Key takeaways
- The orbitofrontal cortex is located in the brain directly above the eyes in humans and rats, and is involved in flexible reward learning, which happens when we don't know which of our choices will lead to the reward until we learn a pattern or set of conditions that lead to the rewarded option.
- When UCLA researchers inactivated the orbitofrontal cortex in rats, the rats performed much more poorly on flexible reward learning tasks. Further investigation revealed a cluster of neurons within this region were the ones most involved in making decisions with uncertain outcomes.
- The discovery could aid the development of new treatments that involve the targeting of rigid thought patterns, such as those in anxiety and substance use disorders in humans, who also have the same kind of brain cells.
Newly identified brain cells evolved along the theme, "Life is uncertain; Eat dessert first." The neurons, located in the front part of the brain, are most active when the outcome of a decision is uncertain, suggesting that they help with decision making, along with learning and mental flexibility in general. The UCLA discovery in rats could aid the development of new treatments that involve the targeting of rigid thought patterns such as those in anxiety and substance use disorders in humans, who also have the same kind of brain cells.
"If we have full knowledge of the things that will happen, then we really don't need to learn, and we don't have to adapt our behavior," said Alicia Izquierdo, a UCLA professor of behavioral neuroscience in the department of psychology and the senior author of a paper published in the journal Nature Communications. "But that is rarely the case. We found these cells in the orbital region of the frontal cortex that are primed for uncertainty, and we think they are essential for learning."
The orbitofrontal cortex is located in a part of the brain directly above the eyes in both humans and rats, and is active when we experience emotions, tastes, smells and the positive rewards of our decisions. Neuroscientists have determined that the orbitofrontal cortex is also involved in flexible reward learning. Reward learning happens when we receive a reward for making the "right" decision but do not receive one for making the "wrong" decision. Reward learning is said to be flexible when we don't know which of our choices will lead to the reward until we learn a pattern or set of conditions that lead to the rewarded option. Reward learning is a process in which desire for the positive reward motivates the learner to persevere through the disappointment or negative results of the wrong choice until the correct pattern is learned.
Because the orbitofrontal cortex has several types of neurons, UCLA doctoral student and paper first author Juan Luis Romero-Sosa and colleagues devised a way to observe the primarily "pyramidal cells" that were active when rats performed flexible reward learning activities, such as touching the right spots on a touchscreen to receive a food reward. They infused the brains with a calcium ion marker widely used in brain imaging studies because it lights up during activity, and a modified virus that expresses synthetic receptors that could switch the neurons "off" depending on if rats were given a drug that binds to those synthetic receptors in the brain to shut down activity.
A tiny light and camera were fitted into the skull to record neuron activity while the rats were performing these learning tasks. At first, the rats got a reward for any task completed. Over several days, the touchscreen tasks became more difficult, with increasingly uncertain outcomes. At the hardest part of this task, there was only a 70% chance of getting a reward, and the other choice held only a 30% percent chance of earning a reward.
The researchers quickly identified cells that lit up when the animals were making decisions.
"The rat has to be constantly adapting to a changing environment. All this means is that the rat is learning to choose one of two options and what the correct option is keeps changing," Romero-Sosa said. "So once the rat discovers the correct option, it will start to select that over and over again. And then after a certain number of trials, the task changes to keep the rat constantly engaged instead of just finding one strategy and exploiting it over and over again. We found subpopulations of neurons in this specific region of the frontal cortex that seem to get more interested in the task as it gets more and more uncertain."
The researchers studied learning for each uncertainty level on alternate days and found that during the days when the orbitofrontal cortex was inactivated across the board, there was a reduction in performance. The animals were not able to keep track of the value of the high probability choice over time, meaning they did not learn well under increasing uncertainty.
"The rats weren't making better choices as often," Romero-Sosa said. "We also found that there was a decrease in adaptive behavioral strategies. This usually means if I make a choice and it gives me a reward, I will make that choice again. There was less of that when we inactivated the orbitofrontal cortex, suggesting that inactivation interferes with good strategy."
"The rats become experts at this as the experiment goes on, but there's this push-pull, or this balance between being adaptable and being precise," Izquierdo said. "If you want to be flexible, you can't be too precise, and vice versa. These experiments are showing us that there's this dynamic between gaining expertise while also adapting to uncertainty. The other area of the brain we imaged from, in secondary motor cortex (or M2), conversely those cells showed preferential activity to certainty, not uncertainty."
The ancestors of rats and humans both evolved in environments where the need to gain expertise had to be balanced against adapting to uncertainty, and the researchers suspect many animals also possess neurons primed for conditions of uncertainty. If their findings are eventually confirmed in humans, the researchers think it could open new avenues in the targeted treatment of those cells that have been either fully damaged or just less functional in people who struggle with adapting to uncertainty. This could include conditions such as anxiety disorders, PTSD, and dementias.
The research was funded by two National Institutes of Health grants: one to fund the research and one specifically for predoctoral scholars like Romero-Sosa.
"The equipment was partially purchased by this grant, and all of the reagents, viruses, animals, the housing of the animals and ability to disseminate the findings were all funded by the NIH," Izquierdo said.
