6:05pm - 7:05pm
Towards a Neural Circuit Basis for Hallucinations: Striatal Dopamine Mediates Hallucination‐Like Perception in Mice
Hallucinations are the defining characteristic of many psychedelic drugs and hallmark of psychotic conditions such as schizophrenia. However, the subjective nature of hallucinations 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. 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. We defined hallucination‐like percepts as false detections in the absence of a signal perceived with high confidence. In humans, hallucination‐like percepts correlated with self‐reported hallucinations, as quantified by a self‐report questionnaire. In mice, hallucination‐like percepts increased after administering ketamine or inducing sensory expectations. Using fiber photometry and genetically encoded dopamine sensors, we found that elevations in dopamine levels in the striatum predicted hallucination‐like perception. We devised a computational model that explains the emergence of hallucination‐like percepts as faulty perceptual inference when prior expectations outweigh sensory evidence. Hallucination‐like percepts could be induced by optogenetic stimulation of meso‐striatal 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. Our cross‐species approach provides a rigorous framework for dissecting the neural circuit mechanisms involved in hallucinations.