Circadian rhythm disruptions are prominent in individuals with psychiatric disorders including addiction and mood disorders. Furthermore, rhythm and sleep-related problems increase the vulnerability for substance abuse and contribute to relapse long after an individual stops abusing drugs. However, the molecular mechanisms by which circadian gene disruption leads to changes in reward value for drugs of abuse has remained unclear. Studies from our lab and others have found that the genes that make up the molecular clock regulate mood and reward related-behavior via direct regulation of gene expression in the ventral tegmental area (VTA)- nucleus accumbens (NAc) dopaminergic reward circuit. CLOCK and NPAS2 are two of the central regulators of molecular rhythms and they are very similar in structure and function. However, while Clock mutant mice have an increase in preference for cocaine, NPAS2 mutant mice have a decreased preference. CLOCK is expressed in both the VTA and NAc while NPAS2 is not expressed in the VTA, and we have recently found that its expression in the NAc is almost exclusively in neurons expressing D1 dopamine receptors. We have also found that local knock-down of NPAS2 in the NAc is sufficient to reduce cocaine preference. Here we will focus on the role of NPAS2 in D1 neurons of the NAc. Our goal in this proposal is to connect the dots between NPAS2 regulated genes, neuronal excitability and addiction-related behavior. We will identify direct transcriptional targes of NPAS2 specifically in D1 neurons and determine their patterns in gene expression. We are particularly interested in genes that are important in regulating neuronal activity. We will also determine how a knock-down of NPAS2 in D1 neurons impacts mEPSCs and AMPA/NMDA ratios in these neurons. These are important indicators of neuronal activity which are involved in the responses to drugs of abuse. Finally, we will determine the role of NPAS2 selectively in D1 neurons in the NAc in reward-related behavior and cocaine self-administration. This gene to physiology to behavior approach will lead us to defined mechanisms that underlie the vulnerability for addiction and help us to develop targeted treatments for the future.
Substance abuse disorders are devastating diseases and there are very few treatments available. This proposal will help uncover the molecular mechanisms in reward-related brain circuits that regulate drug reward and help determine the optimal targets for future therapeutic treatments.
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