Brain-wide circuits for drug-induced changes to cognition

项目总结（项目二）

PROJECT SUMMARY (Project 2) Dissociative and non-dissociative drugs, such as ketamine, PCP, methamphetamine and morphine, exert powerful psychological effects by inducing profoundly altered brain states. The popularity of these drugs, their psychologically and physiologically addictive nature and the rising prevalence of a subclass of dissociative drugs as potential therapeutic agents indicate an urgent need to understand the acute and long-term effects of these 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 a set of highly tractable response properties of neurons across the multiple brain regions that support spatial cognition. Our focus on spatial cognition is motivated by the shared capability of dissociative and non-dissociative drugs to alter neural representations of space. Dissociative drugs are well documented to induce out-of-body experiences and can impair spatial memory. Non-dissociative drugs of abuse can leverage the spatial memory system to encode drug-context associations, leading to drug-associated contexts serving as a potent trigger for relapse to drug use. However, the brain-wide circuit mechanisms underlying these alterations in spatial cognition, as well as how this impacts behavior, remain incompletely understood. Here, we use cutting-edge large scale in vivo electrophysiology combine with behavioral techniques to examine the link between drug-induced spatial cognitive effects and the microcircuits of spatial and memory coding. First, we perform wide-scale electrophysiology to measure the neural correlates of spatial estimates in multiple cortical and sub-cortical brain regions during navigation to investigate how dissociative and non-dissociative drugs induce changes in spatial cognition. Next, we hone in on particular brain regions of interest in freely moving animals to examine how dissociative and non-dissociative drugs drive changes in the neural correlates of behavior in spatial tasks. Finally, in vivo electrophysiology is combined with genetic and behavioral approaches to parse out the molecular basis of ketamine’s potentially therapeutic versus negative effects on spatial cognition. Together, this work will provide new insight regarding the brain wide-circuit mechanisms for cognitive states associated with drugs of addiction and the behavioral impacts of these drug-induced cognitive states on spatial memory and navigational behavior. .