SPECIFIC AIMS External and internal cues associated with the drug use environment often develop into persistent and powerful triggers for relapse to drug seeking. Many studies have reported that epigenetic enzymes, like histone deacetylases (HDACs), that alter chromatin structure and influence gene expression play an important role in addiction-relevant behaviors in animal models. In the previous grant period, we showed that the class IIa HDACs, HDAC5, plays important roles in the regulation of multiple cocaine-induced behaviors, including drug related learning and memory. The HDAC5 target gene, Npas4, emerged as an important, novel transcription factor required in the adult NAc for cocaine conditioned place preference and operant drug discrimination learning in the mouse intravenous self-administration. Our preliminary findings indicate that NPAS4 is induced in DARPP-32-positive medium spiny neurons (MSNs) and parvalbumin-positive fast spiking interneurons (PV- FSIs), but the relevant population(s) in which NPAS4 regulates drug behaviors remains unknown. Our long-term goal is to understand the role and regulation of NPAS4 in the development and/or persistence of drug addiction-related behaviors. Our central hypothesis is that NPAS4 induction within one or more subpopulations of activated NAc neurons promotes glutamatergic synaptic plasticity events that underlie long-lasting drug context/cue learning and memory. We will employ a series of multi-disciplinary, hypothesis testing experiments and cutting-edge molecular genetic approaches that will interrogate the in vivo cell type- specific role and regulation of NPAS4 and NPAS4-expressing cells in the NAc for drug addiction-related learning and memory. We will test and refine our central hypothesis with the following specific aims:
Specific Aim 1 : Determine the cell-type specific roles for NPAS4 during acquisition and extinction of drug self-administration. In this aim, we will take a cell-type specific loss- and gain-of-function approaches to study the function of NPAS4 during operant discrimination and extinction learning in the mouse drug self- administration assay.
Specific Aim 2 : Determine whether NPAS4-positive NAc neurons define a functional ?engram? population linking external cues to drug reward and seeking. Using our newly developed Npas4 enhancer-driven, tamoxifen-dependent cre virus, we will use a chemogenetic approach to manipulate the activity of the NPAS4-positive population and test its role in durg taking and seeking behaviors.
Specific Aim 3 : Determine the cellular function of NPAS4 in the NAc during drug SA. We will use cell- type specific loss- and gain-of-function strategies to evaluate the effects of NPAS4 on excitatory ad inhibitory synapse plasticity in mice self-administering cocaine or heroin.

Public Health Relevance

A major challenge for treating drug addiction is the poor understanding of the molecular mechanisms by which opiates and psychostimulants produce long-lasting vulnerability to relapse, even after long periods of drug abstinence. Understanding how epigenetically-regulated plasticity genes regulate relapse vulnerability could reveal new therapeutic targets for treating drug addicts.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA032708-06
Application #
9594293
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Satterlee, John S
Project Start
2013-07-01
Project End
2023-05-31
Budget Start
2018-07-15
Budget End
2019-05-31
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Medical University of South Carolina
Department
Neurosciences
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29403
Anderson, Ethan M; Sun, Haosheng; Guzman, Daniel et al. (2018) Knockdown of the histone di-methyltransferase G9a in nucleus accumbens shell decreases cocaine self-administration, stress-induced reinstatement, and anxiety. Neuropsychopharmacology :
Li, Xuan; Carreria, Maria B; Witonsky, Kailyn R et al. (2018) Role of Dorsal Striatum Histone Deacetylase 5 in Incubation of Methamphetamine Craving. Biol Psychiatry 84:213-222
Guzman, Daniel; Carreira, Maria B; Friedman, Allyson K et al. (2018) Inactivation of NMDA Receptors in the Ventral Tegmental Area during Cocaine Self-Administration Prevents GluA1 Upregulation but with Paradoxical Increases in Cocaine-Seeking Behavior. J Neurosci 38:575-585
Taniguchi, Makoto; Carreira, Maria B; Cooper, Yonatan A et al. (2017) HDAC5 and Its Target Gene, Npas4, Function in the Nucleus Accumbens to Regulate Cocaine-Conditioned Behaviors. Neuron 96:130-144.e6
Smith, Laura N; Penrod, Rachel D; Taniguchi, Makoto et al. (2016) Assessment of Cocaine-induced Behavioral Sensitization and Conditioned Place Preference in Mice. J Vis Exp :53107
Penrod, Rachel D; Wells, Audrey M; Carlezon Jr, William A et al. (2015) Use of Adeno-Associated and Herpes Simplex Viral Vectors for In Vivo Neuronal Expression in Mice. Curr Protoc Neurosci 73:4.37.1-31