Am I Hearing Things?
Studying Hallucinations in Mice
Background
Our understanding of how hallucinations work has long been nearly as elusive as the phenomenon itself. In the past, it has been difficult to study the neurobiology of psychotic disorders such as schizophrenia, particularly because there has not been a way to model hallucinations in other organisms. However, a breakthrough recently occurred when researchers developed a way to study hallucinations in mice.
Psychotic disorders are characterized by hallucinations, which the study’s researchers defined as “false percepts that are experienced with the same subjective confidence as ‘true’ percepts.”
Method
Clearly, a mouse can’t tell you when it’s hallucinating. To address this issue, researchers created a task that both humans and trained mice could participate in, which would assess when subjects were experiencing a phenomenon similar to a hallucination. Researchers played white noise for humans and mice, and had the subjects identify when they heard a tone in the background.
Subjects sometimes falsely indicated that they had heard a tone. These experiences were called “high-confidence false alarms”, or “hallucination-like percepts” (HALIPs). Humans who experienced hallucinations generally were more likely to have experienced these hallucination-like percepts, based on a self-reported survey taken after the experiment.
To participate in this task, mice were trained to poke a port indicating whether or not they had heard a noise. Researchers also trained the mice to indicate their confidence in their response based on the amount of time the mice invested in getting a reward.
Researchers used multiple measures to confirm the similarities between human and mouse psychosis. For instance, when mice were “primed” to expect to hear the tone, they were more likely to indicate having experienced high-confidence false alarms. Additionally, researchers found that ketamine, a drug that induces psychosis in humans, increased the number of HALIPs in mice.
Summary: Dopamine Levels in the Striatum
After confirming these similarities, researchers monitored the mice’s dopamine levels in a region of the brain known as the striatum. The striatum is a part of the basal ganglia complex, and is located deep in the brain below the cerebral cortex. High dopamine levels in this region are thought to contribute to psychotic episodes. Specifically, the ventral striatum is thought to be involved in the processing of rewards, while the dorsal tail of the striatum is understood to be involved in perceptual processing.
To measure dopamine levels, researchers used GRABda, a fluorescence dopamine sensor, along with fiber photometry techniques. When dopamine binds to a GRABda sensor, a green fluorescence protein bound to the sensor produces light. This fluorescence is detected through fiber photometry, which quantifies the amount of light produced. This in turn indicates the amount of dopamine activity in this area of the brain.
Dopamine levels were found to be elevated before the mice experienced hallucination-like precepts, particularly when these were high-confidence decisions. Researchers then stimulated dopamine release in the striatum while mice were performing the task, and found that the number of high-confidence HALIPs increased. This could be reversed using haloperidol, a dopamine receptor antagonist.
The task used in this experiment will aid in further research of psychotic disorders, as both humans and mice can participate and their responses can be compared. Prior to this study, much of our understanding of the contribution of elevated dopamine levels to schizophrenia was speculative. However, the study provided evidence for this theory and identified the particular activity taking place in the striatum. This research could aid in the development of treatments for psychotic disorders.
