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Mol Brain ; 14(1): 101, 2021 06 29.
Artículo en Inglés | MEDLINE | ID: mdl-34187517

RESUMEN

Mitochondrial function is required for brain energy homeostasis and neuroadaptation. Recent studies demonstrate that cocaine affects mitochondrial dynamics and morphological characteristics within the nucleus accumbens (NAc). Further, mitochondria are differentially regulated by cocaine in dopamine receptor-1 containing medium spiny neurons (D1-MSNs) vs dopamine receptor-2 (D2)-MSNs. However, there is little understanding into cocaine-induced transcriptional mechanisms and their role in regulating mitochondrial processes. Here, we demonstrate that cocaine enhances binding of the transcription factor, early growth response factor 3 (Egr3), to nuclear genes involved in mitochondrial function and dynamics. Moreover, cocaine exposure regulates mRNA of these mitochondria-associated nuclear genes in both contingent or noncontingent cocaine administration and in both rodent models and human postmortem tissue. Interestingly, several mitochondrial nuclear genes showed distinct profiles of expression in D1-MSNs vs D2-MSNs, with cocaine exposure generally increasing mitochondrial-associated nuclear gene expression in D1-MSNs vs suppression in D2-MSNs. Further, blunting Egr3 expression in D1-MSNs blocks cocaine-enhancement of the mitochondrial-associated transcriptional coactivator, peroxisome proliferator-activated receptor gamma coactivator (PGC1α), and the mitochondrial fission molecule, dynamin related protein 1 (Drp1). Finally, reduction of D1-MSN Egr3 expression attenuates cocaine-induced enhancement of small-sized mitochondria, causally demonstrating that Egr3 regulates mitochondrial morphological adaptations. Collectively, these studies demonstrate cocaine exposure impacts mitochondrial dynamics and morphology by Egr3 transcriptional regulation of mitochondria-related nuclear gene transcripts; indicating roles for these molecular mechanisms in neuronal function and plasticity occurring with cocaine exposure.


Asunto(s)
Cocaína/farmacología , Proteína 3 de la Respuesta de Crecimiento Precoz/genética , Regulación de la Expresión Génica , Dinámicas Mitocondriales/genética , Neuronas/metabolismo , Transcripción Genética , Adulto , Animales , Núcleo Celular/efectos de los fármacos , Núcleo Celular/genética , Proteína 3 de la Respuesta de Crecimiento Precoz/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Genes Mitocondriales , Humanos , Masculino , Ratones Endogámicos C57BL , Persona de Mediana Edad , Dinámicas Mitocondriales/efectos de los fármacos , Neuronas/efectos de los fármacos , Núcleo Accumbens/metabolismo , Regiones Promotoras Genéticas/genética , Unión Proteica/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ribosomas/metabolismo , Transcripción Genética/efectos de los fármacos , Adulto Joven
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