Baroncelli Laura, Scali Manuela, Sansevero Gabriele, Olimpico Francesco, Manno Ilaria, Costa Mario, Sale Alessandro
Neuroscience Institute, National Research Council, I-56124 Pisa, Italy.
Neuroscience Institute, National Research Council, I-56124 Pisa, Italy, NEUROFARBA, University of Florence, Florence, Italy, and.
J Neurosci. 2016 Mar 23;36(12):3430-40. doi: 10.1523/JNEUROSCI.1787-15.2016.
During an early phase of enhanced sensitivity called the critical period (CP), monocular deprivation causes a shift in the response of visual cortex binocular neurons in favor of the nondeprived eye, a process named ocular dominance (OD) plasticity. While the time course of the CP for OD plasticity can be modulated by genetic/pharmacological interventions targeting GABAergic inhibition, whether an increased sensory-motor experience can affect this major plastic phenomenon is not known. We report that exposure to environmental enrichment (EE) accelerated the closure of the CP for OD plasticity in the rat visual cortex. Histone H3 acetylation was developmentally regulated in primary visual cortex, with enhanced levels being detectable early in enriched pups, and chromatin immunoprecipitation revealed an increase at the level of the BDNF P3 promoter. Administration of the histone deacetylase inhibitor SAHA (suberoylanilide hydroxamic acid) to animals reared in a standard cage mimicked the increase in H3 acetylation observed in the visual cortex and resulted in an accelerated decay of OD plasticity. Finally, exposure to EE in adulthood upregulated H3 acetylation and was paralleled by a reopening of the CP. These findings demonstrate a critical involvement of the epigenetic machinery as a mediator of visual cortex developmental plasticity and of the impact of EE on OD plasticity.
While it is known that an epigenetic remodeling of chromatin structure controls developmental plasticity in the visual cortex, three main questions have remained open. Which is the physiological time course of histone modifications? Is it possible, by manipulating the chromatin epigenetic state, to modulate plasticity levels during the critical period? How can we regulate histone acetylation in the adult brain in a noninvasive manner? We show that the early exposure of rat pups to enriching environmental conditions accelerates the critical period for plasticity in the primary visual cortex, linking this effect to increased histone acetylation, specifically at the BDNF gene level. Moreover, we report that the exposure of adult animals to environmental enrichment enhances histone acetylation and reopens juvenile-like plasticity.
在称为关键期（CP）的增强敏感性早期阶段，单眼剥夺会导致视皮层双眼神经元的反应发生偏移，偏向未剥夺的眼睛，这一过程称为眼优势（OD）可塑性。虽然针对GABA能抑制的基因/药物干预可调节OD可塑性的CP时间进程，但增加的感觉运动经验是否会影响这一主要的可塑性现象尚不清楚。我们报告，暴露于环境丰富化（EE）可加速大鼠视皮层中OD可塑性的CP关闭。组蛋白H3乙酰化在初级视皮层中受到发育调控，在丰富环境饲养的幼崽早期可检测到其水平升高，染色质免疫沉淀显示BDNF P3启动子水平增加。向饲养在标准笼中的动物施用组蛋白脱乙酰酶抑制剂SAHA（辛二酰苯胺异羟肟酸）可模拟在视皮层中观察到的H3乙酰化增加，并导致OD可塑性加速衰退。最后，成年期暴露于EE会上调H3乙酰化，并伴随着CP的重新开放。这些发现证明了表观遗传机制作为视皮层发育可塑性的介质以及EE对OD可塑性的影响的关键作用。
虽然已知染色质结构的表观遗传重塑控制视皮层的发育可塑性，但仍有三个主要问题未解决。组蛋白修饰的生理时间进程是怎样的？通过操纵染色质表观遗传状态，是否有可能在关键期调节可塑性水平？我们如何以非侵入性方式调节成年大脑中的组蛋白乙酰化？我们表明大鼠幼崽早期暴露于丰富的环境条件可加速初级视皮层可塑性的关键期，将这种效应与组蛋白乙酰化增加联系起来，特别是在BDNF基因水平。此外，我们报告成年动物暴露于环境丰富化可增强组蛋白乙酰化并重新开启类似幼年的可塑性。
