A cartoon shows a silhouette of a human head without a top. Smaller people stand around the head. Most are elevated by ladders and poles and pulling on threads that start in the head and end in question marks.

Mapping out the molecular pathways and neural circuitry that enable decision making could help clinicians identify better targets for treating mental health disorders.

credit: istock.com/Flashvector

What foraging teaches about mental health

Investigating the neural and molecular pathways that help foragers decide when to look for better resources could lead to new ways to treat mental health conditions.
Andrew Saintsing, PhD
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When a group of foragers finds a lake teeming with fish or a grove of trees ripe with fruit, it makes sense for them to hunker down for a while and exploit the bounty. But the longer they stay and consume, the scarcer the available resources become. After a certain amount of time, the best decision for the group is to move on and search for an unharvested patch of trees or an unfished stretch of river.

Although the forager lifestyle is less common today than it was for ancestral humans, people in industrial societies still face decisions about how long to stay in a familiar situation and when to seek out new options that could be more beneficial. A person might wonder if they could find a more stimulating job, a more fulfilling relationship, or a better place to live. Scrolling through online listings for the perfect house and hiking between salt licks to find big game are very different actions, but Nick Sidorenko, a neuroeconomist at the University of Zurich, thinks that the underlying brain activity that drives people to look for better options in both cases likely depends on the same neuronal circuitry.

Nick Sidorenko wears a black sport jacket over a red shirt.
Nick Sidorenko is a neuroeconomist studying how foraging behaviors can inform the neuroscience of decision making.
credit: University of Zurich

Sidorenko entered the relatively new field of neuroeconomics, which he described as “decision-making neuroscience,” because he wanted to understand how abnormalities in the brain’s decision-making apparatus could lead to mental health issues. “Let’s say an anxious person doesn’t want to try anything new,” he said. “This is what we call aberrant decision making because we know that we actually need to have balance between the two. We need to explore from time to time. We also need to stick to what we know from time to time.” 

Ultimately, Sidorenko would love to see therapeutics and interventions for mental health disorders emerge from decision-making research, but the field of neuroeconomics is so new that its adherents are currently focused on foundational research questions. In a recent PNAS study, Sidorenko and his colleagues investigated the roles that different branches of the nervous system play in optimizing a person’s decision making (1). 

“The goal of this particular study was to understand, first of all, what are the molecular pathways involved in guiding people in this foraging context?” said Sidorenko. “Now, this information can be used to make the clinical scientists, if they would like to focus their studies on a particular system, work [on] a particular pathway.”

Sidorenko and his team solicited participants to play a simple video game that simulated the experience of foraging. Before letting the participants play the game, the researchers split them into different treatment groups and administered distinct substances that manipulated a particular branch of the nervous system: the dopaminergic, noradrenergic, or cholinergic system. 

The first group received methylphenidate, the active ingredient of the ADHD medication Ritalin. Ritalin keeps neurons from clearing released dopamine, maintaining higher activity in the reward-processing dopaminergic system. The second took reboxetine, which is the active ingredient in the antidepressant Edronax. It works similarly to methylphenidate but acts on noradrenaline, which activates the noradrenergic system to keep the body alert and focused. The final group took nicotine, a substance that can relax the body and reduce anxiety because of its ability to activate neurons in the cholinergic system.

In the video game, participants in each of the three treatment groups and a fourth group that received only a placebo roleplayed as dairy farmers who moved from cow to cow to collect the animals’ milk. The catch was that different cows produced milk at different rates, and that rate of milk production fell the longer the participant stayed with the same cow. The participants had to decide how long to stay with each cow so that they could maximize the total amount of milk they collected in their allotted time.   

After the participants completed the session, Sidorenko and his colleagues compared the actual amount of time the participants spent with each cow to the optimal amount. As it turned out, all of the participants tended to overstay and overharvest. Enhancing the dopaminergic system had no effect on that tendency, but patients who took reboxetine left patches sooner. Interestingly, that reboxetine-driven eagerness to move on didn’t translate into more optimal foraging time. Only nicotine helped patients optimize their foraging time, suggesting that the cholinergic system affects the decision-making process and could be a potential pharmacological target for someone who displays aberrant decision making.

Because achieving a more optimal foraging time in this game generally meant moving on more quickly, Sidorenko wanted to test whether nicotine actually influenced the decision-making process and didn’t just make participants more impulsive. To that end, he and his colleagues designed a second computer game where the participants tried to fill a glass to a certain height based on what they knew about how quickly it was filling up. Participants who took nicotine were better at this game as well, but it was because they were less likely to stop filling the glass early, suggesting that they were less impulsive. Thus, nicotine improved their decision making for each game in opposite ways.

That extra experimental step really sold Alex Lloyd, a University College London psychologist, on the findings. He wasn’t involved in this study, but he also researches foraging behaviors to understand what they can indicate about a person’s mental health. Because many similar studies would only draw experimental data from the foraging task itself and rely on demographic information and voluntary responses to fill in the rest of the details, Lloyd thought that Sidorenko’s emphasis on looking for additional experimental data to strengthen his conclusions really set his work apart. “It gives you that extra confidence that this is [an] effect of the drugs,” said Lloyd. “It’s not mediated through something else that’s obscuring that effect.”

Lloyd eagerly anticipates the clinical applications of this study and others like it, but he thinks that there’s still a lot of groundwork needed. He is concerned about the lack of reproducibility in these types of experiments. “This is not unique to this paper. It’s a general criticism across the board,” he said. But in this particular study, he questioned why each subject didn’t play the foraging game before and after they had received their treatment or placebo. Lloyd said, “Without knowing whether these sorts of tasks are reliable over time, we don’t know, in a clinical context, if that’s actually going to be useful for diagnostics.”

Now, Sidorenko intends to investigate which specific areas of the brain nicotine and reboxetine interacted with to influence the decisions of participants during the game. The goal, as always, will be to identify effective targets for treating people who need help.

Reference

  1. Sidorenko, N. et al. Acetylcholine and noradrenaline enhance foraging optimality in humans. PNAS  120, e2305596120 (2023).

About the Author

  • Andrew Saintsing, PhD
    Andrew joined Drug Discovery News as an Intern in 2023. He earned his PhD from the University of California, Berkeley in 2022 and has written for Integrative and Comparative Biology and the Journal of Experimental Biology. As an intern at DDN, he writes about everything from microbes in the digestive tract to anatomical structures in the inner ear.

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