UC Irvine

Epigenetic mechanisms regulate critical processes of neuroplasticity that drive cocaine- seeking. Previous work from our lab identified the class I histone deacetylase (HDAC) HDAC3 acts as a negative regulator of cocaine-associated memory formation in the nucleus accumbens (NAc). However, it remains unknown whether this occurs via HDAC3’s deacetylase function. It also unclear whether HDAC3 regulates cocaine-induced in a cell-type specific manner within the NAc. Cocaine induces distinct changes in the two major cell populations of the NAc (D1R- and D2R-medium spiny neurons) and activation of these cell types drive opposing behavioral responses to cocaine. In the present dissertation, we investigated whether HDAC3’s deacetylase activity acts in a cell-type specific manner within the NAc to regulate behavioral responses to cocaine. In these experiments, we demonstrate that HDAC3’s deacetylase activity drives molecular and cellular mechanisms of plasticity within the NAc. In addition, we show how HDAC3’s activity within D1R-MSNs, not D2R-MSNs, affects cocaine-associated memory formation and cocaine seeking behaviors. We also demonstrate how HDAC3 regulates histone acetylation to drive changes in gene expression and synaptic plasticity within D1R-MSNs. Overall, this work illustrates how cocaine disrupts HDAC3-dependent mechanisms in a cell-type specific manner to drive cocaine-seeking behaviors.