Tracking hallucinations in mice

The origins of hallucinations, a symptom of certain psychiatric disorders, have been very difficult to studybestdesigns / iStock / Getty Images Plus

Hallucinations are a defining symptom of psychotic disorders such as schizophrenia. One proposed cause of hallucinations is excess levels of the brain chemical dopamine. But the mechanism by which dopamine might produce hallucinations is poorly understood. The only way to tell if someone is hallucinating is from their own reports of their experience. This makes it difficult to study hallucinations in animal model systems.

A team led by Drs. Katharina Schmack at Cold Spring Harbor Laboratory and Adam Kepecs at Washington University in St. Louis set out to develop a method to detect hallucination-like experiences in mice. The research was supported in part by NIH’s National Institute of Mental Health (NIMH) and National Institute on Drug Abuse (NIDA). The study appeared on April 2, 2021, in Science.

The researchers created a computer task that could be performed by both people and mice. In the task, researchers played a sound signal against a background of white noise. Human participants reported whether they heard the signal, as well as their confidence in their response, using a computer interface. The researchers trained the mice to poke their noses into one of two ports, depending on whether they heard the signal. They gauged the mouse’s confidence in its decision by how long the mouse was willing to wait at the port before receiving a reward.

In some cases, humans and mice were confident they’d heard a signal even when no signal was played. The researchers considered these confident “false alarms” to be hallucination-like events. Human participants also completed a questionnaire designed to measure hallucination-like symptoms. The questionnaire scores correlated with the frequency of false alarms in the computerized task. These results suggest that the researchers were measuring similar hallucination-like experiences in mice and people.

Past studies have found that people who experience hallucinations are more likely to do so when they expect to see or hear something. So, the researchers altered the mice’s expectations by playing the signal more or less often. They also treated the mice with ketamine, a drug known to induce psychotic experiences in people. Playing the sound more often or administering ketamine increased the frequency of the confident false alarms.

Having established these techniques, the researchers next explored the relationships between hallucination-like experiences and dopamine in mice. They measured dopamine levels in a brain region called the striatum during the signal-recognition task. The striatum plays a role in reward processing and perceptual processing. The researchers found elevated dopamine levels in the striatum before confident false alarms. Artificially boosting dopamine levels in the region increased the false alarm rate and confidence. In contrast, treating the mice with an antipsychotic drug that blocks dopamine receptors prevented this effect.

These findings may shed light on the role of dopamine in hallucinations. They also provide a method for further studies of psychotic-like behavior in animal models. This could open a path to develop more effective schizophrenia treatments. However, it’s still not clear if the findings are relevant to the hallucinations that occur in human psychiatric disorders.

“There seems to be a neural circuit in the brain that balances prior beliefs and evidence, and the higher the baseline level of dopamine, the more you rely on your prior beliefs,” Kepecs says. “We think that hallucinations occur when this neural circuit gets unbalanced, and antipsychotics rebalance it.”

—by Brian Doctrow, Ph.D.