NEURAL SIGNATURES OF PSILOCYBIN-EVOKED HALLUCINATION-LIKE PERCEPTION IN RAT AUDITORY AND MEDIAL PREFRONTAL CORTEX

Hallucinations are perceptual experiences that occur in the absence of corresponding external stimuli, yet their neural origins remain poorly understood, in part due to the difficulty of modeling hallucinations in animals. Here, we developed a behavioral and neural framework to identify hallucination-like perception (HALIP) in rats as high-confidence false alarms during an auditory detection task with explicit confidence reports. We combined this task with the administration of psilocybin, a serotonergic hallucinogen, and electrophysiological single-unit recordings in the primary auditory cortex (A1) or medial prefrontal cortex (mPFC) to identify the neural signatures of psilocybin-induced HALIPs. Rats were chronically implanted with Neuropixels 1.0 or 2.0 probes in A1 or mPFC. After injecting saline (control) or psilocybin (1 mg/kg), we found that psilocybin significantly increased HALIPs without changing low-confidence errors or overall task performance. Computational modeling revealed that psilocybin increased the animals’ reliance on signal priors, thereby driving HALIPs. From >1000 unique recorded units, we quantified tuning to the primary decision variables, signal-to-noise ratio, and signal prior, which together determined choices. Both A1 and mPFC showed encoding for signal-to-noise ratios and signal priors, with A1 showing a higher fraction of tuned neurons and stronger tuning. Neurons were tuned either to evidence alone or jointly to evidence and priors, and a subset of prior-encoding neurons predicted false alarms and HALIPs. Together, our findings offer critical insight into the neural circuit basis of psychedelic-induced hallucinations the neural basis of hallucinations.