Mice with hallucination-like behaviors reveal insight into psychotic illness

The common laboratory mouse has yielded many insights into illnesses as diverse as cancer, diabetes, and the AIDS virus COVID-19. However, the lab mouse has been neglected when it comes to studying psychiatric disorders since the rodent mind is seen to be too different from the human mind to be useful in studying mental disease. However, a recent research indicates that the functioning and malfunctioning of human and mouse brains are linked in fundamental ways. This novel method, developed by scientists at Washington University School of Medicine in St. Louis, provides a potential starting point for the creation of much-needed new treatments for schizophrenia.

Scientists have found a method to investigate the molecular origins of hallucinations, a key sign of psychosis. Their findings were published in the journal Science on April 2. The researchers used computer-based training to make both humans and mice hear fictitious noises while completing a task. Researchers were able to quantify hallucination-like experiences in humans and mice by evaluating how well they performed on a task. To investigate the brain circuits causing hallucinations, they used a novel method that opened up mental symptoms to the sort of research that has been so successful for illnesses in other body parts. According to lead author Adam Kepecs, PhD, a professor of neurology and psychiatry at the School of Medicine and a BJC Investigator, “it’s so simple to embrace the notion that psychosis is essentially human thing” “Right now, though, we’re neglecting individuals who are suffering from severe mental illnesses. Psychotic patients’ prognosis has not improved much in the last several decades since the disease’s neurobiology is still poorly understood. Every other area of biomedicine has benefited from the use of animal models. Until we can mimic mental disorders in animals well, we will not be able to make headway in treating them.”

Psychosis is a condition in which a person has lost all sense of reality. False beliefs (delusions) may be formed during a psychotic episode, and individuals may become convinced of what they see or hear even when it isn’t true (hallucinations). Schizophrenia or bipolar disease may cause psychotic episodes, but individuals who are healthy might also have symptoms like delusions or hallucinations. Dr. Katharina Schmack, MD, PhD of Cold Spring Harbor Laboratory and colleagues devised a computer game that could be completed by both humans and mice as part of Kepecs’ research on hallucinations. In one experiment, the scientists produced a sound and the participants responded by pressing a button (humans) or sticking their noses into a port (mice). Background noise masked the sound, making the job more difficult. Using a slider on a scale, participants evaluated their confidence in their ability to correctly identify a genuine sound; mice expressed their confidence by how long they waited for a reward. A hallucination-like occurrence was classified by the researchers when a participant assertively claimed hearing a sound that was not played.

Despite its simplicity, the exercise seemed to tap into the hallucination-related brain circuits in those who had experienced them. People who had more hallucination-like experiences during the experiment were also more likely to have spontaneous hallucinations, as measured by questionnaires used to evaluate psychiatric symptoms in the general population. Despite this, no one in the study had been diagnosed with a mental illness. Beliefs and expectations may lead to hallucinations in those who aren’t ready to have them. When individuals anticipate hearing a particular term, they are more likely to report hearing it even though it was not uttered. People who are prone to hallucinations are more vulnerable to this kind of priming, according to prior research.

Kepecs stated that in a loud setting, “human speech is extremely difficult to understand.” “To comprehend spoken language, we must constantly weigh our previous understanding of human speech against what we hear right now. It’s easy to see how this system might become unbalanced, causing you to start hearing strange sounds.” To see whether mice could be primed in the same manner, Kepecs and colleagues changed the frequency at which the sound was delivered to alter the mice’s expectations. It was found that when the sound was played repeatedly, the mice were much more likely to falsely claim that they had heard it. The researchers also employed a medication that causes hallucinations to better link mouse and human experience. Healthy individuals who are given the drug ketamine may have distorting impressions of sight and sound, and they may even experience psychotic episodes. Prior to completing the task, the mice were administered ketamine, which resulted in greater hallucinations.

Researchers discovered these key commonalities in hallucinations between mice and humans and then delved further into the molecular basis behind them. To learn what occurs during hallucination-like experiences, researchers might employ an array of tools for monitoring and manipulating brain circuits, which they could learn by studying mice. Dopamine, a neurotransmitter in the brain associated with hallucinations, has long been studied. Antipsychotic medicines that inhibit dopamine are effective in treating hallucinations. However, the exact mechanism by which dopamine alters brain circuits to cause hallucinations is still a mystery. Dopamine increases preceded hallucination-like occurrences in mice, and increasing dopamine levels artificially led to even more hallucination-like episodes. Antipsychotic medication haloperidol, which inhibits dopamine, may be used to stop these behavioral consequences. If your baseline amount of dopamine is high, you’ll be more likely to depend on your previous beliefs. “Antipsychotics are thought to restore equilibrium to the brain’s hallucination-inducing neuronal circuit. Due to the fact that our computer game likely activates the same circuit, hallucination-like occurrences occur. Hallucinations occur in a wide variety of animals, and our computational method allows us to finally explore the neurological foundations of this enigmatic phenomenon.”

Journal Reference: K. Schmack, M. Bosc, T. Ott, J. F. Sturgill, A. Kepecs. Striatal dopamine mediates hallucination-like perception in miceScience, 2021; 372 (6537): eabf4740 DOI: 10.1126/science.abf4740

Categories: Clinical