Scientists induced hallucinatory mice of the condition to study psychosis

When you try to hear someone speak in a noisy crowd, your brain helps by fulfilling what you missed, based on expectations built from past experiences.

Our brains can sometimes misunderstand this, but in general, this system is pretty good at maintaining speed. It seems that this system could also be involved in hallucinations.

New research suggests that hallucinations occur when our brains begin to believe that this system of expectations is before – and not just in support of – what our senses tell us. Although it can occasionally happen to anyone, in its extremes, hallucinations are symptoms of serious mental illnesses such as schizophrenia or bipolar disorder.

To understand how our brains create this malfunction, neuroscientist Katharina Schmack of Cold Spring Harbor and colleagues developed a model of hallucinations in mice – a challenging task because you can’t ask rodents what they are experiencing.

“We are currently failing people with serious psychiatric conditions. The prognosis for psychotic patients has not improved significantly in recent decades, and that’s because we don’t really understand the neurobiology of the disease,” explained Kepecs, a neuroscientist at the University of Washington.

“Animal models have led to advances in every other field of biomedicine. We will not make progress in treating psychiatric illnesses until we have a good way to model them on animals.”

Clearly, the animal model is desperately needed, but it should also be applied with caution. As with physiological studies that rely on animal models, we also need a thorough understanding of their limitations, such as how they, their development, and environmental conditions differ from us, as well as how they are similar, in order to draw sound conclusions.

The researchers addressed some of these factors by also making direct comparisons with human subjects during their tests.

Human volunteers and mice were presented with a computerized task of detecting the background noise. Humans indicated whether they heard a tone by clicking on one of the two buttons, and mice were trained to respond to the tone by sticking their head into one port if they heard it or into another port if they did not.

Of the 220 human volunteers, those who experienced hallucinations on their own initiative (measured by a psychiatric symptom assessment questionnaire) were more likely to discover a tone when he was not there with great confidence – an event similar to a hallucination.

When mice were given the well-known hallucinogen – ketamine – they were more likely to hear a tone when he was not more confident, measured by how long they were willing to wait for the reward.

The team could also prepare mice to more reliably falsely detect this tone, by releasing the tone more often, which increases their expectation to hear the tone. It happens to people too.

By monitoring the brains of mice, the researchers discovered elevated levels of dopamine before falsely hearing the tone – a chemical known to play a role in human hallucinations. The team then showed that elevated dopamine levels were more likely to cause hallucinatory events in mice and could be reduced by an antipsychotic drug that blocks dopamine.

“There seems to be a nervous system in the brain that balances previous beliefs and evidence, and the higher the baseline dopamine level, the more you rely on your previous beliefs,” Kepecs explained. “We think hallucinations occur when this neural circuitry becomes unbalanced and antipsychotics balance it.”

Of course, Schmack and colleagues still don’t know for sure whether the hallucinatory event they caused in mice and humans overlaps in neurobiology with the spontaneous hallucinations experienced by healthy people – or those experienced during psychotic episodes.

But the system they have now developed will allow researchers to further explore these issues, as well as look for new ways to treat psychotic disorders.

“We are very excited about this computational approach to studying hallucinations among species that allows us to finally explore the neurobiological roots of this mysterious experience,” Kepecs said.

This research was published in Science.

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