The results of studies by researchers at Washington University School of Medicine in St. Louis have provided what they suggest is a promising entry point to the development of new therapies for schizophrenia.

The team devised a form of computer game as an experimental approach to study how hallucinations are produced in the brain. The results of their tests in mice indicated that an increase of dopamine in the brain’s striatum triggers auditory hallucination-like experiences. The findings reveal a possible causal role for dopamine-dependent neurological circuits in symptoms of psychosis, and could offer insights that lead to novel targeted approaches to treating psychotic disorders such as schizophrenia.

“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,” said Adam Kepecs, PhD, a professor of neuroscience and of psychiatry, and a BJC investigator at the Washington University School of Medicine. “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. 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.”

Kepecs is senior author of the team’s report, which is published in Science, and titled, “Striatal dopamine mediates hallucination-like perception in mice.”

Psychotic disorders such as schizophrenia represent enormous human, social, and economic burdens, the authors noted. However, the prognosis for psychotic disorders hasn’t improved to any great extent over recent decades because understanding of the underlying neurobiology has “remained stagnant.”

Psychosis occurs when a person loses touch with reality. During a psychotic episode people may become delusional—acquire false beliefs—or confidently believe that they are seeing or hearing things that actually are not occurring. These are visual and auditory hallucinations. While a psychotic episode can be a sign of a serious mental illness such as schizophrenia or bipolar disorder, people without mental illness also can experience symptoms such as hallucinations.

It’s believed that auditory and visual hallucinations may be caused by excessive dopamine in the brain; people experiencing hallucinations can be treated using antipsychotic medications that block dopamine. “Elevated dopamine is believed to induce psychotic symptoms because dopamine receptor blockers reduce psychotic symptoms, dopamine agonists can induce psychotic symptoms, and patients with psychosis show signs of increased dopamine transmission in the brain,” the team explained.

But how dopamine acts to change brain circuitry and produce hallucinations in disorders such as schizophrenia isn’t known. “… a mechanistic, neural circuit–level link between dopamine and the symptoms of schizophrenia has remained a subject of speculation,” the investigators noted. Evaluating the dopamine hypothesis of psychosis is also particularly challenging, as hallucinatory experiences often rely on self-reporting, which is an ability that is lacking in model organisms such as mice. “Animal models that fully recapitulate the diagnostic criteria for psychotic disorders are impossible because animals cannot describe their subjective experiences.” This means that neuroscientists have relied on indirect behavioral measures of the disorder. And while such behavioral results have provided important neurobiological insights, they typically don’t predict human outcomes, so our understanding of how best to effectively treat psychotic disorders remains limited.

Kepecs, together with first author Katharina Schmack, MD, PhD, a research associate at Cold Spring Harbor Laboratory, developed a behavioral model to study and quantify hallucination-like perception in mice. They developed a computer game that could be completed by both people and mice. “Hallucinations are false percepts that are experienced with the same subjective certainty or confidence as true percepts,” the authors explained. “We, therefore, operationalized hallucinations in a sensory detection task as false alarms (incorrect reports that a signal was present) that are experienced with high confidence.”

The researchers trained people and mice to complete a task that effectively induced them to hear imaginary sounds. To do this, they played a particular sound, and subjects indicated that they’d heard the sound by clicking a button (people) or poking their noses into a port (mice). The task was made challenging by obscuring the sound with background noise.

People’s beliefs and expectations can prime them to experience hallucinations. Expecting to hear a certain word makes it more likely that people actually report that they have heard it, even when it wasn’t spoken. In fact, previous studies have shown that people who are prone to hallucinations are particularly susceptible to this kind of priming.

People in the study rated how confident they felt that they’d accurately identified a real sound by moving a slider on a scale. Mice indicated their confidence by how long they waited for a reward. When a subject confidently reported that he or she had heard a sound that was not actually played, the researchers labeled that a hallucination-like event.

To test whether mice also can be primed the same way, Kepecs and colleagues manipulated the mice’s expectations by adjusting how frequently the sound was played. When the sound was played frequently, the mice were even more likely to confidently but wrongly report that they’d heard it—similar to people. By analyzing performance of the task, the researchers were able to objectively measure hallucination-like events in people and mice.

“Human speech is very difficult to comprehend in a noisy environment,” Kepecs 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.”

To better connect mouse and human experience, the researchers also used a drug that induces hallucinations. Ketamine can induce distortions in perceptions of sight and sound and can trigger psychotic episodes in healthy people. Mice that were given ketamine before performing the task also reported more hallucination-like events.

Having established the crucial similarities between mice and people, the researchers then investigated the biological roots of hallucinations. By studying mice, they could make use of an arsenal of technologies for monitoring and controlling brain circuits to figure out what happens during hallucination-like events.

Through the use of dopamine-sensor measurements and pharmacological manipulations, the authors demonstrated a brain circuit link between excessive striatal dopamine and hallucination-like experience in the mice. And while the researchers observed that elevations in dopamine levels preceded hallucination-like events—and that artificially boosting dopamine levels induced more hallucination-like events—these behavioral effects could be blocked by administering the antipsychotic drug haloperidol, which blocks dopamine.

“It’s so easy to accept the argument that psychosis is a fundamentally human thing and say, ‘Forget about mice’,” said Kepecs, “but right now, we’re failing people with serious psychiatric conditions. 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. Animal models have driven advances in every other field of biomedicine. We’re not going to make progress in treating psychiatric illnesses until we have a good way to model them in animals.”

According to the authors, the novel behavioral approach opens the door for mice to be used as a promising translational model of common psychotic symptoms and, perhaps, therapeutic approaches based on selective modulation of dopamine function. “Our results also yield circuit-level insights into the long-standing dopamine hypothesis of psychosis and provide a rigorous framework for dissecting the neural circuit mechanisms involved in hallucinations,” they concluded. “Taken together, our cross-species computational psychiatry approach and results present a promising entry point to identify novel treatment targets in dopamine-dependent circuits and to develop urgently needed mechanistic treatments for schizophrenia.”

In an accompanying Perspective, Miriam Matamales, PhD, postdoctoral research associate, at the Decision Neuroscience Laboratory, School of Psychology, University of New South Wales, wrote, “Although much remains to be explored in these circuits, the findings of Schmack et al., add to a growing body of literature indicating that beyond striatal dopamine’s function in reinforcement of learning and decision-making, it also plays a key role in the neuromodulation of perception. Nevertheless, it is starting to become clear that elegantly designed behavioral neuroscience experiments can effectively bridge the gap between complex psychiatric disorders and the neural systems that underpin them.”

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