Drugs of abuse induce changes in gene expression that are integral for long-term changes in plasticity that underlie addiction-related behaviors. Researches have often assessed the specific genes that undergo aberrant expression profiles during drug use. However, there are many factors that regulate these gene expression profiles. Transcription is a tightly regulated process that involves DNA, transcription factors, epigenetic mechanisms and the transcriptional machinery. Access to DNA is a factor that regulates gene expression necessary cell function. DNA is wrapped around a histone octamer to form a nucleosome. The nucleosome is then further compacted to form chromatin. The role of epigenetic mechanisms in the regulation these multiple levels of compaction has led researchers to examine ways in which these mechanisms modulate transcription necessary for drug-associated behaviors. The epigenetic mechanism that is most prominent in the literature is histone modification. Histone modification refers to the post-translational modifications (acetylation, phosphorylation, methylation etc.) that can be made to the tails of histone. These modifications regulate gene expression by loosening or tightening the interaction between DNA and histones as well as providing recruitment signals for non-histone proteins involved in transcriptional regulation. Histone modification has been shown to be involved in regulating gene expression specifically required for synaptic plasticity and ultimately drug-associated behaviors. In addition, the entire nucleosome can be repositioned through an ATP-dependent process called nucleosome remodeling. Nucleosome remodelers are multi-subunit complexes that use the energy generated from ATP hydrolysis to disrupt the interaction between nucleosome and DNA to move, eject or exchange nucleosomes to facilitate gene expression. Histone modifying enzymes and nucleosome remodelers act in concert to regulate gene expression necessary for cellular function. To date, no study has explored the role of nucleosome remodeling in drug-associated behaviors. The discovery of a neuron-specific nucleosome remodeling complex (nBAF) has led to inroads in understanding of molecular mechanisms that subserve long-term changes in behavior. nBAF has a neuron-specific subunit, BAF53b, that is not found in any other nucleosome remodeler. This dedicated subunit has been shown to be necessary for gene expression required for activity-dependent dendritic outgrowth, synapse formation, dendritic arborization and axonal development. Important, BAF53b has been shown to be critical for gene expression required during long-term memory formation and synaptic plasticity. This research proposal is to understand the role of nBAF, specifically the BAF53b subunit, on cocaine-associated behaviors and memories (Aim 1 and 2) through altered gene expression (Aim 3). Findings from this proposal could provide the first evidence for a novel epigenetic mechanism in drug addiction as well as provide new targets for pharmacological intervention
Cocaine addiction is a prevailing neurobiological disorder affecting nearly 1.4 million Americans. Cocaine is known to cause stable changes in neuronal function leading to long-term alterations in behavior related to drug-seeking and drug-taking, however, the molecular mechanisms underlying the stable changes in neuronal function remain unclear. This research proposal will examine a novel epigenetic mechanism called nucleosome remodeling and its role in mediating cocaine-induced behaviors.
| López, Alberto J; Kramár, Enikö; Matheos, Dina P et al. (2016) Promoter-Specific Effects of DREADD Modulation on Hippocampal Synaptic Plasticity and Memory Formation. J Neurosci 36:3588-99 |
| White, André O; Kramár, Enikö A; López, Alberto J et al. (2016) BDNF rescues BAF53b-dependent synaptic plasticity and cocaine-associated memory in the nucleus accumbens. Nat Commun 7:11725 |
