Striatal dopamine dynamics across temporal scales in brain-specific Atp2a2 heterozygous knockout mice during reward conditioning

Abstract

Dysregulated dopamine signaling is implicated in schizophrenia and mood disorders, yet how disease-associated genes alter dopamine dynamics during behavior remains poorly understood. ATP2A2 encodes sarco/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2), a regulator of intracellular Ca2+ homeostasis, and has been associated with psychiatric vulnerability. Brain-specific Atp2a2 heterozygous conditional knockout (het-cKO) mice exhibit behavioral abnormalities and elevated extracellular dopamine in the nucleus accumbens (NAc) with microdialysis, but it lacks the temporal resolution to resolve rapid, context-dependent dopamine dynamics. Here, we used dual-site fiber photometry with the genetically encoded dopamine sensor dLight1.2 to monitor dopamine signals simultaneously in the NAc and tail of the striatum (TS) during classical reward conditioning. Control and het-cKO mice acquired task-related licking comparably. Nevertheless, het-cKO mice showed enhanced NAc reward-evoked dopamine responses in the pooled analysis, with indications of more frequent and longer-lasting spontaneous transients. Responses to unexpected reward omission were larger in het-cKO mice in both regions during the early phase, but they were not detected after further training. Notably, late-phase suppression of reward-predictive NAc dopamine responses by a preceding aversive outcome persisted in het-cKO mice, although evidence for genotype dependence was inconclusive. Regional dopamine transporter (DAT) protein expression showed no clear genotype differences. These findings identify context-dependent alterations in dopamine signaling across multiple temporal scales and striatal regions in brain-specific Atp2a2 haploinsufficiency, highlighting intracellular Ca2+ regulation and dopamine release as priorities for direct investigation. These results may help clarify the biological links between ATP2A2 haploinsufficiency and neuropsychiatric dysfunction.