Introduction

Hallucinations are a key symptom in psychotic disorders. They are highly subjective and hard to measure in animals. In a study published in Science, Schmack et. al.¹ were able to quantify hallucination-like perception in mice by a sound detection task. They defined the hallucination-like perceptions as high-confidence false alarms, in which the mice indicated hearing a sound stimulus without one present. Ketamine and heightened stimulus expectancy, two hallucinogenic manipulations used, increased these false alarms. Higher striatal dopamine levels were recorded prior to them, and optogenetic stimulation, which increased dopamine in the tail of the striatum, increased their occurrence. This could be reversed by administering antipsychotic drug haloperidol. The approach used in this study could help the development of novel treatment options for psychotic disorders.

Background

Hallucinations are percepts without an actual stimulus present². Increase in striatal dopamine is thought to play a role in hallucinations, which are one of the main symptoms of psychotic disorders^3,4. Most antipsychotic drugs work by blocking the D2 dopamine receptors, which further indicates that the increased dopamine is a key player in psychotic symptoms⁵. But since hallucinations are subjective experiences, and animals cannot tell whether they hallucinate, it is not easy to determine when an animal is hallucinating.  Schmack et. al. created a task which can be used to determine if hallucination-like perception occurs in mice.

Methods

Mice were presented a task where they had to indicate whether they heard a signal, that was embedded to a background noise, by poking through a choice port for hearing or not hearing the signal. Also, their time investment in the decision making was measured. The researchers concluded that the higher the time investment the more confident the choice. Based on this they could monitor hallucination-like perception in mice. These were defined as high-confidence false alarms, meaning that the mice indicated they heard a stimulus, even though there was none present and that the time investment was high. The high-confidence false alarms in mice were correlated with self-reported hallucinations in humans.

The researchers tested whether these false alarms could be produced either by administering ketamine or heightening the expectations for the stimulus, since these are known to induce hallucinations in humans^6,7. The dopamine levels in the ventral striatum and the tail of the striatum were measured using genetically encoded dopamine sensors with fiber photometry. They also optogenetically boosted the dopamine in the tail of the striatum to test whether that could be used to increase the hallucination-like perceptions. 

Results

Both ketamine and high expectation for a stimulus increased the high-confidence false alarms in mice. The dopamine levels were elevated in ventral striatum as well as in the tail of the striatum preceding these hallucination-like perceptions. Elevated dopamine in ventral striatum was associated with reward expectations whereas elevated dopamine in tail of the striatum was associated with perceptual expectations. When the dopamine in the tail of the striatum was optogenetically boosted, the high-confidence false alarms increased. This effect could be reversed by administering antipsychotic drug haloperidol. In all three manipulations correctly hearing a signal when one was present was not affected. 

Conclusion

The theory that dopamine and dopaminergic pathways are key players in schizophrenia, the dopamine hypothesis of schizophrenia, have been a long-standing idea for decades⁸. But the mechanisms have not been fully clear⁹. The researchers found that the elevated dopamine in striatum either encodes for reward or perceptual expectations depending on the striatal location (ventral or tail respectively). This led them to conclude that the hallucination-like percepts arise from bias that favors previous expectations and that this bias is caused by the elevated dopamine levels. Even though they cannot be sure whether the neural processes of the hallucination-like percepts are overlapping with spontaneous hallucinations, the results of this study help to understand the relationship with striatal dopamine and perception, and their approach might be helpful in developing new treatments for schizophrenia.

[+] References

[+] Other Work By Meri Kokki