Researchers identify and manipulate neural circuits for risk/reward decision-making in primates

Life is made up of infinite possibilities, appearing in the real world as multiple choices, which then require decision-making to determine the best course of action. However, every choice also carries a certain amount of uncertainty or “risk.” Therefore, behind every decision lies a complex evaluation process that balances the risks and rewards associated with taking such actions.

This can, in extreme cases, manifest as a pathological behavioral state of high risk-high reward (HH) and low risk-low reward (LL) decision processing that has been associated with gambling disorders.

Although these higher cognitive processes occur seamlessly in the cerebral cortex of our brains – dozens, even hundreds of times per day – the exact underlying neural circuits have remained elusive due to technical difficulties in targeting and the specific manipulation of these neural circuits.

A new study published Sciencefrom a team of researchers led by Dr. Tadashi Isa from the Institute for the Advanced Study of Human Biology (WPI-ASHBi) and the Graduate School of Medicine/Kyoto University, identified and selectively manipulated using of optogenetics, a method that can modulate the activity of specific neurons with light – the distinct neural circuits responsible for the balance between risk and reward-return decision-making in primates.

They show that behavioral changes resulting from stimulation of these circuits accumulate over time and have long-term consequences, independent of any stimulus, thus providing insight into potential mechanisms underlying disease-risk behaviors such as gaming disorders.

Various experimental paradigms have been developed to assess decision-making behavior, with the Iowa Gambling Task arguably being the most famous. However, these neuropsychological tasks are often limited by design, as they cannot sufficiently dissociate higher-order cognitive processes.

To determine the “pure” choice bias between HH and LL decisions, Isa and colleagues first designed their own decision paradigm to decouple risk-dependent choice behavior from other higher-order cognitive processes.

Using eye movement to indicate their choice, macaque monkeys were trained to perform a cue/target choice task with water as reward, consisting of five different HH-LL choices from five different sets of “ equivalent expected value (volume of reward awarded multiplied by probability), i.e. a total of 25 potential options. Consistent with other primate studies investigating risky behaviors, the authors found that primates had an inherent bias toward HH over LL choices.

In the early 20th century, the cerebral cortex was mapped into 52 regions, known as Brodmann areas, based on their distinct cellular morphology and organization. The deeper, or ventral, parts of Brodmann’s area 6 (area 6V) have long been thought to function only as a motor area in humans and primates. But more recently, regions overlapping area 6V have also been associated with decision-making processes, although direct evidence supporting such a function is lacking.

By pharmacologically inactivating several candidate frontal brain regions, using selective GABA_A muscimol receptor agonist, the authors found that the ventral part of area 6V (zone 6VV) was responsible for HH choice behavior. Interestingly, although the orbitofrontal cortex (OFC) and dorsal anterior cingulate cortex (aACC) are thought to play central roles in reward-based decision making in monkeys, inactivation of these regions had little effect. effect on the preference for the choice of HH.

“Indeed, we were really surprised that neither OFC nor aACC were important for risk-dependent decision making,” comments Dr. Ryo Sasaki, first author of the study.

The ventral tegmental area (VTA) of the brain is essential for reward-associated processes, which are integral to risk-related decision making. A subpopulation of dopamine neurons residing in the VTA is connected to the prefrontal cortex, including area 6V, also known as the mesofrontal (or mesocortical) pathway.

To dissect the specific role of the mesofrontal pathway in risk-dependent decision making, Isa and colleagues used an elegant optogenetic strategy, in which an array consisting of 29 LED lights coupled with electrocorticogram (ECoG) electrodes was designed (dimensions: 19 mm x 12 mm) and implanted in area 6V of the brain of primates expressing photoactivatable proteins in VTA neurons.

During the narrow decision-making time window, the authors precisely manipulated the neuronal activity of VTA terminals defined in the 6V area by lighting specific LEDs in their array, while simultaneously recording activity in the 6V area , which also included more superficial or dorsal LEDs. regions (zone 6VD; approximately 2 to 3 mm above zone 6VV).

The authors discovered two subcircuits within the mesofrontal pathway playing distinct roles in risk-dependent decision making. They found that HH preference depended on the VTA-6VV pathway, whereas LL preference depended on the VTA-6VD pathway.

“The spatiotemporal resolution of our LED/ECoG network was essential to distinguish the VTA-6VV and VTA-6VD pathways and to decipher their distinct functional roles in risk-dependent decision-making,” says Sasaki.

These results were then validated by computational decoding, which recapitulated in silico choice preference behavior induced by photostimulation in primates.

Interestingly, upon repetitive stimulation of the VTA-6VV or VTA-6VD pathways, Isa and co-authors observed cumulative effects that persisted over time, leading to long-term changes in preference for the choice of HH and LL in primates, respectively – independent. of any photostimulation. Isa comments: “…such long-term changes in choice behavior were rather unexpected…but this may now also offer a mechanistic explanation of how gambling disorders arise.” »

Exactly how these distinct circuits help balance our daily decision-making remains unclear, but the authors believe other regions of the brain are likely to contribute to this process as well.

“Given the similarities (in structure and function) between human and non-human primate brains, our findings could have potential therapeutic implications, and even applications in the future, for the treatment of pathological forms of risk-taking such as gaming disorders.” he says.

Provided by the Institute for the Advanced Study of Human Biology (ASHBI)