Research Article

Striatal dopamine mediates hallucination-like perception in mice

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Science  02 Apr 2021:
Vol. 372, Issue 6537, eabf4740
DOI: 10.1126/science.abf4740

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How to model hallucinations in mice

There has not been enough progress in our understanding of the basic mechanisms underlying psychosis. Studying psychotic disorders in animal models is difficult because the diagnosis relies on self-reported symptoms that can only be assessed in humans. Schmack et al. developed a paradigm to probe and rigorously measure experimentally controlled hallucinations in rodents (see the Perspective by Matamales). Using dopamine-sensor measurements and circuit and pharmacological manipulations, they demonstrated a brain circuit link between excessive dopamine and hallucination-like experience. This could potentially be useful as a translational model of common psychotic symptoms described in various psychiatric disorders. It may also help in the development of new therapeutic approaches based on anatomically selective modulation of dopamine function.

Science, this issue p. eabf4740; see also p. 33

Structured Abstract

INTRODUCTION

Psychotic disorders such as schizophrenia impose enormous human, social, and economic burdens. The prognosis of psychotic disorders has not substantially improved over the past decades because our understanding of the underlying neurobiology has remained stagnant. Indeed, the subjective nature of hallucinations, a defining symptom of psychosis, presents an enduring challenge for their rigorous study in humans and translation to preclinical animal models. Here, we 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.

RATIONALE

Hallucinations are false percepts that are experienced with the same subjective confidence as “true” percepts. Similar false percepts can be quantitatively evaluated using a sensory detection task in which individuals report whether they heard a signal embedded in a background noise and indicate how confident they are about their answer. Thus, we defined hallucination-like percepts as confident false alarms—that is, incorrect reports that a signal was present, which are reported with high confidence. We reasoned that such experimentally controlled hallucination-like percepts engage neural mechanisms shared with spontaneously experienced hallucinations in psychosis and can therefore serve as a translational model of psychotic symptoms. Because psychotic symptoms are thought to involve increased dopamine transmission in the striatum, we hypothesized that hallucination-like perception is mediated by increased striatal dopamine.

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.

Hallucination-like perception framework and striatal dopamine.

In humans and mice, a computational-behavioral task models hallucinations as high-confidence false percepts. In humans, such hallucination-like percepts are correlated with self-reported hallucinations. In mice, hallucination-like percepts are mediated by striatal dopamine. Data are means ± SEM. *P < 0.05, **P < 0.01.

Abstract

Hallucinations, a central symptom of psychotic disorders, are attributed to excessive dopamine in the brain. However, the neural circuit mechanisms by which dopamine produces hallucinations remain elusive, largely because hallucinations have been challenging to study in model organisms. We developed a task to quantify hallucination-like perception in mice. Hallucination-like percepts, defined as high-confidence false detections, increased after hallucination-related manipulations in mice and correlated with self-reported hallucinations in humans. Hallucination-like percepts were preceded by elevated striatal dopamine levels, could be induced by optogenetic stimulation of mesostriatal dopamine neurons, and could be reversed by the antipsychotic drug haloperidol. These findings reveal a causal role for dopamine-dependent striatal circuits in hallucination-like perception and open new avenues to develop circuit-based treatments for psychotic disorders.

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