Novel Roles for the Activity-Regulated Genes Arc and Npas4 in Stress- and Cocaine-Induced Plasticity

Mood, anxiety, and substance abuse disorders are chronic medical illnesses that contribute significantly to morbidity and mortality worldwide. Currently, these conditions are treated symptomatically using pharmacological and psychotherapeutic approaches; however, the efficacy of these modalities is limited by the dearth of understanding of neurobiological mechanisms underlying mental illness. The high rate of mortality associated with mood, anxiety, and substance abuse disorders is compounded by their shared comorbidity, warranting an investigation into potential shared pathophysiological mechanisms. Studies from human patients and rodent models suggest that these mechanisms may be attributed to disrupted structural and functional plasticity in brain regions involved in mood, reward, and motivation, including the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC). However, the molecules and signaling pathways within these structures that regulate these behaviors, and how they are dysregulated in pathological psychiatric conditions, have yet to be fully identified and characterized. Here, we focus on two key proteins that participate in activity-dependent synaptic plasticity, the neuronal Per Arnt Sim Domain protein 4 (NPAS4) and the activity-regulated cytoskeleton-associated protein (Arc). We utilize a series of ethologically relevant behavioral paradigms to identify Arc and NPAS4 as two important mediators of stress, anxiety, and addiction-related behaviors. Npas4 and Arc, two activity-regulated genes, are robustly induced by stressful, anxiogenic stimuli. Loss of either gene confers an antidepressant and anxiolytic response in mice, and these behavioral phenotypes are mediated by local function of these two proteins in limbic forebrain regions. In a related study, we ask whether loss of Arc influences behavioral responses to cocaine administration. We find that Arc knockout (KO) animals exhibit increased sensitivity to the locomotor activating and rewarding effects of cocaine, and these two phenotypes are associated with a selective increase in synaptic strength in the NAc. Taken together, our results highlight a heretofore-unidentified role for Arc and NPAS4 in stress- and anxiety-like behaviors, as well as Arc in cocaine-related behavioral adaptations. We propose that these two molecules play a vital role in regulating synaptic and behavioral plasticity evoked by exposure to stress and drugs of abuse, likely via experience-dependent synaptic remodeling.