How dopamine leads to hallucinations

Hallucinations (perceptual experiences without external stimuli) seen in conditions such as schizophrenia are thought to result from giving too much weight to priors, creating an imbalance at the expense of actual sensory evidence. Sustained high-dopamine tone in the striatum has been proposed to contribute to this imbalance; however, it has remained unclear how the dopaminergic perturbation leads to the generation of hallucinations. Schmack et al. have developed a cross-species computational psychiatry approach to directly relate human and rodent behavior and used this approach to study the neural basis of hallucination-like perception in mice. Here is the summary of their results and their conclusion:   

RESULTS

We set up analogous auditory detection tasks for humans and mice. Both humans and mice were presented with an auditory stimulus in which a tone signal was embedded in a noisy background on half of the trials. Humans pressed one of two buttons to report whether or not they heard a signal, whereas mice poked into one of two choice ports. Humans indicated how confident they were in their report by positioning a cursor on a slider; mice expressed their confidence by investing variable time durations to earn a reward. In humans, hallucination-like percepts—high-confidence false alarms—were correlated with the tendency to experience spontaneous hallucinations, as quantified by a self-report questionnaire. In mice, hallucination-like percepts increased with two manipulations known to induce hallucinations in humans: administration of ketamine and the heightened expectation of hearing a signal. We then used genetically encoded dopamine sensors with fiber photometry to monitor dopamine dynamics in the striatum. We found that elevations in dopamine levels before stimulus onset predicted hallucination-like perception in both the ventral striatum and the tail of the striatum. We devised a computational model that explains the emergence of hallucination-like percepts as a consequence of faulty perceptual inference when prior expectations outweigh sensory evidence. Our model clarified how hallucination-like percepts can arise from fluctuations in two distinct types of expectations: reward expectations and perceptual expectations. In mice, dopamine fluctuations in the ventral striatum reflected reward expectations, whereas in the tail of the striatum they resembled perceptual expectations. We optogenetically boosted dopamine in the tail of the striatum and observed that increasing dopamine induced hallucination-like perception. This effect was rescued by the administration of haloperidol, an antipsychotic drug that blocks D2 dopamine receptors.

CONCLUSION

We established hallucination-like perception as a quantitative behavior in mice for modeling the subjective experience of a cardinal symptom of psychosis. We found that hallucination-like perception is mediated by dopamine elevations in the striatum and that this can be explained by encoding different kinds of expectations in distinct striatal subregions. These findings support the idea that hallucinations arise as faulty perceptual inferences due to elevated dopamine producing a bias in favor of prior expectations against current sensory evidence. Our results also yield circuit-level insights into the long-standing dopamine hypothesis of psychosis and provide a rigorous framework for dissecting the neural circuit mechanisms involved in hallucinations. We propose that this approach can guide the development of novel treatments for schizophrenia and other psychotic disorders.