Source: Washington
University School of Medicine
Summary: A computer
game that induces mice to experience hallucination-like events could be a key
to understanding the neurobiological roots of psychosis, according to a new
study.
The humble
lab mouse has 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, its rodent mind considered too different from
that of humans to provide much insight into mental illness.
A new study,
however, shows there are important links between human and mouse minds in how
they function -- and malfunction. Researchers at Washington University School
of Medicine in St. Louis devised a rigorous approach to study how
hallucinations are produced in the brain, providing a promising entry point to
the development of much-needed new therapies for schizophrenia.
The study,
published April 2 in the journal Science, lays out a way to probe
the biological roots of a defining symptom of psychosis: hallucinations. The
researchers trained people and mice to complete a computer-based task that
induced them to hear imaginary sounds. By analyzing 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 fruitful 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 about mice'," said senior author Adam Kepecs, PhD, a
professor of neuroscience and of psychiatry, and a BJC Investigator at the
School of Medicine. "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."
Psychosis
occurs when a person loses touch with reality. During a psychotic episode,
people may acquire false beliefs (delusions) or confidently believe 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 mental illness also can
experience symptoms such as hallucinations.
To study how
hallucinations occur, Kepecs -- with first author Katharina Schmack, MD, PhD,
of Cold Spring Harbor Laboratory, and colleagues -- set up a computer game that
could be completed by both people and mice. The researchers played a particular
sound, and subjects indicated that they'd heard it 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 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.
While simple
in design, the task appeared to tap into the brain circuits underlying
hallucinations. People with more hallucination-like events during the
experiment also were more likely to experience spontaneous hallucinations -- as
measured by questionnaires designed to evaluate psychiatric symptoms in the
general population -- even though no participants were diagnosed with a
psychiatric condition.
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.
"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 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.
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 these 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.
The brain
chemical dopamine has long been known to play a role in hallucinations. People
experiencing hallucinations can be treated with antipsychotic medications that
block dopamine. But how dopamine changes brain circuits to produce
hallucinations has remained unknown.
When
studying mice, 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.
"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. 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."
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