Prefrontal circHomer1 regulates synaptic and behavioral adaptations induced by psychostimulants

Abstract

Substance use disorder (SUD) represents a substantial challenge in neuropsychiatric medicine, with the molecular mechanisms underlying its etiology remaining elusive. The molecular underpinnings of SUD suggest a pivotal role for circular RNAs (circRNAs) in its pathophysiology. Herein, we present a study on circHomer1, a circRNA enriched in neurons, which is abnormal expression upon cocaine exposure. Employing models of repeated cocaine exposure and conditioning place preference (CPP), alongside virus-mediated gene regulation techniques, we revealed the contributory function of circHomer1 in cocaine-induced rewarding effects and synaptic adaptations. We found a notably downregulation of circHomer1 expression in the prelimbic cortex consequent to repeated cocaine exposure in both rat model and patients with cocaine use disorder. Elevation of circHomer1 levels resulted in a pronounced attenuation of cocaine-induced CPP, whereas suppression of circHomer1 expression enhanced the rewarding effects. These outcomes were specifically observed in excitatory neurons, implicating a cell type-specific function of circHomer1. Furthermore, the restoration of circHomer1 rescued the reduction of mushroom-type dendritic spines and rectified deficits in the frequency of spontaneous excitatory postsynaptic currents associated with prolonged cocaine exposure. The modulatory actions of circHomer1 on cocaine-induced behavioral and synaptic responses were mediated by the dopamine receptor D1. Intriguingly, the effects of circHomer1 were selective to psychostimulant drugs, with no influence on food or opioid reward. Our findings highlight the significant role of circHomer1 in regulating psychostimulants reward and identify a novel molecular regulator of the actions of psychostimulants on the brain’s reward circuitry, providing a new strategy for treating drug addiction.