaka

Reward and punishment are powerful drivers of human behavior, causing us to seek out pleasurable experiences while avoiding negative ones. We constantly use information about the outcomes of our past actions to decide how to behave in the future. Over the past several decades, Okihide Hikosaka, chief of the Neuronal Networks Section at the National Eye Institute, has conducted pioneering work to shed light on how the brain allows us to make decisions based on the expected outcome of our actions.

Hikosaka’s work has revealed how motivation and the expectation of reward affect neural activity in a brain region called the basal ganglia to influence behavior, specifically eye movements. This research has provided key insights into the motivational deficits experienced by patients with depression, Parkinson’s disease and other disorders associated with basal ganglia damage.

“Hikosaka is working on a central problem in neuroscience: What is the mechanism in the brain that provides rewards for some behaviors and punishments for other behaviors,” said Robert Wurtz, chief of the Visual Motor Integration Section at the National Eye Institute and Hikosaka’s former postdoctoral adviser. “The answer to this question is central to understanding how the brain controls our behavior. Hikosaka has provided the critical experimental insights for answering these questions.”

For his seminal contributions to the field of visual neuroscience, Okihide Hikosaka has been named the recipient of the 2015 Golden Brain Award from the Berkeley, California-based Minerva Foundation. The award, now in its 31st year, recognizes outstanding contributions in vision and brain research. Hikosaka was honored in a private ceremony on Saturday, October 17th, at the Society for Neuroscience's 45th annual meeting in Chicago.

“We discovered that a deep brain structure called the basal ganglia plays an essential role in decision making, especially when the decision is made based on past emotional experiences, for example, a reward or threat,” Hikosaka said. “Importantly, we found that the basal ganglia contain at least two separate mechanisms: one for voluntary and conscious decisions and the other for automatic and unconscious decisions. The voluntary and automatic mechanisms together should allow us to survive in both stable and flexibly changing environments.”

When Hikosaka started his research career, virtually no oculomotor researcher was interested in the basal ganglia, and very few basal ganglia researchers were interested in eye movements. This situation changed in the mid-1980s with the publication of landmark studies in the Journal of Neurophysiology. In these studies, Hikosaka and Wurtz discovered that the basal ganglia control movements, specifically eye movements, by tonic inhibition that is released only briefly to allow the movement to be generated. “The tonic inhibition of movement and its transient release has provided the best evidence for how the basal ganglia modulate movements in both health and disease,” said Wurtz, who himself received the Golden Brain Award in 1991.

As an independent investigator, Hikosaka went on to show how expected reward influences neural activity in the basal ganglia, specifically in a subregion called the caudate nucleus, to control eye movements. In a study published in Nature Neuroscience in 1998, animals were trained to make eye movements to four locations on a screen, and they received a juice reward after they moved their eyes to only one of these locations. The animals made eye movements toward the location associated with a reward more quickly than to locations not associated with a reward, due to a stronger release from tonic neural inhibition in the basal ganglia. The findings have clear evolutionary implications, as the ability to act fast to receive a reward imparts a strong survival advantage. 

Hikosaka and his collaborators also shed light on the role of a reward chemical called dopamine in this process. It had been generally assumed that dopamine-releasing neurons that send signals to the basal ganglia were homogenous in function, uniformly representing reward-related information in a similar manner. But in a study published in Nature in 2009, Hikosaka and his team demonstrated the existence of distinct types of dopamine neurons.

In this study, animals were either rewarded with juice or punished with air puffs directed at the face. While some dopamine neurons were activated by the expectation of the juice reward and inhibited by the expectation of an upcoming air puff, a separate set of dopamine neurons were strongly activated by expected reward and punishment. The findings completely revised the prevailing concept of the role of dopamine neurons in emotion and motivation.

In other groundbreaking experiments, Hikosaka and his collaborators discovered that the dopamine neurons receive negative value signals, which indicate either the expectation of punishment or no upcoming reward, from an evolutionarily conserved brain region called the lateral habenula. In studies published in Nature in 2007 and Nature Neuroscience in 2008, the researchers found that neurons in the lateral habenula were activated when animals were either not rewarded or punished with an air puff to the face. By contrast, these neurons showed a decrease in activity when the animals were rewarded with juice.

The findings suggest that the lateral habenula plays a role in adaptively controlling reward-seeking and punishment-avoidance behaviors. This research inspired subsequent studies that revealed a role for the lateral habenula in psychiatric disorders such as depression, drug addiction and schizophrenia, which are characterized by impairments in motivation and reward-related decision-making.

More recently, Hikosaka and his team changed widely held beliefs about the neural basis of decision-making by discovering that neurons in the basal ganglia represent stable object values. Choosing valuable objects is critical for survival. For example, when an animal forages in the forest, it may encounter many objects, but would benefit from choosing to eat appetizing food items while avoiding bitter, nauseating, or inedible items. Such choices need to be prompt and efficient, because the animal may not thrive if it uses a slow trial-and-error strategy to decide which items to taste. These efficient choices are likely based on stable, long-term memories of the value of objects, enabling automatic, unconscious decision-making to increase the chance of survival.

Hikosaka and his team examined this question in a study published in 2012 in The Journal of Neuroscience. They let animals look at many visual objects (typically more than 300) repeatedly for many days. Half of them were always associated with a large reward (good objects), and the other half with a small reward (bad objects). The researchers found that neurons in the posterior part of the basal ganglia showed completely opposite responses to the good and bad objects. Moreover, these neurons retained high-capacity memories for a long time (at least 100 days). Owing to the basal ganglia neuronal activity, the animals chose a good object among bad objects and did so very quickly (about 0.2 sec). The findings show that the basal ganglia use stable object values to guide automatic, unconscious behavior and thereby guide decisions that may be critical for survival.

This impressive body of research has revealed that the basal ganglia are crucial for decision-making based on emotional experiences. Importantly, this is achieved by two separate neuronal circuits including separate dopamine pathways, one for voluntary motivation and the other for automatic skills. The findings may lead to new therapies targeting these basal ganglia circuits differentially, one for people with mood disorders to improve their motivation and the other for people with Parkinson’s disease to improve their daily routine behaviors.

“Okihide Hikosaka is a pioneer in exploring how the basal ganglia of the brain produce two fundamental features of behavior: the modulation of movements and their alteration by reward,” Wurtz said. “He provided key evidence that the basal ganglia are closely related to motivation and reward. These observations and many others, made over more than three decades, have shaped our understanding of both the movement and motivation functions of the basal ganglia and their diseases, including Parkinson’s disease and depression.”