Valzania Alessandro, Catale Clarissa, Viscomi Maria Teresa, Puglisi-Allegra Stefano, Carola Valeria
IRCCS Fondazione Santa Lucia, Via Fosso di Fiorano 63, 00143 Rome, Italy.
Department of Biology and Biotechnologies, University of Rome "La Sapienza", Piazzale A. Moro 5, 00185, Italy.
Physiol Behav. 2017 Mar 15;171:7-12. doi: 10.1016/j.physbeh.2016.12.027. Epub 2016 Dec 23.
Psychostimulants induce stable changes in neural plasticity and behavior in a transcription-dependent manner. Further, stable cellular changes require transcription that is regulated by epigenetic mechanisms that alter chromatin structure, such as histone acetylation. This mechanism is typically catalyzed by enzymes with histone acetyltransferase or histone deacetylase (HDAC) activity. Class IIa HDACs are notable for their high expression in important regions of the brain reward circuitry and their neural activity-dependent shuttling in and out of the cell nucleus. In particular, HDAC5 has an important modulatory function in cocaine-induced behaviors and social defeat stress-induced effects. Although a mutation in HDAC5 has been shown to cause hypersensitive responses to chronic cocaine use whether this response worsens during chronic early life stress has not been examined yet. In this study, we exposed mouse pups to two different early life stress paradigms (social isolation, ESI, and social threat, EST) to determine whether the heterozygous null mutation in HDAC5 (HDAC5+/-) moderated the effects of exposure to stress in early life on adult cocaine-induced conditioned place preference (CPP). Notably, HDAC5+/- mice that had been exposed to ESI were more susceptible to developing cocaine-induced CPP and more resistant to extinguishing this behavior. The same effect was not observed for HDAC5+/- mice experiencing EST, suggesting that only ESI induces behavioral changes by acting precisely through HDAC5-related biological pathways. Finally, an analysis of c-Fos expression performed to discover the neurobiological substrates that mediated this phenotype, identified the dorsolateral striatum as an important structure that mediates the interaction between HDAC5 mutation and ESI. Our data demonstrate that decreased HDAC5 function is able to exacerbate the long-term behavioral effects of adverse rearing environment in mouse.
精神兴奋剂以转录依赖的方式诱导神经可塑性和行为的稳定变化。此外，稳定的细胞变化需要由改变染色质结构的表观遗传机制调节的转录，例如组蛋白乙酰化。这种机制通常由具有组蛋白乙酰转移酶或组蛋白脱乙酰酶（HDAC）活性的酶催化。IIa类HDAC因其在大脑奖赏回路的重要区域高表达以及它们在细胞核内外的神经活动依赖性穿梭而引人注目。特别是，HDAC5在可卡因诱导的行为和社会挫败应激诱导的效应中具有重要的调节功能。虽然已经表明HDAC5的突变会导致对长期使用可卡因的超敏反应，但尚未研究这种反应在慢性早期生活应激期间是否会恶化。在本研究中，我们将幼鼠暴露于两种不同的早期生活应激范式（社会隔离，ESI，和社会威胁，EST），以确定HDAC5的杂合无效突变（HDAC5+/-）是否能调节早期生活应激暴露对成年可卡因诱导的条件性位置偏爱（CPP）的影响。值得注意的是，暴露于ESI的HDAC5+/-小鼠更容易发展出可卡因诱导的CPP，并且对消除这种行为更具抵抗力。对于经历EST的HDAC5+/-小鼠未观察到相同的效果，这表明只有ESI通过精确作用于与HDAC5相关的生物学途径来诱导行为变化。最后，通过对c-Fos表达的分析来发现介导这种表型的神经生物学底物，确定背外侧纹状体是介导HDAC5突变与ESI之间相互作用的重要结构。我们的数据表明，HDAC5功能的降低能够加剧小鼠不良饲养环境的长期行为影响。
