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 extracellular signal-regulated kinase (ERK) 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 remains 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 3D imaging of neuronal morphology, immunostaining and behavior, was used to disentangle the roles of nuclear calcium in NAc medium-sized spiny neurons (MSN) expressing the dopamine D1 (D1R) or D2 (D2R) receptor on cocaine-evoked responses.

Results: The D1R-mediated potentiation of calcium influx through glutamate N-methyl-D-aspartate receptors (NMDAR), which shapes cocaine effects, also drives nuclear calcium transients. Fiber photometry revealed that cocaine-treated mice display a sustained nuclear calcium increase in NAc D1R-MSN. Disrupting nuclear calcium in D1R-MSN, but not D2R-MSN, blocks cocaine-evoked morphological changes of MSN and gene expression, and blunts cocaine's rewarding effects.

Conclusions: Our study unravels the dynamics and roles of cocaine-induced nuclear calcium signaling increases in D1R-MSN on molecular, cellular and behavioral adaptations to cocaine, and brings a significant breakthrough as it could contribute to the development of innovative strategies with therapeutic potential to alleviate addiction symptoms.