Characterization of the 3D Structure of Chromatin in D1 and D2 Medium Spiny Neurons of the Nucleus Accumbens

The 3D structure of chromatin is tightly regulated in concert with cell differentiation during development and with epigenetic regulation of gene expression throughout life. Despite extensive characterization at the transcriptional and epigenetic levels of D1-type and D2-type medium spiny neurons (MSNs) in the nucleus accumbens (NAc) – the ventral portion of the striatum important for reward – a 3D map of chromatin structure in these two neuronal cell types is lacking. Here, we provide a high-density map of chromatin structure from male mice in D1 and D2 MSNs including chromatin loops, topological associating domains (TADs), sub-TADs, and compartments. The data suggest broad convergence in overall 3D chromatin structure between these two closely aligned cell types, but also clear differences consistent with transcriptional divergence previously demonstrated for the two MSN types. We also demonstrate that various exposures to cocaine (acute, chronic, or chronic + acute) – which dramatically alter transcriptional patterns in NAc MSNs – produce far more subtle changes in 3D chromatin structure. Thus, while the 3D structure of chromatin in NAc MSNs appears to be an important concomitant of cell type, it is not broadly leveraged by cocaine to mediate changes in gene expression that contribute to a state of addiction. Significance Statement D1-type and D2-type subtypes of medium spiny neurons are present in the nucleus accumbens and perform different roles in drug addiction. This study maps the genome-wide 3D structure of chromatin in the neuronal subtypes and examines how chronic cocaine exposure alters the chromatin landscape of D1 and D2 MSNs.