NPAS4 ENHANCER RNA FORMS DNA:RNA HYBRID R-LOOP TO CONTROL REWARD-RELATED BEHAVIORAL ADAPTATION THROUGH ACTIVITY-DEPENDENT GENE EXPRESSION

Abstract Neuronal activation induces immediate early response genes expression, essential for behavioral adaptation to emotional stimuli. Npas4 is rapidly induced by synaptic activity, regulating behavioral responses to cocaine reward conditioning and chronic stress. A novel long non-coding RNA (LncRNA) transcribed from Npas4 enhancer is identified as essential for emotional stimuli-induced Npas4 mRNA expression and formation of cocaine reward-associated context in NAc and chronic stress-induced deficits in sucrose preference in mPFC. Notably, LncRNA forms DNA:RNA hybrid structure R-loop, required for synaptic activity-dependent Npas4 mRNA expression through regulating 3D chromatin loop structure connected between Npas4 promoter and enhancer. The findings highlight an unprecedented mechanism of LncRNA function through the formation of R-loop for 3D chromatin loop structure, providing novel insights into the regulation of synaptic activity-dependent gene expression.