How Your Brain Learns Aversion After Food Poisoning

Have you ever eaten something that made you sick – and years later, you still can’t stand the thought of it? That’s not just bad luck; it’s your brain hard at work.

A recent study from Princeton University, published in Nature, reveals how the brain forms long-lasting food aversions by processing signals from the gut. Researchers found that illness-related messages are relayed to the brain through a specific neural pathway, reshaping memory and decision-making in the process.

Why food poisoning leaves a lasting impact

The relationship between our digestive system and brain, known as the gut-brain axis, is gaining attention in neuroscience. This bidirectional communication network regulates digestion but also influences emotions, cognition and behavior. One example of this connection is the development of lasting food aversions following episodes of food poisoning. These experiences indicate a strong link between the gut and the brain, where physical illness can lead to enduring changes in dietary preferences and behaviors. Many individuals can recall a time when eating a particular food made them sick, leading them to avoid it for years later, or even a lifetime.

“I haven't had food poisoning in a while, but now whenever I talk to people at meetings, I hear all about their food poisoning experiences,” said lead author Dr. Christopher Zimmerman, a postdoctoral fellow at Princeton Neuroscience Institute.

Historically, research into conditioned taste aversion has provided insights into how negative experiences associated with certain foods can lead to their avoidance. Studies have demonstrated that when individuals consume a particular food and subsequently experience nausea or vomiting, they often develop a strong aversion to that food, sometimes lasting for decades.

Despite these findings, the precise mechanisms underlying the gut-brain interaction in the context of memory formation remain unknown. Questions persist about how signals from the digestive system are processed by the brain to influence learning and memory. Addressing these gaps is necessary for developing interventions for conditions where this communication may be disrupted.​

How gut signals influence memory formation

The recent study sought to understand how illness-related signals from the gut influence memory and decision-making. Zimmerman and colleagues first introduced mice to a novel flavor that they had never encountered before – grape Kool-Aid.

“Normally, scientists in the field will use sugar alone, but that's not a normal flavor that you would encounter in a meal. Kool-Aid, while it's still not typical, is a little bit closer since it has more dimensions to its flavor profile,” said Zimmerman.

The mice were conditioned to associate the flavor with sickness by receiving an injection of lithium chloride that mimicked food poisoning symptoms about 30 minutes after consumption.

When tested two days later, the mice were given a choice between drinking Kool-Aid or water. Most mice strongly avoided the flavored drink, demonstrating that they had formed an aversion to it. Control mice that had received Kool-Aid, but no illness-inducing injection continued to drink it normally.

The researchers used brain imaging to track neural activity across different regions. They found that neurons in the central amygdala – an area involved in emotional learning – were activated at multiple points: while the mice drank the novel liquid, while they later experienced sickness, and again when they recalled the negative experience.

“If you look across the entire brain, at where novel versus familiar flavors are represented, the amygdala turns out to be a really interesting place because it's preferentially activated by novel flavors at every stage in learning,” said Zimmerman.

The study also revealed that other brain regions, including those involved in taste perception, sensory processing and emotional learning, contributed to forming and retrieving the aversive memory.

The team also pinpointed a crucial neural connection between the gut and the brain. They identified a set of neurons in the hindbrain that produced calcitonin gene-related peptide (CGRP), a protein known to transmit pain and discomfort signals. These CGRP neurons are projected directly to the central amygdala.

To test whether these neurons were responsible for forming the food aversion, the team used optogenetics – a technique that allows precise control of neurons using light – to artificially stimulate the CGRP neurons in healthy mice. Even without actual illness, this manipulation was enough to cause the mice to develop an aversion to Kool-Aid. When the researchers inactivated these neurons, the mice failed to form a food aversion after experiencing sickness, confirming that CGRP neurons are necessary for this learning process.

Unlike immediate cause-and-effect learning, such as touching a hot stove and feeling pain, food poisoning involves a delay – the so-called “meal-to-malaise” gap. The study suggests that novel flavors may “tag” certain brain cells, keeping them sensitive to illness-related signals for hours after consumption. This process allows the brain to associate sickness with the previously ingested food, even with a significant time delay.

“It was as if the mice were thinking back and remembering the prior experience that caused them to later feel sick. It was very cool to see this unfolding at the level of individual neurons,” said corresponding author Dr. Ilana Witten, professor of neuroscience at Princeton Neuroscience Institute.

The gut-brain link in health and disease

The findings from this study extend far beyond food aversion. Many conditions involving gut-brain communication, such as irritable bowel syndrome (IBS), anxiety disorders and chronic nausea, may involve similar neural pathways. People with IBS often experience heightened gut sensitivity, and research suggests that emotional stress can exacerbate their symptoms. Similarly, individuals with anxiety disorders frequently report gastrointestinal discomfort, highlighting the intricate link between emotional regulation and digestive health.

By identifying the neural circuits that relay gut distress signals to the brain, this study provides a foundation for exploring new treatment strategies. Targeting CGRP neurons or their connections to the central amygdala could offer novel ways to alleviate symptoms in conditions where gut discomfort triggers emotional distress. Drugs that modulate CGRP activity are already being investigated for migraines and could potentially be adapted for disorders where gut-brain communication is dysregulated.

“Often when we learn in the real world, there's a long delay between whatever choice we’ve made and the outcome. But that’s not typically studied in the lab, so we don't really understand the neural mechanisms that support this kind of long delay learning,” said Zimmerman.

“Our hope is that these findings will provide a framework for thinking about how the brain might leverage memory recall to solve this learning problem in other situations,” he added.

Reference: Zimmerman CA, Bolkan SS, Pan-Vazquez A, et al. A neural mechanism for learning from delayed postingestive feedback. Nature. 2025. doi: 10.1038/s41586-025-08828-z

This article is a rework of a press release issued by Princeton University. Material has been edited for length and content.