People suffering from psychotic episodes often experience both visual and aural hallucinations, due in part to the neurochemical dopamine; antipsychotics block dopamine receptors in the brain. But little is known about precisely how brain circuits change in response to elevated dopamine levels. The humble mouse might be able to help. An increase in dopamine in the brain can trigger auditory hallucinations in mice, according to a recent paper published in the journal Science—a surprising link between how human and mouse minds malfunction.
While the very notion of hallucinating mice might strike some as amusing, co-author Adam Kepecs of the Washington University School of Medicine in St. Louis emphasizes that it is not a joke and that mouse studies really can shed light on human psychosis. "It's so easy to accept the argument that psychosis is a fundamentally human thing and say, 'Forget about mice'," he said. "But right now, the prognosis for psychotic patients has not substantially improved over the past decades, and that's because we don't really understand the neurobiology of the disease."
Kepecs' lab has focused largely on developing a more complete understanding of confidence in rats by studying their neurocircuitry, with a long-term goal of shedding light on self-reported confidence in humans. Lead author Katharina Schmack is a psychiatrist at Cold Spring Harbor Laboratory in New York who studies psychosis and schizophrenia. The two authors saw an opportunity for an interdisciplinary study of psychotic disorders in animals.
Kepecs encountered a fair amount of skepticism from colleagues at first, even though animal models have driven almost every major advance in biomedical science, particularly mice. So why not use mice in neuroscience experiments? Some might argue that humans and mice are just too different for anything useful to be learned about something as advanced as hallucinations. And even if mice are hallucinating, they have no means of communicating that experience to the human experimenters.
"I think it's just an intuition that it's not going to work—that [a mouse] doesn't feel like 'us,'" Kepecs told Ars. "Until quite recently, we couldn't study the brain, even in a mouse, to the precision that we can now. But neuroscience has made incredible advances in the last decade. We know what brain regions are unique to us. There's no evidence that those are the regions that are implicated in psychosis. It's many of the more common regions that are implicated. We're not going to make progress in treating psychiatric illnesses until we have a good way to model them in animals."
Of mice and men
Kepecs et al. set up a computer game that could be played by both mice and humans. The researchers played various sounds, obscured by background noise, and asked subjects to indicate whether or not they had heard them. "Human speech is very difficult to comprehend in a noisy environment," he said. "We are always balancing our prior knowledge of human speech against what we're hearing in the moment to understand spoken language. You can easily imagine that this system can get imbalanced, and all of a sudden you're hearing things."
Human subjects clicked a button whenever they heard a sound; the mice would poke their noses into a port. The human subjects were asked to rate how confident they felt about identifying a real sound (versus an imagined one) by moving a slider on a scale. Kepecs et al. found that human subjects who reported more hallucination-like auditory sounds during the experiment were also more likely to experience spontaneous hallucinations, even though none had a psychiatric condition.
"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 said. "We think that hallucinations occur when this neural circuit gets unbalanced, and antipsychotics rebalance it. Our computer game probably engages this same circuit, so hallucination-like events reflect this circuit imbalance."
That neural circuit likely lies within the sensory striatum, which sits between brain stem circuitry and the cortex—a region in which dopamine is strongly expressed. Striatal dopamine is known to reinforce learning and decision-making. "That's also where a lot of the auditory and visual cortical areas project to," Kepecs said. So we shouldn't be surprised that it would be a key region involved with hallucinations.
Time for ketamine
The researchers assessed the corresponding confidence levels of the mice by measuring how long the mice waited for a reward. They found that the mice could be "primed" just like the human subjects, simply by changing how often the sound was played to toy with the rodents' expectations. The more often the sound was played, the more likely the mice were to confidently "report" they had heard something when no sound had been played.
Next, the team implanted small fiber-optic sensors in the mice to record the dopamine levels in real time and gave some of the mice ketamine, which can distort perceptions of sight and sound. Mice who got the ketamine were far more likely to show signs of hallucination-like events. This is evidence for a similar brain-circuit link between excess dopamine in the sensory striatum and hallucinatory experiences. The brains of the hallucinating mice were "mistuned" by the excess dopamine. Kepecs thinks that people with aural hallucinations have brains that are similarly mistuned, although he has yet to experimentally prove it.
The hope is that this research might shed light on the underlying neural circuits responsible for hallucinations and one day lead to improved therapies for treating psychosis in humans. "Despite the tremendous debilitating nature of [psychotic] conditions, there has not been a change in how we treat it for a long time," said Kepecs. "Frankly, pharmaceutical companies have given up, and it's largely due to the stagnant understanding of neurobiology. We are very excited about this computational approach to study hallucinations across species that enables us to finally probe the neurobiological roots of this mysterious experience."
DOI: Science, 2021. 10.1126/science.abf4740 (About DOIs).
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