Life is full of choices, each with its own level of risk and reward. In order to make the best decisions, the brain undergoes a complex evaluation process that balances these factors. However, in some cases, this process can become pathological, leading to high-risk and high-reward decision-making often seen in gambling disorders.
Understanding the neural circuits responsible for this type of decision-making has been challenging. However, a new study published in Science has made significant progress in identifying and manipulating these circuits in primates. Led by Dr. Tadashi Isa at the Institute for the Advanced Study of Human Biology (WPI-ASHBi) and Graduate School of Medicine/Kyoto University, the researchers used optogenetics, a method that uses light to modulate specific neurons, to selectively manipulate these circuits.
The study found that stimulating these circuits led to behavioral changes in primates that accumulated over time and had long-term consequences, independent of any external stimuli. This provides insights into the underlying mechanisms of pathological risk-taking behaviors, such as gambling disorders.
Traditional experimental paradigms for evaluating decision-making behavior have had limitations in uncovering the pure choice bias between high-risk and high-reward (HH) and low-risk and low-reward (LL) decisions. To overcome these limitations, the researchers designed their own decision paradigm that isolated risk-dependent choice behavior from other cognitive processes.
Using macaque monkeys trained to perform a cue/target choice task with water as the reward, the researchers found that the monkeys had an inherent bias for HH choices over LL choices. The specific neural circuits responsible for this bias were then identified.
Previous research had suggested that the ventral part of Brodmann area 6 (area 6V) in the cerebral cortex, previously thought to only function as a motor area, may be involved in decision-making. Through pharmacological inactivation of several candidate brain regions, the researchers determined that the ventral part of area 6V (area 6VV) was responsible for HH choice behavior.
Interestingly, the traditional brain regions associated with reward-based decision-making, the orbitofrontal cortex (OFC) and the dorsal anterior cingulate cortex (aACC), had little effect on the preference for HH choices when inactivated.
The researchers then investigated the role of the mesofrontal pathway, which connects the ventral tegmental area (VTA) of the brain to the prefrontal cortex, specifically area 6V. Using an optogenetic strategy, the researchers manipulated the neural activity of VTA terminals in area 6V and found that HH preference was dependent on the VTA-6VV pathway, while LL preference was dependent on the VTA-6VD pathway.
Repetitive stimulation of these pathways led to cumulative effects that persisted over time, resulting in long-term changes in preference for HH and LL choices in the primates. This provides a potential mechanistic explanation for the development of gambling disorders.
While the exact contribution of these circuits to everyday decision-making is still unclear, the researchers believe that other brain regions likely play a role as well. The similarities between human and non-human primate brains suggest that these findings may have therapeutic implications for the treatment of pathological risk-taking behaviors in humans, such as gambling disorders.
In summary, this study has made significant progress in understanding the neural circuits involved in risk/reward decision-making in primates. By selectively manipulating these circuits, the researchers have provided insights into the underlying mechanisms of pathological risk-taking behaviors, opening up potential avenues for therapeutic interventions.
