Reelin Signaling and Function in Cocaine Response

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Psychostimulant abuse is a public health crisis that affects millions of individuals in the United States and results in profound economic, social, and individual harm. However, despite rapid increases in overdose deaths linked to stimulant drugs like cocaine, there are still no approved therapeutic options for stimulant abuse disorders. Psychostimulant drugs act through well-defined signaling mechanisms to elevate dopaminergic neurotransmission in the nucleus accumbens (NAc), a key reward-linked brain structure that integrates information from diverse brain regions to directly influence motivated behavior. Further, cocaine causes epigenetic and transcriptional reorganization in medium spiny neurons (MSNs) in the NAc, promoting maladaptive shifts in cell signaling and synaptic function. Our preliminary data indicates that expression of Reln mRNA, which codes for the large secreted extracellular matrix protein Reelin, is enriched in a subpopulation of MSNs that are robustly activated by cocaine. Although Reelin knockout animals exhibit impaired response to psychostimulants and Reelin plays a critical role in synaptic plasticity and memory formation in other brain regions, the role of Reelin in cocaine-related cellular and behavioral adaptations has never been studied. In this proposal, we will test the overarching hypothesis that Reelin signaling is required for the maladaptive molecular, physiological, and behavioral effects of cocaine in the NAc. Specific Aim 1 of this proposal will combine bidirectional CRISPR-based manipulations and single-cell RNA sequencing to determine how Reelin signaling impacts transcriptional responses to cocaine and dopamine receptor activation. Specific Aim 2 will use in vitro and in vivo single unit recordings and ex vivo slice electrophysiology to test the hypothesis that Reelin regulates cocaine response by modulation of physiological and synaptic properties of MSNs. Finally, Specific Aim 3 will use cell-specific in vivo Reelin manipulations in combination with behavioral assays of cocaine and natural reward to test the hypothesis that Reelin enhances the behavioral effects of cocaine. Together, these experiments will identify Reelin target genes in the NAc, dissect molecular signaling pathways by which Reelin alters MSN function and physiology, and determine whether Reelin expression within the NAc modulates cocaine-related behavioral plasticity. These studies will reveal fundamental mechanisms by which Reelin contributes to psychostimulant response, and will pave the way for future experiments to explore how this unique Reln-expressing cell population contributes to motivated behavior.