RESUMEN
Neuroadaptations in the nucleus accumbens (NAc) underlie cue-induced cocaine craving that intensifies ("incubates") during abstinence and is believed to contribute to persistent relapse vulnerability. Changes in gene expression often govern perpetual behavioral abnormalities, but epigenetic plasticity during prolonged abstinence from drug exposure is poorly understood. We examined how E3 ubiquitin ligase TRIM3 dysregulates chromatin remodeler INO80 to mediate cocaine craving during prolonged abstinence. We found that INO80 expression increased in the NAc on abstinence day 30 (AD30) but not on AD1 following cocaine self-administration. Furthermore, TRIM3, which mediates degradation of INO80, was reduced on AD30, along with TRIM3-INO80 interaction. Viral-mediated gene transfer of INO80 or TRIM3 governed cocaine craving during prolonged abstinence. Lastly, chromatin immunoprecipitation followed by massively parallel DNA sequencing identified INO80-mediated transcriptional regulation of predicted pathways associated with cocaine plasticity. Together, these results demonstrate a novel ubiquitin-proteasomal-epigenetic mechanism by which TRIM3-INO80 mediates cocaine craving during prolonged abstinence.
Asunto(s)
ATPasas Asociadas con Actividades Celulares Diversas/metabolismo , Cocaína/farmacología , Núcleo Accumbens/efectos de los fármacos , Ubiquitina-Proteína Ligasas/metabolismo , ATPasas Asociadas con Actividades Celulares Diversas/genética , Animales , Cromatina/metabolismo , Modelos Animales de Enfermedad , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Humanos , Masculino , Núcleo Accumbens/metabolismo , Regiones Promotoras Genéticas , Unión Proteica , Subunidades de Proteína/genética , Subunidades de Proteína/metabolismo , Ratas , Ratas Sprague-Dawley , Autoadministración , Síndrome de Abstinencia a Sustancias/metabolismo , Síndrome de Abstinencia a Sustancias/patología , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
The nucleus accumbens (NAc) is a primary brain reward region composed predominantly of medium spiny neurons (MSNs). In response to early withdrawal from repeated cocaine administration, de novo dendritic spine formation occurs in NAc MSNs. Much evidence indicates that this new spine formation facilitates the rewarding properties of cocaine. Early withdrawal from repeated cocaine also produces dramatic alterations in the transcriptome of NAc MSNs, but how such alterations influence cocaine's effects on dendritic spine formation remain unclear. Studies in non-neuronal cells indicate that actin cytoskeletal regulatory pathways in nuclei have a direct role in the regulation of gene transcription in part by controlling the access of co-activators to their transcription factor partners. In particular, actin state dictates the interaction between the serum response factor (SRF) transcription factor and one of its principal co-activators, MAL. Here we show that cocaine induces alterations in nuclear F-actin signaling pathways in the NAc with associated changes in the nuclear subcellular localization of SRF and MAL. Using in vivo optogenetics, the brain region-specific inputs to the NAc that mediate these nuclear changes are investigated. Finally, we demonstrate that regulated SRF expression, in turn, is critical for the effects of cocaine on dendritic spine formation and for cocaine-mediated behavioral sensitization. Collectively, these findings reveal a mechanism by which nuclear-based changes influence the structure of NAc MSNs in response to cocaine.