Kyoto University successfully alter the risk/reward decision-making process in the brain through optical stimulation: Clarification of the brain neural circuit mechanism

The research group consisting of Assistant Professor Ryo Sasaki and Professor Tadashi Isa of the Graduate School of Medicine at Kyoto University, Professor Jun Ohta of the Graduate School of Science and Technology at Nara Institute of Science and Technology, and Associate Professor Kenta Kobayashi of the National Institute for Physiological Sciences, National Institutes of Natural Sciences announced that they had discovered the brain neural circuit that regulates the balance between reward and risk. Using path-selective optogenetic activity manipulation in a macaque monkey that was performing an advanced cognitive task, they successfully controlled the monkey's volitional preference. The result is expected to be applicable to addiction treatment and other areas. Their achievement was published on January 4, 2024, in the international academic journal Science.

In a situation where an animal needs to accept either "high failure probability/high reward rate (high risk/high return [HH])" or "low failure rate/low reward rate (low risk/low return [LL])," it makes a choice based on the flexible decision-making that depends on the situation and environment. On the other hand, many points remain unclear about the mechanisms of the brain neural circuits that integrate the reward/risk information and control their balance.

The research group used macaque monkeys (Japanese macaques), whose brains are relatively homologous to the human brain, to examine the frontal lobe, which is assumed to be involved in complex decision-making during task execution. The theme involved a two-choice task in which participants selected circles of different colors displayed on the screen, with rewards (amount of juice) and probabilities varying among colors (25 colors). When researchers investigated the monkeys' preferences in advance, all six preferred HH.

By subdividing the areas of the prefrontal cortex and suppressing each one individually during a task, the group investigated the divided area where this risk preference disappeared and found that it was the Brodmann area 6V in the ventral tegmental area (VTA). This region was previously considered a higher-order center of movement, but no detailed analysis had been performed. Furthermore, regarding the route in which the input to Brodmann area 6V is made, the research group targeted the VTA in the midbrain, which is suspected to play an important role in decision-making for reward acquisition. They selectively stimulated the pathway with optogenetic techniques and examined whether each stimulus changes a monkey's decision-making. The research group previously revealed a very strong dopaminergic projection from VTA to Brodmann area 6V.

The optogenetic method involves the introduction and expression of a membrane protein that senses light and allows ions to pass through into specific neurons in the central nervous system. This enables the specific activation or inhibition of neurons within milliseconds by light illumination. However, delivering light to the deep parts of the brains of primates has been challenging due to their large size.

Accordingly, the researchers developed a technology that uses red light with high tissue penetration and implanted the developed probe (cortical electroencephalogram electrode with a light-emitting diode [LED]) into the 6V areas in the left and right brain. The probe is shaped like a 19 × 12 mm diagonally cut rectangle within which 29 LED electrodes are embedded. However, it can provide optical stimulation to a very limited area.

When various parts of area 6V were precisely stimulated during task performance, the optical stimulation of 6VV increased the HH preference, whereas the stimulation of 6VD alleviated the HH preference. Brain activity itself was also activated by 6VV stimulation and suppressed by 6VD stimulation. 6VV and 6VD were very close (only about 3 mm apart). Furthermore, repeated optical stimulation to 6VV resulted in the dependent accumulation of effects and fixed the HH preference.

A neurocomputational decoding analysis further confirmed that the behavior change can be explained by the altered brain activity. Efforts have started to alleviate addiction using transcranial magnetic stimulation to the prefrontal cortex. This study also revealed that the two areas that increase and alleviate the HH preference are located in close proximity, indicating a high likelihood that the stimulation must be applied in a pinpoint manner. In humans, 6VV and 6VD appear to be only 1−2 cm apart.

Isa commented, "Each person has a unique personality that makes their life unique, and a mental illness arises from its distortion. We are conducting this research in the hope that understanding such brain mechanisms will lead to treatment options. Although I finally got a clue, I am still only halfway there. We hope that the results will lead to the development of animal models of addiction and treatments for it."

Journal Information
Publication: Science
Title: Balancing risk-return decisions by manipulating the mesofrontal circuits in primates
DOI: 10.1126/science.adj6645