The Brain's Response to Uncertainty and Ambiguity

Scientists explore how ambiguity alters physiology and stress resilience.

By Lauren Arcuri

Humans today have access to more information than ever. We might think this fire hose of data helps us be less fearful, but more often, it stokes anxiety and contributes to our feeling of uncertainty. It can be a real challenge to make sense of the deluge of details we receive from multiple sources daily, much of it contradictory.

“Our brains are designed to seek certainty,” says Aoife O’Donovan, PhD, professor in the Department of Psychiatry and Behavioral Sciences at the University of California San Francisco (UCSF) and director of the UCSF Trauma and Health Research on Immunity, Vitality and Emotions (THRIVE) Laboratory. “But uncertainty is inevitable in life.” 

It makes sense that our hunter-gatherer ancestors, dependent on foraging for food and navigating unpredictable dangers while traveling through difficult terrain, preferred certainty. In our modern world, we face different kinds of threats but still have to cope with a great deal of uncertainty in our lives. But our nervous systems still prefer the known to the unknown. “We’re living in a time when we have so much information, it’s hard to find some certainty in the midst of all that,” O’Donovan says.

All that uncertainty has a profound effect on our physiology. How our systems react to uncertainty—and our tolerance for stress and our resilience to it—are shaped by our life experiences.

How the Brain and Body Respond to Uncertainty and Ambiguity

There are two main kinds of uncertainty from a neuroeconomic perspective, says Paul Glimcher, PhD, chair and professor in the Department of Neuroscience, professor in the Department of Psychiatry and director of the Institute for Translational Neuroscience at NYU Langone Health in New York. “Donald Rumsfeld famously called these ‘known unknowns’ and ‘unknown unknowns,’” he says. “‘Known unknowns’ is a kind of uncertainty we often refer to as facing risk in a technical sense,” when you know what the chances are of a given outcome. “In ‘unknown unknowns,’ or ambiguous uncertainty, we have no idea how likely it is that a given outcome will happen,” Glimcher says. “Of course, in most cases, with time and experience, ambiguous uncertainty turns into risky uncertainty.”

People are generally risk-averse overall, but they “tend to treat ambiguous situations as roughly two times as bad as risky situations,” Glimcher says. 

When we face ambiguity, but not risk, the amygdala, an almond-shaped brain structure that regulates decision-making and emotional responses, activates. In experiments, participants may be offered a lottery ticket with a known chance of paying off, or one where the chance is unknown, or ambiguous. “You might view that ambiguous lottery ticket as worth very little,” Glimcher says. On functional MRI, researchers see activation in the amygdala of participants in the unknown situation, but much less in the one where they know their chance of winning.

In both risky and ambiguous situations, Glimcher says, they see activation in the ventromedial prefrontal cortex and ventral striatum. The degree of activation correlates with how much the subject wants the lottery ticket. “There are indications subjects want the ticket less when it is ambiguous, compared to when it’s risky,” he says.

Diving deeper, Glimcher and his colleagues have found that while overall, people tend to prefer risk to ambiguity, “different people have different aversions to each. There is a lot of interindividual variation,” he says. Risk attitudes tend to correlate with thickness of the parietal cortex, among other things. “People who have a lot more gray matter there are more tolerant of risks, and people with less are less,” Glimcher says. And as we age, we tend to become less tolerant of risk and ambiguity. “Significant elders, people in their 80s and 90s, are generally very averse to taking risks.”

Ambiguous circumstances, or uncertainty, means that our imagination can run away with us—we can conjure every possible bad thing that might happen, even very unlikely things. Many people experienced this in the early days of the COVID-19 pandemic, when we knew very little about the disease and how it spread. 

To make matters worse, our physiology doesn’t distinguish between actual and imagined stressors. “We activate our biological stress response in anticipation of upcoming stressors,” O’Donovan says.

An impending threat or stressor has an impact on every bodily system, says Scott Russo, PhD, endowed chair in affective neuroscience, director of the Center for Affective Neuroscience and director of the Brain Body Research Institute at the Icahn School of Medicine at Mount Sinai in New York. Our body primes our systems to respond. Part of that response is immune system activation, including inflammation. Russo’s research focuses on how and why resilient people are able to switch off the acute immune response to stress after the immediate threat is gone, before it causes long-term damage to their own tissues.

Resilience is a Learned, Adaptive Response to Stress

Researchers have long viewed stress as a trigger of disease or illness, but “our studies of resilience have shown us that most of us don’t respond to chronic, even very traumatic, stressors in a maladaptive way,” Russo says. “Most of us are quite adaptable.”

It turns out, resilience isn’t merely the absence of a physiological stress response. It seems to be an active process of adaptation, Russo explains. “Resilient individuals adapt [to stress] in a way that actively alters circuits in the brain that control reward perception, preventing some of the most negative impacts of stress,” he says. 

