HDAC3 Activity within the Nucleus Accumbens Regulates Cocaine-Induced Plasticity and Behavior in a Cell-Type-Specific Manner

Abstract

Epigenetic mechanisms regulate processes of neuroplasticity critical to cocaine-induced behaviors. This includes the Class I histone deacetylase (HDAC) HDAC3, known to act as a negative regulator of cocaine-associated memory formation within the nucleus accumbens (NAc). Despite this, it remains unknown how cocaine alters HDAC3-dependent mechanisms. Here, we profiled HDAC3 expression and activity in total NAc mouse tissue following cocaine exposure. Although chronic cocaine did not affect expression of Hdac3 within the NAc, chronic cocaine did affect promoter-specific changes in HDAC3 and H4K8Ac occupancy. These changes in promoter occupancy correlated with cocaine-induced changes in expression of plasticity-related genes. To causally determine whether cocaine-induced plasticity is mediated by HDAC3's deacetylase activity, we overexpressed a deacetylase-dead HDAC3 point mutant (HDAC3-Y298H-v5) within the NAc of adult male mice. We found that disrupting HDAC3's enzymatic activity altered selective changes in gene expression and synaptic plasticity following cocaine exposure, despite having no effects on cocaine-induced behaviors. In further assessing HDAC3's role within the NAc, we observed that chronic cocaine increases Hdac3 expression in Drd1 but not Drd2 -cells of the NAc. Moreover, we discovered that HDAC3 acts selectively within D1R cell-types to regulate cocaine-associated memory formation and cocaine-seeking. Overall, these results suggest that cocaine induces cell-type-specific changes in epigenetic mechanisms to promote plasticity important for driving cocaine-related behaviors. SIGNIFICANCE STATEMENT Drugs of abuse alter molecular mechanisms throughout the reward circuitry that can lead to persistent drug-associated behaviors. Epigenetic regulators are critical drivers of drug-induced changes in gene expression. Here, we demonstrate that the activity of an epigenetic enzyme promotes neuroplasticity within the nucleus accumbens (NAc) critical to cocaine action. In addition, we demonstrate that these changes in epigenetic activity drive cocaine-seeking behaviors in a cell-type-specific manner. These findings are key in understanding and targeting cocaine's impact of neural circuitry and behavior.

Epigenetic Targeting of Histone Deacetylases in Diagnostics and Treatment of Depression

“…Brain-specific HDAC4 knockout in mice impaired hippocampus-dependent memory and long-term synaptic plasticity [112]. Chronic cocaine-induced promoter-specific change in HDAC3, which is known as a negative regulator of memory formation, in the NAc and interfering HDAC3 activity restored cocaine-induced synaptic plasticity [113]. In addition, SIRT1 knockout mice also exhibited impaired memory and hippocampal plasticity [72].…”

The Mechanisms and Boundary Conditions of Drug Memory Reconsolidation

“…Acetylation and deacetylation of chromatin is another signaling pathway involved in regulating the formation of drug context-associated memories contributing to addiction-like behaviors (Rogge et al, 2013;Bender and Torregrossa, 2020;Campbell et al, 2021). These processes are regulated by two kinds of functionally similar enzymes.…”

Hippocampal Cannabinoid 1 Receptors Are Modulated Following Cocaine Self-administration in Male Rats

“…In addition, it is important to emphasize that gene-regulatory processes may include multifaceted epigenetic regulations such as histone modifications associated with DNA methylation. Interestingly, a recent study demonstrated that disrupting HDAC3 histone deacetylase activity altered target-specific changes in gene expression and synaptic plasticity in the NAc following cocaine exposure, but had no effect on behavioral responses to cocaine [110]. This provides further evidence for the complexity of epigenetic mechanisms driving cocaine-related behaviors, and emphasize the difficulty of establishing causal relationships with a single set of experiments.…”