Psychoactive and dissociative drugs, such as ketamine, MDMA and methamphetamine, exert powerful psychological effects by inducing profoundly altered brain states. The popularity of these drugs, their psychologically and physiologically addictive nature and their rising prevalence as potential therapeutic agents indicate an urgent need to understand the acute and long-term effects of psychoactive and dissociative drugs on brain-states. A large gap exists however, in our understanding of the circuit mechanisms underlying drug-altered states themselves. To bridge this gap, we seek to elucidate the molecular, circuit and network mechanisms of drug induced cognitive states by taking advantage of the well-defined parahippocampal microcircuit. The neural basis for the representation of space depends, in part, on neural circuits in the parahippocampal cortex, which translate the external environment into an internal map of space that supports spatial navigation and memory. Our preliminary data points to significant effects of ketamine and methamphetamine administration on parahippocampal circuit codes, which are characterized by cells with highly tractable response properties and a clear behavioral relevance. Here, we use a highly interdisciplinary approach that combines in vivo electrophysiology with computational modeling, imaging and behavioral techniques to examine the link between drug-induced neurocognitive effects and the microcircuits of spatial and memory coding. First, we combine in vivo physiological, computational and imaging approaches to elucidate whether the microcircuit effects of ketamine reflect an altered sensory experience or a change in the internal computations that generate spatial maps. Next, we use high-density in vivo electrophysiology and behavioral paradigms to determine the circuit and network mechanisms for encoding psychoactive drug associated goals, spatial cues and relapse triggers. Finally, in vivo electrophysiology is combined with frame-projected independent-fiber photometry to parse out the circuit basis of MDMA?s pro-social effects. Combined, these studies will provide important insights into the circuit underpinnings of drug-induced states by leveraging our understanding of the neural codes in a high-order cortical region crucial to the cognitive processes of memory and self-localization.
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