Cell Subtype Transcriptional Mechanisms in Cocaine Addiction

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DESCRIPTION (provided by applicant): Currently, there are no viable therapeutic treatments for psychostimulant addiction. Likely, because the mechanism of action of therapeutic candidates on select cell subtypes, in the heterogeneous central nervous system, is unknown. Shedding light on distinct molecular pathway events in distinct cell subtypes, that mediate stimulant addiction, is necessary for development of effective therapeutics. Recent studies demonstrate an imbalance of function and molecules in striatal medium spiny neuron (MSN) subtypes, those enriched in dopamine (DA) D1 vs. D2 receptors, in psychostimulant addiction. Yet, there are no systematic studies examining which synaptic inputs and signaling pathways regulate distinct transcriptional changes in MSN subtypes and how these molecular changes ultimately mediate psychostimulant addiction. We will investigate a transcription factor, early growth response 3 (Egr3), that is regulated by cocaine in a cell-type specific manner in the ventral striatum (nucleus accumbens-NAc) and in turn regulates transcription of key molecular players, in the cocaine addictive phenotype. Egr3 is regulated through dopamine (DA)-D1 and brain derived neurotrophic factor (BDNF)-TrkB signaling pathways. These signaling pathways, in the ventral tegmental area (VTA)-NAc circuit, are critical for mediating behavioral responses to cocaine. We will use optogenetic and pharmacological tools combined with novel cell-type selective transcriptome profiling to investigate how the Egr3 transcription factor pathway is mediated in MSN subtypes through VTA-NAc signaling pathways in cocaine abuse. We will then examine the functional role of the Egr3 transcription factor pathway in MSNs in mediating relapse for cocaine, a hallmark symptom of addiction, using genetic tools to selectively perturb levels of Egr3 or the Egr3 co-repressor, Nab2. Our findings could lead to novel and effective treatment strategies for psychostimulant addiction that target MSN subtypes, which would greatly impact the lives of individuals suffering from this chronic disease.