Dopamine levels predict hallucination-like experiences in mice

April 1, 2021
What makes mice hallucinate? And how can we tell if they've done so? (AP Photo/Robert F. Bukaty)

What makes mice hallucinate? And how can we tell if they've done so? (AP Photo/Robert F. Bukaty)

Scientists at Cold Spring Harbor Laboratory and Washington University School of Medicine found that mice that had experiences analogous to hallucinations in humans showed higher dopamine responses, reinforcing the theory that the neurotransmitter may play a role in psychotic disorders such as schizophrenia.

A new study, published Thursday in Science, presented a novel translational model for exploring a complex, fundamentally human phenomenon via animal models. It detailed how, over the course of several weeks, mice were trained to detect sound tones against a backdrop of white noise. The mice earned a reward by investing varying lengths of time to indicate how confident they were about hearing a particular tone. 

Researchers then injected one group of mice with ketamine — a drug known to induce hallucinations in humans — and led a separate group of undosed mice to anticipate a signal by repeating the signal more frequently across trials. The scientists expected the mice from both groups to report hearing a tone even when no tone was present, mimicking an auditory hallucination in humans. 

But, "We actually saw something which was even cooler. Before we even played the tone, dopamine was tonically higher," Katharina Schmack, a psychiatrist and research investigator at Cold Springs Harbor who was the lead author of the paper, told The Academic Times. "So we somehow saw something that is even more surprising — that it seems that this dopamine at a certain point predicts how these mice were perceiving into the future." 

In other words, the mice that were made to anticipate a tone as well as those that had received ketamine both showed an exaggerated dopamine response following these interventions, leading to higher rates of hallucinatory-like experiences compared to mice that had not received either stimulus. 

In order to track the mice's dopamine levels, the researchers injected the animals with a specially engineered virus that infects brain cells. Those cells then produced bioluminescent proteins that light up when they connect with dopamine neurotransmitters in the brain. The scientists specifically targeted the striatum, an area of the brain responsible for responding to rewards and threats.

The researchers also tested a similar process of tone identification in 220 humans across more than 100,000 trials. Perhaps unsurprisingly, people who self-reported more experiences with hallucinations in their everyday lives were more likely to confidently confirm that they had heard a tone, even when no tone had been initiated.

"The basic idea is that perception, even under normal conditions, really relies on your prior beliefs," said Adam Kepecs, a professor of neuroscience and psychiatry at Washington University School of Medicine and the paper's corresponding author. "If you're in a noisy restaurant, you need to anticipate a little bit what you're going to hear. And it allows you to understand [your surroundings], and that's a good thing." 

But problems can arise, Kepecs noted, when our prior beliefs allow us to misperceive incoming stimuli, resulting in a hallucination. In some cases, these phantom perceptions can be entirely benign and forgettable, such as falsely feeling one's cellphone vibrate when there was in fact no vibration.

"But at the same time, we don't know when this process becomes pathological, and we cannot speak to this with our data right now," Schmack said.

Over the past few decades, psychiatrists have shifted their diagnostic tools to better recognize the wide array of symptoms and outcomes that patients with psychosis may exhibit. The latest version of the Diagnostic and Statistical Manual of Mental Disorders, for instance, eliminates strict subcategories such as "paranoid" and "catatonic," instead referring to schizophrenia as a wide spectrum of disorders. 

Others have advocated for eliminating the schizophrenia diagnosis altogether in favor of a more open-ended conception of psychosis — one that recognizes the phenomenon as a continuum of experiences, similar to how researchers now think about autism and ADHD. 

Psychiatrists are also interested in detecting the threshold at which hallucinatory experiences become a clinical problem that requires medical intervention. Many otherwise healthy individuals experience transitory hallucinations, with an average lifetime prevalence of nearly 10%, according to one meta-analysis. And even people with persistent auditory or visual hallucinations can live unbothered by their experiences, as long as those hallucinations are not accompanied by emotional and cognitive problems or other troubling symptoms.

The study's findings align with the dopamine hypothesis — a leading theory in the psychiatric community that posits that psychotic experiences stem from issues with dopaminergic receptors in the brain. Most antipsychotic medications, which can help alleviate hallucinations for some patients with psychotic disorders, act as dopamine inhibitors, but the precise ways in which they work remain unclear.

The researchers were careful to refer to the auditory phenomena in their experiment as hallucination-like experiences, since they were produced in the highly controlled artificial environment of the lab. In the real world, the researchers noted, hallucinations can arise unexpectedly, and secondary symptoms such as anxiety may augment their content or intensity.

The team noted that more extensive animal research could one day provide new clues for pharmaceutical companies to create more effective antipsychotic drugs. For now, though, the researchers are excited to have isolated one piece of the puzzle. 

"That's exactly how neuroscience handles things," Kepecs said. "Teasing apart this really complex thing — psychosis — into its constituent pieces."

The study, "Striatal dopamine mediates hallucination-like perception in mice" published April 1 in Science, was authored by Katharina Schmack, Marion Bosc and J.Fitz Sturgill, Cold Spring Harbor Laboratory; Torben Ott and Adam Kepecs, Cold Spring Harbor Laboratory and Washington University School of Medicine.

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