The humble lab mouse provided invaluable clues to understanding diseases ranging from cancer to diabetes to COVID-19. But when it comes to psychiatric conditions, the lab mouse has been sidelined as its rodent mind is considered too different from humans to provide much information about mental illness.
A new study, however, shows that there are important links between human and mouse minds in how they function – and how they do not function. Researchers at Washington University St. Louis School of Medicine have devised a rigorous approach to study how hallucinations are produced in the brain, providing a promising entry point for the development of much-needed new therapies for schizophrenia .
The study, published April 2 in the journal Science, presents a way to probe the biological roots of a determining symptom of psychosis: hallucinations. The researchers trained people and mice to perform a computer task that prompted them to hear imaginary sounds. By analyzing the performance of the task, the researchers were able to objectively measure hallucination-like events in people and mice. This innovative approach allowed them to study the neural circuits underlying hallucinations, opening up mental symptoms to the kind of scientific studies that have been so successful for diseases in other parts of the body.
“It’s so easy to take the argument that psychosis is a fundamentally human thing and say, ‘Forget the mice,’” said lead author Adam Kepecs, PhD, professor of neuroscience and psychiatry, and BJC researcher at the School of Medicine. . “But at the moment, we are failing people with severe psychiatric disorders. The prognosis for psychotic patients has not improved significantly over the past few decades, and that’s because we don’t really understand the neurobiology of the disease. . Animal models have led to advancements in the field. In all other areas of biomedicine. We are not going to advance in the treatment of psychiatric illnesses until we have a good way to model them in animals . “
Psychosis occurs when a person loses touch with reality. During a psychotic episode, people may develop false beliefs (delusions) or confidently believe that they are seeing or hearing things that are not happening (hallucinations). A psychotic episode can be a sign of a serious mental illness like schizophrenia or bipolar disorder, but people without a mental illness can also experience symptoms like hallucinations.
To study how hallucinations occur, Kepecs – along with first author Katharina Schmack, MD, PhD, of the Cold Spring Harbor Laboratory, and her colleagues – put together a computer game that could be completed by people and mice. Researchers played a particular sound, and subjects reported hearing it when clicking a button (people) or pushing their nose into a port (mouse). The task was made difficult by obscuring the sound with background noise. Study participants rated how confident they felt they had accurately identified an actual sound by moving a cursor on a scale; the mice indicated their confidence by how long they waited for a reward. When a subject confidently stated that he or she heard a sound that was not actually played, the researchers called the event a hallucination.
Although simple in design, the task seemed to tap into the brain circuits underlying the hallucinations. People with more hallucination-type events during the experience were also more likely to experience spontaneous hallucinations – as measured by questionnaires designed to assess psychiatric symptoms in the general population – even though no participant was diagnosed with a psychiatric disorder.
People’s beliefs and expectations can cause them to experience hallucinations. Expecting to hear a certain word increases the likelihood that people will report hearing it, even if it has not been spoken. In fact, previous studies have shown that people prone to hallucinations are particularly sensitive to this type of priming.
“Human speech is very difficult to understand in a noisy environment,” Kepecs said. “We always balance our prior knowledge of human speech with what we hear right now to understand spoken language. You can easily imagine that this system can be out of balance, and all of a sudden you hear things.
To test whether mice can also be prepared in the same way, Kepecs and his colleagues manipulated mice expectations by adjusting the frequency of sound playback. When the sound was played frequently, mice were even more likely to confidently but mistakenly report that they had heard it – like people.
To better connect the experience of mice and humans, the researchers also used a drug that causes hallucinations. Ketamine can induce distortions in the perception 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.
After establishing these crucial similarities between mice and humans, the researchers went on to study the biological roots of hallucinations. By studying mice, they could use an arsenal of brain circuit monitoring and control technologies to understand what happens during hallucination-like events.
It has long been known that the brain chemical dopamine plays a role in hallucinations. People with hallucinations can be treated with antipsychotic drugs that block dopamine. But how dopamine alters brain circuitry to produce hallucinations remains unknown.
In studying mice, the researchers observed that the rise in dopamine levels preceded hallucination-like events and that the artificial increase in dopamine levels induced more hallucination-like events. These behavioral effects could be blocked by the administration of the antipsychotic haloperidol, which blocks dopamine.
“There seems to be a neural circuit in the brain that balances out previous beliefs and evidence, and the higher the baseline level of dopamine, the more you rely on your earlier beliefs,” Kepecs said. “We believe hallucinations occur when this neural circuit is out of balance and antipsychotics rebalance it. Our computer game probably engages this same circuit, so hallucination-type events reflect this circuit imbalance. We are very excited about this computational approach to studying hallucinations between species. this allows us to finally probe the neurobiological roots of this mysterious experience. “