From synapse to function: cocaine-induced cell-type- and circuit-specific accumbal proteome changes

Icahn School Of Medicine At Mount Sinai, New York NY

Investigators

Abstract

Projection Summary/Abstract Substance use disorders remain a major public health issue in the US and have proven exceptionally difficult to treat due to their complex neurobiological underpinnings. Dysregulated signaling within the nucleus accumbens (NAc) appears to play a critical role in promoting drug-seeking and relapse. Compared to our understanding of transcriptional responses to drugs of abuse, little is known about the adaptation in the proteomic landscape of synapses, especially in cell-type- and circuit-specific manners. Such proteomic adaptations are likely to drive reciprocal interactions between drug-induced transcriptional responses and synaptic dysfunction, thereby perpetuating the “addiction cycle.” In my career, I will build an independent research program that investigates the interplay between drug-induced long-term synaptic proteomic adaptations and the underlying transcriptional responses that drive these adaptations in a cell-type- and circuit-specific manner within the brain’s reward regions. This proposal will elucidate the synaptic proteome changes in NAc medium spiny neurons (MSNs) in response to cocaine with unprecedented cellular and circuit specificity. It will then genetically manipulate a synaptic target to explore its role in cocaine addiction behaviors such as craving and relapse, with the aim of eventually developing new treatments for substance use disorders. Under the mentorship of Drs. Eric Nestler, Paul Kenny, and Li Shen, I will behaviorally (cocaine self-administration), cellularly/molecularly (CRISPR), and bioinformatically determine and characterize the cocaine-induced cell-type- and circuit-specific synaptic proteome changes in NAc. Experiments proposed in Aims 1 and 2 will also prepare me to examine cocaine- induced synaptic proteome changes in a circuit-specific manner (mPFC-NAc) in Aim 3 of this award. The expertise gained from completing these proposed studies, in concert with my strong background in neuroproteomics and neuropharmacology, will lay the groundwork for my independent laboratory, focusing on drug-induced synaptic proteomic adaptations and transcriptional responses across reward brain regions with specificity to drug-type, cell-type, and circuit. By addressing gaps in our understanding of cocaine-induced synaptic proteomic adaptations and their functional implications in drug-seeking and relapse behaviors, this research aims to advance targeted therapeutic strategies for cocaine addiction.