Estradiol signaling pathways mediating sex differences in striatal synaptic plasticity

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Substance use disorders affect ~15% of the population, with gender differences in all stages of substance use. Female sex-steroid hormones explain some of the disparity, such as accelerated transition from casual use to addiction, as estradiol produces sex-specific differences in rodent learning and cocaine self-administration. Prolonged cocaine use is known to engage dorsal striatal circuits. Synaptic plasticity in such circuits is critical for a variety of types of reward learning, highlighting the potential role such plasticity could play in substance use disorders. Thus, understanding sex differences in cocaine use requires determining how estradiol impacts molecular signaling and synaptic plasticity in the dorsal striatum. Our preliminary results show that estradiol, acting at estradiol receptor type α, impairs long term potentiation (LTP) in dorsomedial striatum (DMS) in estrous females; however, the cell type in which estradiol acts has yet to be identified. Striatal spiny projection neurons (SPNs) are either direct pathway SPNs, which promote action, or indirect pathway SPNs, which inhibit action, and changes in these SPNs are critical for various behavioral consequences. Thus, it is essential to understand LTP deficits in both direct and indirect pathway SPNs. In this proposal, we will test the hypothesis that estradiol impairs LTP in indirect pathway SPNs in the DMS. LTP in the dorsal striatum critically depends on activation of extracellular regulated kinase (ERK), which also is modified by both cocaine and estradiol. Estradiol enhances cocaine-mediated dopamine release and interacts with metabotropic glutamate receptors to modify ERK activation, but an unbiased approach is needed to determine whether estradiol impacts other signaling pathways. Our preliminary results have identified several signaling pathways that are modified by estradiol; however, a critical question is how cocaine interacts with estradiol to modulate these signaling pathways. We propose cutting-edge molecular and transgenic approaches combined with novel computational modeling to test the hypothesis that estradiol-mediated changes in gene expression impair LTP and to determine how cocaine further modifies the signaling pathways underlying synaptic plasticity. In Specific Aim 1, we perform electrophysiology in transgenic mice to determine whether LTP is impaired by estradiol in one or both SPNs. In Specific Aim 2, we use innovative techniques of single nuclei RNA sequencing, translating ribosome affinity purification followed by RNA sequencing and spatial transcriptomics to identify signaling pathways modified by estradiol and cocaine self-administration in a cell-type specific and spatial manner. In Specific Aim 3, we use innovative, data-driven modeling of signaling pathways followed by model-driven experiments to causally test which interactions between critical signaling pathways produce estradiol-mediated deficits in LTP. Successful completion of the proposed research will delineate how estradiol influences synaptic plasticity in dorsal striatum, including in conjunction with cocaine, and provide a foundation for future work to understand sex differences in reward learning and the consequences of cocaine use.