PROJECT SUMMARY Olfactory hallucinations occur in many disorders, including Parkinson’s disease, epilepsy, schizophrenia, and migraines, but the neural mechanisms underlying these hallucinations are unknown. Mice have a powerful olfactory system that is well-studied at the molecular, systems, and behavioral levels. Importantly, hallucinogens such as LSD, psilocybin, and DOI primarily act on serotonin pathways, which feed heavily into the mouse olfactory system. The proposed research will determine the behavioral changes in olfactory-driven behaviors and identify the impact on neural activity in the olfactory bulb. Mechanistic studies of hallucination in animal models are fundamentally limited, since other animals do not verbalize what they perceive. However, in lieu of a verbal report, internal states can be inferred from an animal’s externally observable behavior. Using machine-learning tools, our lab has shown that a mouse’s behavioral states can be inferred from close analysis of sniffing and movement. In this project, we will investigate the mouse hallucinogen response using high resolution behavioral analysis and neuronal ensemble recordings in the olfactory bulb. We hypothesize that hallucinogens will impact olfactory perceptual reports and strategic sniffing behavior. Further, we hypothesize that the neural activity in the olfactory bulb will resemble odor-evoked activity in the absence of odor after hallucinogen administration. To address our hypothesis about perceptual reports, in aim 1 we will train freely-moving mice on a two- alternative choice task to locate the source of an odor while recording movement and sniffing. After the mice are trained, we will administer DOI or saline. Our hypothesis predicts that DOI will induce false alarms, decrease accuracy, and decrease confidence in the presence of an odor stimulus. To address our hypothesis about neural activity, in aim 2 we will record movement, sniffing, and neural activity in the olfactory bulb during spontaneous, uninstructed, freely-moving behavior. We will test the prediction that hallucinogen administration alters the neural dynamics of the olfactory bulb to resemble odor-evoked activity in the absence of an odor stimulus. Completion of this proposal will provide insight into the behavior and neural circuitry of olfaction and help inform treatment and policy on the use of hallucinogens to treat various disorders.

PROJECT NARRATIVE Olfactory hallucinations can be symptomatic of various psychiatric or neurological disorders, including schizophrenia, Parkinson’s disease, epilepsy, and migraines. This project will determine olfactory-based behavioral and neural changes induced by hallucinogens in mice. These studies will further our understanding of sensory processing during perceptual disturbances, a necessary component for the advancement of diagnosis and treatment of several disorders.