PROJECT SUMMARY Recent years have seen a dramatic increase in the interest of using psychedelics as experimental therapies for drug addition, depression and anxiety disorders. However, psychedelics are also powerful drugs that alter neural functions in the brain. To understand their potential benefits or risks, it is important to determine the neurophysiological effects of psychedelics on neural circuits in vivo. The psychedelic drug lysergic acid diethylamide (LSD) is a classic hallucinogen that can alter perceptual and cognitive functions in humans and animals. This project studies the neurophysiological impacts of LSD on the sensory and memory neural circuits in freely behaving rats. We will focus on a hypothesis that the interactions between the visual cortex and the hippocampus are reduced by LSD, which leads to imprecise spatial representations during active spatial navigation and impaired neural activity reactivations during offline behavior that are important for memory retrieval and consolidation. To test the hypothesis, we will simultaneously record neurons in the hippocampus and the visual cortex while rats under LSD learn or perform a spatial working memory task and while they sleep. We will determine how hippocampal and visual cortical activities and their interactions are altered by LSD during active and immobile behavior and during sleep, how the alterations depend on LSD dosage and the serotonergic 5HT2A receptors, how they are correlated with behavioral task performances, and how they can be augmented or alleviated by manipulating the network oscillations typical of active and offline behavior. This study will reveal the in vivo neurophysiological effects of the psychedelic drug LSD, advance our understanding on how alterations in the sensory and memory circuits may contribute to the psychotic state generated by drugs and in psychiatric disorders such as schizophrenia, and uncover potential risks when psychedelics are explored as novel therapies for drug addiction and mental disorders.

PROJECT NARRATIVE This project studies how the psychedelic drug lysergic acid diethylamide (LSD) alters the neurophysiological functions of the sensory and memory neural circuits inside the living brain. Its outcomes will advance our understanding of how sensory and memory functions are impacted by classic hallucinogens, uncover possible risks when such drugs are explored as potential therapeutics for mental disorders such as depression, anxiety disorders and drug abuse, and provide insights into how hallucinatory symptoms in schizophrenia and other psychiatric disorders may be produced and treated.