This R01 grant is aimed at better understanding the molecular mechanisms by which chronic exposure to drugs of abuse induces long-lasting changes in the brain's reward circuits that contribute to the complex behavioral abnormalities that define an addicted state. Our work focuses on the transcription factor, FosB, which is induced in the nucleus accumbens (NAc) and other key brain reward regions in response to chronic administration of virtually all drugs of abuse. FosB is unique in that it accumulates to appreciable levels only after chronic drug exposure and, because of its unusual stability, persists for weeks-months of withdrawal. FosB is thus one mechanism by which chronic drug exposure can drive long-lasting changes in gene expression that contribute to addiction. Indeed, considerable evidence supports the view that induction of FosB in NAc mediates a state of heightened reward and motivation that could contribute to aspects of the addiction process. In this competitive renewal, we will characterize the precise mechanisms through which FosB exerts these actions. Using state-of-the-art genome-wide chromatin assays, we will identify the genes in the NAc that are direct targets for FosB in the context of cocaine and opiate administration. Such genes, in turn, provide novel insight into the molecular and cellular basis of drug-induced neural and behavioral plasticity. Interestingly, when FosB binds to its target genes, it can either activate or repress them. Our hypothesis is that such activation vs. repressive actions are determined by the chromatin milieu of the affected gene. As well, despite the fact that cocaine and opiates induce FosB in the same subtype of NAc neuron, partially non-overlapping genes are regulated by FosB in response to the two drugs. Once again, our hypothesis is that this specificity is mediated by differences in other chromatin changes that cocaine and opiates induce at specific genes. In addition to exploring FosB's regulation of target genes, we will also characterize several mechanisms that are crucial in determining the amount and activity of FosB induced in the NAc. Together, these studies will identify many novel actions of drugs of abuse which can be exploited for the development of improved diagnostic tests and treatments for addiction.

Public Health Relevance

We believe that the best way to ultimately develop improved diagnostic tests and treatments for drug addiction is through a better understanding of the basic biological mechanisms involved. This R01 grant renewal will contribute importantly to this goal by defining many novel genes and proteins, and therefore novel biochemical pathways and neural mechanisms, involved in the addiction process.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DA007359-26
Application #
8663202
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Pollock, Jonathan D
Project Start
1991-08-01
Project End
2016-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
26
Fiscal Year
2014
Total Cost
$514,907
Indirect Cost
$211,127
Name
Icahn School of Medicine at Mount Sinai
Department
Neurosciences
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Yin, Zhou; Machius, Mischa; Nestler, Eric J et al. (2017) Activator Protein-1: redox switch controlling structure and DNA-binding. Nucleic Acids Res 45:11425-11436
Engmann, Olivia; Labonté, Benoit; Mitchell, Amanda et al. (2017) Cocaine-Induced Chromatin Modifications Associate With Increased Expression and Three-Dimensional Looping of Auts2. Biol Psychiatry 82:794-805
Cahill, M E; Walker, D M; Gancarz, A M et al. (2017) The dendritic spine morphogenic effects of repeated cocaine use occur through the regulation of serum response factor signaling. Mol Psychiatry :
Yu, Jun; Yan, Yijin; Li, King-Lun et al. (2017) Nucleus accumbens feedforward inhibition circuit promotes cocaine self-administration. Proc Natl Acad Sci U S A 114:E8750-E8759
Ribeiro, Efrain A; Scarpa, Joseph R; Garamszegi, Susanna P et al. (2017) Gene Network Dysregulation in Dorsolateral Prefrontal Cortex Neurons of Humans with Cocaine Use Disorder. Sci Rep 7:5412
Dash, Sabyasachi; Balasubramaniam, Muthukumar; Rana, Tanu et al. (2017) Poly (ADP-Ribose) Polymerase-1 (PARP-1) Induction by Cocaine Is Post-Transcriptionally Regulated by miR-125b. eNeuro 4:
Kiraly, Drew D; Walker, Deena M; Calipari, Erin S et al. (2016) Alterations of the Host Microbiome Affect Behavioral Responses to Cocaine. Sci Rep 6:35455
Heller, Elizabeth A; Hamilton, Peter J; Burek, Dominika D et al. (2016) Targeted Epigenetic Remodeling of the Cdk5 Gene in Nucleus Accumbens Regulates Cocaine- and Stress-Evoked Behavior. J Neurosci 36:4690-7
Wang, Tianyuan; Santos, Janine H; Feng, Jian et al. (2016) A Novel Analytical Strategy to Identify Fusion Transcripts between Repetitive Elements and Protein Coding-Exons Using RNA-Seq. PLoS One 11:e0159028
McHenry, Jenna A; Robison, Christopher L; Bell, Genevieve A et al. (2016) The role of ?fosB in the medial preoptic area: Differential effects of mating and cocaine history. Behav Neurosci 130:469-78

Showing the most recent 10 out of 84 publications