Janice Urban, PhD, professor of physiology and biophysics and director of the Center for Neurobiology of Stress Resilience and Psychiatric Disorders at Rosalind Franklin University of Medicine and Science in Illinois, also studies the physiology of resilience. In one of her experiments, rats who were exposed to a stressful stimulus showed an increase in a chemical called neuropeptide Y (NPY) that acts in the amygdala. At the same time, another research team found that injecting NPY into the same region of the brain increased the rats’ social interaction and blunted the behavioral effects of stress. Data from humans also suggested that lower NPY was associated with post-traumatic stress disorder and social anxiety.

The evidence suggested that NPY might be a molecule that enhances resilience to stress. Urban’s research focuses on what activates the NPY-producing neurons and how the receptor mechanisms work. “If there was something unique we could target, we could increase these resilience-promoting mechanisms,” she says.

Thus far, Urban’s research team has discovered that NPY, when delivered to an area called the basolateral amygdala, inhibits specific stress-sensitive pathways that project to the bed nucleus of the stria terminalis (BNST). “That part of the BNST is important for anxiety and fear discrimination,” Urban says. It is also very sensitive to repeated stress; rats subjected to repeated stressors develop hyperactivity in these areas.

“This hyperactivity is caused, in part, by long-term structural changes that make the animals more anxious over time,” Urban says. “But we have found that NPY can buffer these long-term changes, particularly by antagonizing one of the neurotransmitters that causes these changes in the amygdala: corticotropin-releasing factor.” Current research in Urban’s lab focuses on further mapping the neural circuitry of the NPY-responsive amygdala neurons.

The Link Between Stress and Inflammation

Russo’s research on the immune system has led him to conclude that in resilient individuals, the system dampens the fight-or-flight immune response once the acute threat is over, before it does longer-term damage to the body itself. 

“We don’t yet fully understand how they do that,” he says. “It’s thought to be some combination of brain-to-immune pathways that allow resilient individuals to suppress inflammation.” Vulnerable individuals don’t seem to have this same dampening mechanism.

Heightened inflammation, the consequence of an unchecked stress response, is suspected to underlie at least a portion of cases of major depressive disorder. Russo’s lab found that people with depression also have lower levels of a molecular marker called claudin-5, a protein that sits in the junction between cells in the first layer of the blood-brain barrier, suggesting they may have a compromised blood-brain barrier.

In a mouse model of stress vulnerability, Russo has found that the blood-brain barrier becomes leakier in response to stress, allowing in large proteins that normally would not be able to cross into the brain. “They bypass the barrier and directly infiltrate the brain parenchyma, where they can act on neurons and change behavior directly,” he says. Specifically, his team found a cytokine called interleukin-6 in the brain and discovered that it caused depressive behavior in the mice.

Can We train the Body to Be More Resilient to Stress?

Living through chronic stress or traumatic experiences may make someone more prone to the negative effects of uncertainty. “People who have been exposed to a lot of stressors may be more likely to perceive threat in new uncertain situations,” O’Donovan says.

Glimcher and his colleagues administered the STRAIN, a lifetime stress inventory, to a group of adults who also completed a series of questions about lotteries with varying levels of risk and ambiguity. This measures how averse someone is to ambiguity and risk.

“What we’ve found is that this lifetime stressor scale correlated very strongly with people’s aversion to ambiguity,” Glimcher says. “So this led us to believe that ambiguity aversion emerges as a function of the bad stuff that’s happened to you over your lifetime, particularly bad stuff that happens to you in childhood.”

If some individuals possess an innate ability to be resilient—to weather the storms of uncertainty and stress without lasting damage—can scientists learn what drives that resilience to help those of us who wind up inflamed, depressed and sick?

Recent trials have attempted to use monoclonal antibodies to develop targeted anti-cytokine treatments that neutralize specific inflammatory molecules, a type of biologic drug that has been highly effective for certain autoimmune conditions, such as rheumatoid arthritis. “But their utility in depression and other stress conditions has been less clear,” Russo says. 

“What we need is to be able to train the immune system, rather than block or enhance it,” he says. “What we want it to do is turn on when appropriate and turn off when appropriate, like in a resilient individual.”

Treatment might involve introducing the resilience factors, rather than attacking a disease mechanism. Human trials of potential therapeutics are underway after resilience factors were identified in mice models.

O’Donovan says managing uncertainty’s effects on physiology and health requires thinking about it like any other stressor and remembering that the same things that enhance our health will also increase our resilience to psychological stress. “Lifestyle factors like getting enough physical activity; eating a good diet; avoiding smoking, alcohol and other substances that harm the body; having social support—these are all factors that can make us more resilient to stress,” she says.

Prioritizing these behaviors can be difficult when you’re already dealing with uncertainty, so trying to build these healthy habits during the lower-stress times is ideal, she says. “We can do our best to build our stress resilience during these times, knowing this is what is going to get us through the inevitable stressors of life.” 

This article was originally published in the November 2025 issue of The Physiologist Magazine. Copyright © 2025 by the American Physiological Society. Send questions or comments to tphysmag@physiology.org.