Departmental Papers (Department of Systems Pharmacology and Translational Therapeutics)

Document Type

Technical Report

Date of this Version

4-27-2016

Publication Source

Journal of Neuroscience

Volume

36

Issue

17

Start Page

4690

Last Page

4697

DOI

10.1523/JNEUROSCI.0013-16.2016

Abstract

Recent studies have implicated epigenetic remodeling in brain reward regions following psychostimulant or stress exposure. It has only recently become possible to target a given type of epigenetic remodeling to a single gene of interest, and to probe the functional relevance of such regulation to neuropsychiatric disease. We sought to examine the role of histone modifications at the murine Cdk5 (cyclin-dependent kinase 5) locus, given growing evidence of Cdk5 expression in nucleus accumbens (NAc) influencing reward-related behaviors. Viral-mediated delivery of engineered zinc finger proteins (ZFP) targeted histone H3 lysine 9/14 acetylation (H3K9/14ac), a transcriptionally active mark, or histone H3 lysine 9 dimethylation (H3K9me2), which is associated with transcriptional repression, specifically to the Cdk5 locus in NAc in vivo. We gound that Cdk5-ZFP transcription factors are sufficient to bidirectionally regulate Cdk5 gene expression via enrichment of their respective histone modifications. We examined the behavioral consequences of this epigenetic remodeling and found that Cdk5-targeted H3K9/14ac increased cocaine-induced locomotor behavior, as well as resilience to social stress. Conversely, Cdk5-targeted H3K9me2 attenuated both cocaine-induced locomotor behavior and conditioned place preference, but had no effect on stress-induced social avoidance behavior. The current study provides evidence for the causal role of Cdk5 epigenetic remodeling in NAc in Cdk5 gene expression and in the control of reward and stress responses. Moreover, these data are especially compelling given that previous work demonstrated opposite behavioral phenotypes compared with those reported here upon Cdk5 overexpression or knockdown, demonstrating the importance of targeted epigenetic remodeling tools for studying more subtle molecular changes that contribute to neuropsychiatric disease.

Copyright/Permission Statement

Originally published in the Journal of Neuroscience © 2016 Society for Neuroscience, but now published Open Access under a Creative Commons Attribution 4.o international License (CC BY 4.0).

Comments

At the time of this publication, Dr. Heller was affiliated with the Icahn School of Medicine at Mount Sinai, but she is now a faculty member of the University of Pennsylvania.

Keywords

Cdk5, epigenetics, zinc finger

 

Date Posted:22 January 2018

This document has been peer reviewed.