Role of Dynamic Signaling of NRG3-ErbB4 in the Prefrontal Cortex in Mediating Nicotine Withdrawal Phenotypes

The overarching goal of this proposal was to systemically investigate the region specific, functional role of the Neuregulin Signaling Pathway during nicotine use and
WD. Specifically, we will test the central hypothesis that NRG3/ErbB4 signaling in
the PFC is necessary in mediating neural adaptations triggered by chronic nicotine
use. The Specific Aim was to Determine the PFC-specific contributions of ErbB4 to
nicotine WD related behavioral phenotypes and the molecular alterations induced
during chronic nicotine and WD. I made significant progress toward this aims, including optimizing surgical and behavioral protocols, completing key molecular analyses, and advancing transcriptomic studies.

Our data shows that genetic manipulations of the Neuregulin Signaling Pathway may result in differential behavioral responses to nicotine and WD between males and females, suggesting sex-specific effects of prefrontal NRG3-ErbB4. Additionally, we show that NRG3 expression in the medial PFC is reduced with prefrontal ErbB4 KD during WD, suggesting it is an actionable target for reducing anxiety-like behavior during nicotine WD, likely in a sex-specific manner. NRG3 and ErbB4 are implicated in several psychiatric disorders, notably schizophrenia and nicotine
use disorder. Thus, these findings may lead to valuable insights regarding pharmacological treatment of nicotine use and comorbid psychiatric disorders, accelerating potential for personalized approaches to nicotine dependence by establishing a mechanistic model of gene x drug interaction of the NRG3-ErbB4 pathway.