Psychotic mice reveal what happens to the brain during a hallucination

Few things may be more terrifying than the experience of an unbidden hallucination. While some might take drugs to induce hallucinations for recreational purposes, others, like those who have schizophrenia and other brain conditions, can be hounded by these often disturbing episodes.

It’s estimated that 20 million people in the world have schizophrenia, and about 75 percent of people with the condition experience auditory hallucinations. But what happens in the brain during a hallucination has proven difficult to tease out. Thanks to a new study in mice, scientists are starting to get a clear picture of the biology behind this strange phenomenon.

Why it matters — New, safe, and effective treatments for schizophrenia and the hallucinations which define the condition are desperately needed.

According to the World Health Organization, people with schizophrenia who experience hallucinations are between two and three times more likely to die earlier than the general population, often as a result of preventable diseases, including cardiovascular disease, metabolic disease, and infections.

The hallucination experience can be terrifying, infuriating, baffling, and painful. At the same time, the therapies for schizophrenia available now come with dramatic and debilitating side effects, and people often stop taking the drugs as a result.

Adam Kepecs is a professor of neuroscience and psychiatry at the Washington University School of Medicine in St. Louis and one of the researchers on the study. He tells Inverse that current schizophrenia drugs are essentially a blunt instrument for a delicate, complex problem.

“They have many side effects and many, many people stop taking them,” Kepecs says. “Even the ones who stay on the drug don’t have an overall better prognosis than the people who go off of them.”

“It's just a bizarre scenario where we have this class of drugs, that works to a point. But after 50 odd years, they don’t work better,” he says.

What’s new — The study, published Thursday in the journal Science, presents a step forward in tackling one of the main obstacles to developing new drugs for schizophrenia — namely, Kepecs says, the lack of good mouse models to study the condition. This kind of research — modeling a human condition in animals — is central to how scientists develop drugs to treat all manner of conditions, including cancer, he says.

“But studying something as high level and mysterious as hallucinations in a mouse, well the pharmaceutical companies just kind of gave up because they thought there was no way to do it,” he says.

Studying this complex functioning in mice could bring revolutionary insights into the disease and how to treat it, Kepecs explains.

How they did it — In the new study, the researchers trained both mice and people to play a computer game. The humans in this study were not schizophrenic, but they had reported experiencing spontaneous hallucinations. During the gameplay, the study participants — both human and murine — listened to background noise in which a specific tone was sometimes embedded.

As they listened to the noise, the human participants were asked to either push a button indicating they’d heard a tone, or a button indicating they hadn’t heard the tone. They also reported how confident they were in their decision by sliding a cursor on a scale. Think of it this way: It’s one thing to think you might have heard a noise near your bedroom window, and another entirely to be certain that you heard someone banging on your bedroom window.

The mice were tasked with doing the same, using their noses to poke buttons indicating whether or not they heard the tone. The researchers also did two things to the mice which are known to induce hallucinations in humans — they gave the mice ketamine, and they manipulated the mice's expectations by adjusting how often they played the tone. By doing so, the researchers say, they taught the mice to “expect” to hear something at certain points — and then defied those expectations.

“Say you’re in a noisy restaurant with a friend. You have some expectation of what the friend is going to say — that helps you make out the words in a noisy environment,” Kepecs says.

Using expectations and prior beliefs to understand our present sensory environment is a critical skill, and it makes life easier to navigate.

“Now, if you're overusing [expectations] to the point when there's no one talking to you, but you believe that someone is?” Kepecs says.

“That’s a problem.”

Digging into the details — The researchers already knew that high levels of dopamine are associated with hallucinations.

“We knew that there are antipsychotics that target specific dopamine receptors that work so we knew somehow that dopamine is central. But once you're in a human you really can't study at a detailed mechanistic level of what's going on, so we did not know too much more,” Kepecs says.

To monitor the mice’s dopamine levels during the experiment, the researchers embedded dopamine sensors into the mice’s striatum. The striatum is part of the brain’s reward system and plays a role in how the brain responds to certain sensory stimuli, by releasing dopamine. These stimuli include signals from the auditory and visual cortices.

What they found — In the mice, elevations in dopamine release in the striatum preceded hallucination-like behavior; the mice had increased dopamine levels before poking the button indicating they had heard a noise, despite none being there. The researchers also artificially boosted dopamine through a method called optogenetics, in which neurons’ activity can be controlled through light and genetic engineering. That artificial boosting of dopamine also appeared to cause the mice to have more hallucination-like events.

“In retrospect, it is not so surprising that we’re seeing the connection to the sensory striatum — [hallucinations] are a sensory-perceptual problem, Kepecs says. “And we’ve known dopamine was involved. But we didn’t know how dopamine changes brain circuits to produce hallucinations — that was unknown.”

What’s next — The findings have two important implications, Kepecs says. First, they offer researchers a better understanding of the biology causing hallucinations to happen and an objective measurement that can accurately predict a formerly mysterious phenomenon.

But perhaps more excitingly, he says, is that the study shows that auditory hallucinations such as those experienced by people with schizophrenia can be studied in animal models.

More work is needed before we get there, Kepecs cautions. But ultimately, such translational research has the potential to open up a world of better, more targeted treatments with fewer side effects for people with the condition.

Abstract: Hallucinations, a central symptom of psychotic disorders, are attributed to excessive dopamine in the brain. However, the neural circuit mechanisms by which dopamine produces hallucinations remain elusive, largely because hallucinations have been challenging to study in model organisms. We developed a task to quantify hallucination-like perception in mice. Hallucination-like percepts, defined as high-confidence false detections, increased after hallucination-related manipulations in mice and correlated with self-reported hallucinations in humans. Hallucination-like percepts were preceded by elevated striatal dopamine levels, could be induced by optogenetic stimulation of mesostriatal dopamine neurons, and could be reversed by the antipsychotic drug haloperidol. These findings reveal a causal role for dopamine-dependent striatal circuits in hallucination-like perception and open new avenues to develop circuit-based treatments for psychotic disorders.