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Striatal dopamine mediates hallucination-like sensations in mice



How to model hallucinations in mice

Our understanding of the basic mechanisms of mental illness has not made enough progress. It is very difficult to study psychotic diseases in animal models because the diagnosis relies on self-reported symptoms that can only be evaluated in humans.Schmark Wait. A paradigm was developed to detect and rigorously measure experimental control hallucinations in rodents (see Perspective by Matamales). By using dopamine sensor measurements and electrical and pharmacological manipulations, they demonstrated the brain circuit connection between excessive dopamine and hallucination-like experiences​​. This may be a translation model of common psychotic symptoms described in various psychoses. It may also contribute to the development of new treatments based on anatomically selective modulation of dopamine function.

science, This question p. eabf4740; see also page 33

Structured abstract

Introduction

Mental diseases such as schizophrenia will bring a huge burden to mankind, society and economy. In the past few decades, the prognosis of psychotic diseases has not improved substantially because our understanding of basic neurobiology has remained stagnant. Indeed, a subjective nature of hallucinations, the defining symptoms of psychosis, rigorously human studies and transforming them into preclinical animal models poses a lasting challenge. Here, we developed a cross-species computational psychiatric method to directly correlate the behavior of humans and rodents, and used this method to study the neural basis of hallucination-like perception in mice.

Justification

An illusion is a false perception that has the same subjective confidence as the “real” perception. The sensory detection task can be used to quantitatively assess similar false perceptions, in which individuals report whether they have heard signals embedded in background noise and show their confidence in the answer. Therefore, we define hallucination-like perceptions as credible false alarms, that is, falsely reporting the presence of signals and reporting them with high confidence. We believe that this experimentally controlled hallucination-like sensation participates in the neural mechanism shared with spontaneous hallucinations in psychosis, and therefore can be used as a transformation model for psychotic symptoms. Since psychotic symptoms are thought to be related to an increase in dopamine transmission in the striatum, we hypothesized that hallucination-like perception is mediated by an increase in dopamine in the striatum.

result

We have established similar auditory detection tasks for humans and mice. In half of the experiments, both humans and mice received auditory stimuli, in which tonal signals were embedded in a noisy background. The human presses one of the two buttons to report whether a signal is heard, and the mouse pokes into one of the two selection ports. People show their confidence in the report by placing the cursor on the slider. Mice expressed their confidence by investing in different durations to get rewards. In humans, hallucination-like perception (high-confidence false alarms) is associated with the tendency to spontaneous hallucinations, which is quantified through self-report questionnaires. In mice, hallucination-like sensations are increased by two operations known to induce hallucinations in humans: the administration of ketamine and the increased expectation of signal hearing. Then, we used a genetically encoded dopamine sensor with fiber photometry to monitor the dopamine dynamics in the striatum. We found that an increase in dopamine levels before the start of the stimulation predicts hallucinations in the ventral striatum and the tail of the striatum. We have designed a computational model that explains the hallucinatory perceptions due to false perceptual inferences when previous expectations exceed sensory evidence. Our model illustrates how the fluctuation of two different types of expectations can produce hallucinations: reward expectations and perceptual expectations. In mice, the dopamine fluctuations in the ventral striatum reflect expectations for reward, while in the tail of the striatum, they resemble sensory expectations. We optogenetics enhance the dopamine in the striatal tail and observe that the increased dopamine causes hallucination-like perceptions. Haloperidol is an antipsychotic drug that blocks D2 dopamine receptors, thereby saving this effect.

in conclusion

We established hallucination-like sensations as quantitative behaviors in mice to simulate the subjective experience of the main symptoms of psychosis. We found that hallucination-like perceptions are mediated by elevated dopamine in the striatum, and this can be explained by encoding different kinds of expectations in different striatal subregions. These findings support the false perceptual inference that hallucinations are due to elevated dopamine levels, resulting in a bias toward previous expectations of current sensory evidence. Our findings also yielded insights into the circuit level of the long-standing psychiatric dopamine hypothesis, and provided a rigorous framework for dissecting the neural circuit mechanisms involved in hallucinations. We suggest that this approach can guide the development of new therapies for schizophrenia and other psychotic diseases.

Hallucination-like perception framework and striatal dopamine.

In humans and mice, computational behavioral tasks model hallucinations as high-confidence false perceptions. In humans, this hallucination is related to self-reported hallucinations. In mice, hallucination-like sensations are mediated by striatal dopamine. Data are mean ± SEM. *P <0.05, **P <0.01.

Abstract

Hallucinations are the main symptom of psychosis and are attributed to too much dopamine in the brain. However, the neural circuit mechanism of dopamine producing hallucinations is still elusive, mainly because hallucinations have been difficult to study in model organisms. We developed a task to quantify hallucination-like sensations in mice. Hallucination-like sensations are defined as high-confidence false detections, which increase after hallucination-related operations in mice, and are related to human self-reported hallucinations. Before hallucinations, striatal dopamine levels are elevated, which can be induced by optogenetic stimulation of interstitial dopamine neurons, and can be reversed by the antipsychotic drug haloperidol. These findings reveal the causal role of the dopamine-dependent striatal circuit in hallucination-like perception, and open up a new way for the development of circuit-based psychosis treatment.


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