May 4, 2021
Written by: Greer Prettyman
Psychiatric disorders are challenging to study in animal models because many of the symptoms seem uniquely human. Patients with schizophrenia, for example, often experience hallucinations and paranoid delusions, which are very subjective experiences that are hard to observe from the outside. Although hallucinations can involve any of the senses, auditory hallucinations, or hearing things that aren’t really there, are among the most common for patients with psychosis. During an auditory hallucination, a person may hear voices talking to them or various other sounds. Auditory hallucinations can also occur in people who don’t have a psychiatric illness. For example, people who experience sensory deprivation often begin to hallucinate within a couple of minutes.
A task for mice and men?
People can report when they are hearing something during a hallucination, but scientists can’t ask mice to describe their subjective experiences, limiting the ability to study the neurobiology underpinning this specific symptom. However, a recent study published in the journal Science used a creative task to link a hallucinatory experience in humans and mice, elucidating a potential neural mechanism of hallucinations1.
To understand this task, think back to a time when you got your hearing tested. You were probably asked to wear headphones and indicate when you heard beeps of different volumes and pitches. Did you ever strain to hear something in the silence and maybe even indicate that you heard a tone when you weren’t sure there was one? This experience was the basis of a task that promoted auditory hallucinations and that could be completed by both people and mice.Researchers had human participants complete an auditory detection task. People would listen for tones of different volumes presented within some white noise and then indicate whether they heard one or not. They got a reward for correctly indicating when they heard a tone and for correctly indicating when they didn’t hear anything. After each decision, they also reported how confident they were about their answer. On some of the trials, people reported hearing a tone even when there wasn’t one presented. If they indicated that they were very confident about hearing a tone when it wasn’t there, this “false alarm” was considered to be similar to an auditory hallucination (Figure 1, top).
After the task, researchers asked participants to complete surveys that probed how likely they were to experience hallucinations in their lives, as well as other psychiatric symptoms. People who reported higher levels of spontaneous hallucinations also had more high-confidence false alarms during the tone detection task, validating that the task engages a process related to auditory hallucinations.
Translational neuroscience relies on links between humans and animals to study the brain in animal models in order to draw conclusions about the human brain. Now that the researchers had confirmed that their auditory detection task could measure hallucinatory behaviors in people, they could have mice perform a very similar task.
In the mouse version of the task, the mice used their noses to press different buttons to indicate whether they heard a tone or not. Just like humans, they received a reward (in the form of water droplets, rather than money) for correctly reporting if they heard a tone or didn’t hear one. Although mice cannot report how confident they are, the researchers modeled “confidence” by how long the mice waited for their water reward. Presumably, if the mouse was very confident that it gave the correct answer it would wait for the water, but if it thought it got it wrong it would leave and try again (Figure 1, bottom). Just like people, on some trials the mice had false alarms where they reported hearing a tone that wasn’t there and behaved as if they were very confident that they had heard something, creating a metric for hallucinations.
The researchers performed several tests to validate that these high-confidence false alarms really were related to hallucinations. One way they did this was to increase the likelihood of hallucinatory experiences. First, they gave the mice a drug called ketamine that often causes hallucinations. The researchers reasoned that if the false alarms indicated auditory hallucinations, they should be more likely to occur in animals that had taken ketamine, and this is in fact what they found. They also increased the likelihood of hallucinations by changing expectation for a tone by presenting the tones in almost all trials. You can think of this like the phantom vibrations you might feel when you are expecting a text message to arrive. When mice had greater expectations for a tone, they were more likely to experience false alarms.
Hallucinations and dopamine
With this validated translational task, now the scientists could begin to probe the neural mechanisms underlying these hallucinatory experiences. They hypothesized that a molecule in the brain called dopamine was involved in hallucinations because the drugs used to stop hallucinations, antipsychotics, work by blocking dopamine signaling. Now, they were able to record dopamine signaling while mice performed the auditory detection task to get a better idea of exactly how dopamine related to hallucinations. They found that dopamine signaling was increased in two brain regions, the ventral striatum and the dorsal tail of the striatum, just prior to the high-confidence false alarm experiences, compared to trials when mice correctly indicated that there was no tone.
The researchers then took what is known about dopamine signaling to build a computational model to describe what might be occurring during hallucinations. The foundation of the model was that perception arises from a combination of sensory input and expectations about those sensory inputs based on previous experiences. Dopamine signaling in the ventral striatum and tail of the striatum mapped on to different components of the model, suggesting a neural mechanism for how too much dopamine in specific regions of the brain could throw off the balance between real sensory input and perception of sounds that ultimately leads to hallucinations.
The last step to validating their model was to artificially activate or block dopamine signaling and see what happened. The researchers used a technique called optogenetics to stimulate dopamine neurons in the tail of the striatum during the auditory detection task. When dopamine was stimulated, the mice experienced more frequent false alarms, supporting the hypothesis that too much dopamine activity leads to hallucinations. The antipsychotic drug called haloperidol, on the other hand, blocked the increase in hallucinations when given prior to stimulations of dopamine neuron stimulation, consistent with this drug’s ability to prevent hallucinations in people.
With this innovative paradigm, the scientists were able to link patterns of dopamine signaling with hallucination-like behavior in animals for the first time. This type of translational research is critical for advancing treatment of a wide range of psychiatric conditions. In the future, tasks like these could even be used to test new therapeutics for complex psychiatric symptoms, with the hope of improving mental health treatment and outcomes.
- Schmack, K., et al. (2021). Striatal dopamine mediates hallucination-like perception in mice. Science372(6537): eabf4740.
Cover image by cottonbro via Pexels