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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. The study of psychotic disorders in animal models is difficult because the diagnosis is based on self-reported symptoms that can only be assessed in humans. Schmack et al. has developed a paradigm to rigorously probe and measure experimentally controlled hallucinations in rodents (see Matamales Perspective). Using measurements from dopamine sensors and circuit and pharmacological manipulations, they demonstrated a brain circuit link between excessive dopamine and a hallucination-like experience. This could potentially be useful as a translational model of common psychotic symptoms described in various psychiatric disorders. It can also help in the development of new therapeutic approaches based on the anatomically selective modulation of dopaminergic function.
Science, this issue p. eabf4740; see also p. 33
Structured summary
INTRODUCTION
Psychotic disorders such as schizophrenia impose enormous human, social and economic burdens. The prognosis for psychotic disorders has not improved significantly over the past decades as our understanding of the underlying neurobiology has remained stagnant. Indeed, the subjective nature of hallucinations, a defining symptom of psychosis, presents a lasting challenge for their rigorous study in humans and their translation into 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.
REASONING
Hallucinations are false percepts that are experienced with the same subjective confidence as “true” percepts. Similar false percepts can be quantitatively assessed using a sensory detection task in which individuals report whether they have heard a signal embedded in background noise and indicate how confident they are of their response. Thus, we have defined hallucination-type percepts as safe false alarms, that is, incorrect reports indicating that a signal was present, which are reported with great confidence. We thought that such experimentally controlled hallucination-like percepts engage neural mechanisms shared with hallucinations spontaneously experienced in psychosis and therefore may serve as a translational model of psychotic symptoms. Since psychotic symptoms are believed to involve increased transmission of dopamine in the striatum, we hypothesized that hallucination-like perception is mediated by an increase in striatal dopamine.
RESULTS
We have implemented similar auditory detection tasks for humans and mice. 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 the two buttons to signal whether or not they heard a signal, while mice pushed into one of two ports of choice. Humans indicated how confident they were in their report by placing a cursor over a slider; the mice expressed their confidence by investing varying amounts of time 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 perceptions were increased with two manipulations known to induce hallucinations in humans: administration of ketamine and increased waiting to hear 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 the onset of the stimulus predicted hallucination-like perception in both the ventral striatum and the tail of the striatum. We have designed a computational model that explains the emergence of hallucination-like percepts as a consequence of erroneous perceptual inference when prior expectations outweigh sensory evidence. Our model clarified how hallucination-like percepts can result from fluctuations in two distinct types of expectations: reward expectations and perceptual expectations. In mice, fluctuations in dopamine in the ventral striatum reflected expectations of reward, while in the tail of the striatum, they resembled perceptual expectations. We optogenetically boosted dopamine in the tail of the striatum and observed that the increase in dopamine induced a hallucination-like perception. This effect was saved by the administration of haloperidol, an antipsychotic drug that blocks dopamine D2 receptors.
CONCLUSION
We established hallucination-like perception as quantitative behavior in mice to model the subjective experience of a cardinal symptom of psychosis. We found that hallucination-like perception is mediated by elevations of dopamine in the striatum and that this can be explained by encoding different types of expectations in separate striatal subregions. These results support the idea that hallucinations arise as erroneous perceptual inferences due to high dopamine producing a bias in favor of past expectations over current sensory evidence. Our results also provide circuit-level information on the long-held 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 new treatments for schizophrenia and other psychotic disorders.
In humans and mice, a computational-behavioral task models hallucinations as false percepts of high confidence. 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 excess dopamine in the brain. However, the neural circuit mechanisms by which dopamine produces hallucinations remain elusive, in large part because hallucinations have been difficult to study in model organisms. We have developed a task to quantify hallucination-like perception in mice. Hallucination-like percepts, defined as high confidence false detections, increased after manipulations related to hallucinations in mice and correlated with self-reported hallucinations in humans. Hallucination-like percepts were preceded by high levels of striatal dopamine, could be induced by optogenetic stimulation of mesostriatal dopaminergic neurons, and could be reversed by the antipsychotic drug haloperidol. These results reveal a causal role of striatal dopaminergic circuits in hallucinatory-type perception and open up new avenues for developing circuit-based treatments for psychotic disorders.
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