Epigenetics and addiction

Abstract

As an individual becomes addicted to a drug of abuse, nerve cells within the brain's reward circuitry adapt at the epigenetic level during the course of repeated drug exposure. These drug-induced epigenetic adaptations mediate enduring changes in brain function which contribute to life-long, drug-related behavioral abnormalities that define addiction. Targeting these epigenetic alterations will enhance our understanding of the biological basis of addiction and might even yield more effective anti-addiction therapies. However, the complexity of the neuroepigenetic landscape makes it difficult to determine which drug-induced epigenetic changes causally contribute to the pathogenic mechanisms of drug addiction. In this review, we highlight the evidence that epigenetic modifications, specifically histone modifications, within key brain reward regions are correlated with addiction. We then discuss the emerging field of locus-specific neuroepigenetic editing, which is a promising method for determining the causal epigenetic molecular mechanisms that drive an addicted state. Such approaches will substantially increase the field's ability to establish the precise epigenetic mechanisms underlying drug addiction, and could lead to novel treatments for addictive disorders.

Figure 1.. Chronic drug use alters the epigenome in reward processing neurons.

Top: In drug naïve conditions, medium spiny neurons (MSNs) within the nucleus accumbens (NAc) receive dopaminergic inputs from the ventral tegmental area (VTA) and glutamatergic inputs from several cortical and thalamic brain regions. These MSNs receive and integrate reward-related signals, and the homeostasis in nuclear epigenome writer and eraser enzymes within these MSNs enable normal reward-processing required for organismal survival. The NAc contains two types of MSNs, D1- and D2-type, named for the dopamine receptor they predominantly express. Only a D1-type MSN is shown. Bottom: Chronic drug use perturbs the balance in writer and eraser enzymes, resulting in a multitude of epigenetic adaptations at specific loci within the MSN nucleus. These adaptations, in conjunction with drug induction of certain transcription factors (e.g., ΔFosB). mediate transcriptional changes at many genes, including those that encode neurotransmitter receptors, cytoskeletal proteins, and ion channels, among many others. The cumulative consequence of these transcriptional adaptations is altered MSN morphology (e.g., increased dendritic spine density is shown) and physiological function in relation to reward processing which underlies behavioral maladaptations that define addiction.

Figure 2.. Neuroepigenetic editing tools.

Such tools are bi-functional constructs that consist of a DNA-binding domain that is designed to target a desired sequence of genomic DNA with high affinity and specificity and an effector moiety that mediates an epigenetic modification proximal to the region of DNA-binding. This results in epigenetic editing restricted to a single genomic locus, the specificity of which must be validated extensively to ensure minimal off-target binding. The most widely used DNA-binding domains are zinc finger proteins (ZFPs) and, more recently, RNA-guided CRISPR/dCas9. Here, we highlight a ZFP-G9a fusion that our group has generated for targeted gene repression in brain (top), as well as a dCas9-CREB fusion for in vivo gene-targeted activation (bottom). Figure modified with permission from reference 44: Hamilton, P. J., Lim, C. J., Nestler, E. J. & Heller, E. A. Neuroepigenetic Editing. Methods in molecular biology 1767, 113-136, doi:10.1007/978-1-4939-7774-1_5 (2018).

Figure 3:. In vivo delivery methods for neurocpigcnctic editing tools.

A summary of the properties of routinely used viral vectors available for delivery of neuroepigenetic editing tools to the brain of awake, behaving animals. While other approaches exist, the vast majority of published work on neuroepigenetic editing in brain cells utilize these viral delivery strategies coupled with stereotaxic surgery. Figure reproduced with permission from reference 44: Hamilton, P. J., Lim, C. J., Nestler, E. J. & Heller, E. A. Neuroepigenetic Editing. Methods in molecular biology 1767, 113-136, doi:10.1007/978-1-4939-7774-1_5 (2018).