A novel role for E2F3b in regulating cocaine action in the prefrontal cortex

Abstract

Drug abuse is a multifaceted disorder that involves maladaptive decision making. Long-lasting changes in the addicted brain are mediated by a complex circuit of brain reward regions. The prefrontal cortex (PFC) is one region in which chronic drug exposure changes expression and function of upstream transcriptional regulators to alter drug responses and aspects of the addicted phenotype. We reported recently that the transcription factor E2F3a is a critical mediator of cocaine responses in the nucleus accumbens. E2F3a is one of two splice variants of the E2f3 gene; the other is E2F3b. Another recent study predicted E2F3 as an upstream regulator of the transcriptional response to cocaine self-administration (SA) in PFC. Based on previous findings that E2F3a and E2F3b have divergent regulatory roles, we set out to study the putative transcriptional role of these transcripts in PFC in the context of repeated I.P. cocaine exposure. We implemented viral-mediated isoform-specific gene manipulation, RNA-sequencing, advanced bioinformatics analyses, and animal behavior to determine how E2F3a and E2F3b contribute to persistent cocaine-induced transcriptional changes in PFC. We show that E2F3b, but not E2F3a, in PFC is critical for cocaine locomotor and place preference behaviors. Interestingly, RNA-seq of PFC following E2f3b overexpression or I.P. cocaine exposure showed very different effects on expression levels of differentially expressed genes. However, we found that E2F3b drives a similar transcriptomic pattern to that of cocaine SA with overlapping upstream regulators and downstream pathways predicted. These findings reveal a novel transcriptional mechanism in PFC that controls behavioral and molecular responses to cocaine.