Nuclear Calcium Signaling in D₁ Receptor–Expressing Neurons of the Nucleus Accumbens Regulates Molecular, Cellular, and Behavioral Adaptations to Cocaine

Background: The persistence of cocaine-evoked adaptations relies on gene regulations within the reward circuit, especially in the ventral striatum (i.e., nucleus accumbens [NAc]). Notably, activation of the ERK (extracellular signal-regulated kinase) pathway in the striatum is known to trigger a transcriptional program shaping long-term responses to cocaine. Nuclear calcium signaling has also been shown to control multiple forms of transcription-dependent neuroadaptations, but the dynamics and roles of striatal nuclear calcium signaling in preclinical models of addiction remain unknown. Methods: A genetically encoded cell type–specific nuclear calcium probe has been developed to monitor calcium dynamics in the nuclei of striatal neurons, including in freely moving mice. A cell type–specific inhibitor of nuclear calcium signaling combined with 3-dimensional imaging of neuronal morphology, immunostaining, and behavior was used to disentangle the roles of nuclear calcium in NAc medium spiny neurons (MSNs) expressing the dopamine D₁ receptor (D1R) or D₂ receptor (D2R) on cocaine-evoked responses. Results: The D1R-mediated potentiation of calcium influx through glutamate NMDA receptors, which shapes cocaine effects, also drives nuclear calcium transients. Fiber photometry revealed that cocaine-treated mice showed a sustained nuclear calcium increase in NAc D1R-MSNs. Disrupting nuclear calcium in D1R-MSNs, but not D2R-MSNs, blocked cocaine-evoked morphological changes of MSNs and gene expression and blunted cocaine's rewarding effects. Conclusions: Our study unravels the dynamics and roles of cocaine-induced nuclear calcium signaling increases in D1R-MSNs on molecular, cellular, and behavioral adaptations to cocaine and represents a significant breakthrough because it could contribute to the development of innovative strategies with therapeutic potential to alleviate addiction symptoms.