Dissecting and modulating cell type and circuit-specific epigenetic mechanisms of cocaine addiction - Abstract: Millions of Americans are current or past cocaine users, with 2% of the US population reporting to have used the drug in the past year. Cocaine is highly addictive, and cocaine addiction is devastating to society and individuals, leading to financial loss, job loss and violence within families. Additionally, cocaine abuse is responsible for 40% of drug-related emergency room visits and 1 in every 5 overdoses. Cocaine acts as a monoamine reuptake inhibitor, preventing the dopamine from being transported back into cells after its synaptic release, which leads to prolonged and enhanced dopamine action. Cocaine use especially affects the limbic system, in particular, nucleus accumbens, as well as hippocampus, the amygdala and the prefrontal cortex, leading to changes in activity and long-term rewiring of the circuitry, which causes cocaine craving and addiction. Previous studies identified the major brain regions associated with cocaine addiction, as well as demonstrating that long-term cell- intrinsic molecular changes, such as in epigenetic signaling, underlie the establishment of cocaine addiction. However, the knowledge of how cell type-specific molecular changes resulting from cocaine use lead to rewiring of circuits relevant to cocaine-seeking behavior is currently limited. Moreover, treatments of cocaine addiction that prevent drug seeking via restoring the normal states of neurons and circuits that are dysregulated as the result of repeated cocaine use are desperately needed. We will utilize mice repeatedly exposed to cocaine in a well-established conditioned place preference paradigm to investigate cell type and circuit-specific epigenetic mechanisms underlying cocaine addiction. Using a combination of a novel approach we developed called inducible barcoded rabies virus with activity-dependent neuronal tagging and single-cell genomics, we propose to identify epigenetic changes in specific limbic system neuronal cell types and circuits active during cocaine- seeking behavior. We will then test the hypothesis that cocaine-seeking behavior can be erased by performing epigenetic editing of hippocampal neurons projecting to the nucleus accumbens that are active during detection of cocaine-conditioned cues. To that end, we will utilize a novel gene editing tool we developed called CRISRP- rabies to modulate epigenetic states of specific neuron types within defined hippocampal-NAc circuits conditioned by cocaine use. We believe that our study will discover conceptually novel mechanisms of cocaine addiction and will build a foundation for new types of therapies of drug addiction by rewiring specific circuits responsible for drug seeking behavior.
