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The study of mice and humans offers a new approach to the study of mental illness
The humble laboratory mouse has provided invaluable clues to understanding diseases ranging from cancer to diabetes to COVID-19. But when it comes to psychiatric illnesses, the lab mouse has been withdrawn and its rodent mind has been viewed as too different from humans to give much insight into mental illness.
However, a new study shows that there are important links between the human and mouse minds in terms of how they work and how they malfunction. Researchers at the Washington University Medical School in St. Louis devised a rigorous approach to studying how hallucinations are produced in the brain. This is a promising entry point for the development of much-needed new therapies for schizophrenia.
The study, published April 2 in the journal Science, shows a way to examine the biological roots of a defining symptom of psychosis: hallucinations. The researchers trained humans and mice to do a computerized task that caused them to hear imaginary sounds. By analyzing the performance of the task, the researchers were able to objectively measure hallucination-like events in humans and mice. This innovative approach enabled them to study the neural circuitry underlying hallucinations and open up mental symptoms to scientific studies that have been so fertile for diseases of other parts of the body.
“It’s so easy to accept the argument that psychosis is a fundamentally human thing and say, ‘Forget mice,” said senior author Adam Kepecs, PhD, professor of neuroscience and psychiatry and BJC researcher at the School of Medicine. “But right now we are failing people with serious psychiatric illnesses. The prognosis for psychotic patients has not improved much in the past few decades, and that’s because we don’t really understand the neurobiology of the disease. Animal models have advances in everyone else.” We will not make any progress in treating psychiatric disorders until we have a good opportunity to model them on animals. “
Psychosis occurs when a person loses touch with reality. During a psychotic episode, people may acquire false beliefs (delusions) or have confidence that they are seeing or hearing things that are not occurring (hallucinations). A psychotic episode can be a sign of a serious mental illness such as schizophrenia or bipolar disorder, but people without a mental illness can also have symptoms such as hallucinations.
To investigate how hallucinations occur, Kepecs – together with first author Dr. med. Katharina Schmack from the Cold Spring Harbor Laboratory and colleagues – developed a computer game that can be played by both humans and mice. The researchers played a specific sound, and the subjects said they heard it by clicking a button (people) or sticking their noses into a port (mice). The task was challenged by obscuring the sound with background noise. Study participants rated how confident they were that they had accurately identified a real sound by moving a slider on a scale. Mice showed their confidence in how long they waited for a reward. When a subject confidently reported that he or she heard a note that was not actually being played, the researchers referred to it as a hallucination-like event.
Although the task was simple, the task seemed to unlock the brain circuits that underlie hallucinations. People with more hallucination-like events during the experiment were also more likely to have spontaneous hallucinations – as measured by questionnaires assessing psychiatric symptoms in the general population – even though none of the participants was diagnosed with a psychiatric illness.
People’s beliefs and expectations can lead them to experience hallucinations. If you expect to hear a particular word, the more likely people will actually report that they heard it, even if it wasn’t spoken. In fact, previous studies have shown that people who are prone to hallucinations are particularly prone to this type of primer.
“Human language is very difficult to understand in a noisy environment,” said Kepecs. “We always balance our previous knowledge of human language against what we are hearing in order to understand the spoken language. You can easily imagine that this system can become unbalanced and suddenly you hear things. “
To test whether mice can be primed the same way, Kepecs and colleagues manipulated the mice’s expectations by adjusting how often the sound was played. If the note was played frequently, the mice were even more likely to safely, but incorrectly, report that they had heard it – much like humans.
To better combine the mouse and human experience, the researchers also used a drug that induces hallucinations. Ketamine can lead to distortions in the perception of images and sound and trigger psychotic episodes in healthy people. Mice given ketamine prior to performing the task also reported more hallucination-like events.
After discovering these crucial similarities between mice and humans, researchers examined the biological roots of hallucinations. By studying mice, they could use an arsenal of technologies to monitor and control brain circulation to find out what happens during hallucination-like events.
The brain chemical dopamine has long been known to play a role in hallucinations. People who have hallucinations can be treated with antipsychotics that block dopamine. However, it is unknown how dopamine alters brain circuits to cause hallucinations.
When studying mice, the researchers observed that increases in dopamine levels preceded hallucination-like events and that artificially increasing dopamine levels elicited more hallucination-like events. These behavioral effects could be blocked by administering the antipsychotic drug haloperidol, which blocks dopamine.
“There appears to be a neural circuit in the brain that reconciles previous beliefs and evidence. The higher the baseline level of dopamine, the more reliant you are on your previous beliefs,” said Kepecs. “We believe hallucinations occur when this neural circuit becomes unbalanced and antipsychotics bring it back into balance. Our computer game probably uses the same circuit, so hallucination-like events reflect this circuit imbalance. We are very excited about this computational approach to studying hallucinations between species that allows us to finally explore the neurobiological roots of this mysterious experience. “
Schmack K., Bosc M., Ott T., Sturgill JF, Kepecs A. Striatal dopamine mediates hallucination-like perception in mice. Science. April 2, 2021.
This study was supported by the Leopoldina (German Academy of Sciences), grant number LDPS 2010-03; the German Research Foundation, grant number OT 562 / 1-1; the Brain and Behavior Research Foundation, grant number 26726; the National Institutes of Mental Health (NIMH) and the National Institute on Drug Abuse (NIDA).
The 1,500 faculty physicians at Washington University School of Medicine are also medical staff at Barnes-Jewish and St. Louis Children’s Hospitals. The School of Medicine is a leader in medical research, teaching, and patient care and is consistently one of the best medical schools in the country according to the US News & World Report. The School of Medicine is affiliated with BJC HealthCare through its connections with the Barnes-Jewish and St. Louis Children’s Hospitals.