School of Life Sciences, University of Warwick, Coventry, CV4 7AL, UK.
Centre for Discovery Brain Sciences, 1 George Square, Edinburgh EH8 9JZ, UK.
J Neurosci. 2020 Jun 10;40(24):4644-4660. doi: 10.1523/JNEUROSCI.2765-19.2020. Epub 2020 May 6.
Experience powerfully influences neuronal function and cognitive performance, but the cellular and molecular events underlying the experience-dependent enhancement of mental ability have remained elusive. In particular, the mechanisms that couple the external environment to the genomic changes underpinning this improvement are unknown. To address this, we have used male mice harboring an inactivating mutation of mitogen- and stress-activated protein kinase 1 (MSK1), a brain-derived neurotrophic factor (BDNF)-activated enzyme downstream of the mitogen-activated protein kinase (MAPK) pathway. We show that MSK1 is required for the full extent of experience-induced improvement of spatial memory, for the expansion of the dynamic range of synapses, exemplified by the enhancement of hippocampal long-term potentiation (LTP) and long-term depression (LTD), and for the regulation of the majority of genes influenced by enrichment. In addition, and unexpectedly, we show that experience is associated with an MSK1-dependent downregulation of key MAPK and plasticity-related genes, notably of EGR1/Zif268 and Arc/Arg3.1, suggesting the establishment of a novel genomic landscape adapted to experience. By coupling experience to homeostatic changes in gene expression MSK1, represents a prime mechanism through which the external environment has an enduring influence on gene expression, synaptic function, and cognition. Our everyday experiences strongly influence the structure and function of the brain. Positive experiences encourage the growth and development of the brain and support enhanced learning and memory and resistance to mood disorders such as anxiety. While this has been known for many years, how this occurs is not clear. Here, we show that many of the positive aspects of experience depend on an enzyme called mitogen- and stress-activated protein kinase 1 (MSK1). Using male mice with a mutation in MSK1, we show that MSK1 is necessary for the majority of gene expression changes associated with experience, extending the range over which the communication between neurons occurs, and for both the persistence of memory and the ability to learn new task rules.
经验有力地影响神经元功能和认知表现，但支持智力增强的经验依赖性的细胞和分子事件仍然难以捉摸。特别是，将外部环境与支持这种改善的基因组变化联系起来的机制尚不清楚。为了解决这个问题，我们使用了携带丝裂原和应激激活蛋白激酶 1（MSK1）失活突变的雄性小鼠，MSK1 是脑源性神经营养因子（BDNF）激活的丝裂原激活蛋白激酶（MAPK）通路下游的一种酶。我们表明，MSK1 是空间记忆的经验诱导改善的充分程度所必需的，是突触动态范围的扩展的必要条件，例如海马长时程增强（LTP）和长时程抑制（LTD）的增强，以及大多数受富集影响的基因的调节。此外，出乎意料的是，我们表明，经验与 MSK1 依赖性 MAPK 和可塑性相关基因的下调有关，特别是 EGR1/Zif268 和 Arc/Arg3.1，这表明建立了适应经验的新型基因组景观。通过将经验与基因表达的稳态变化相结合，MSK1 代表了一种主要的机制，通过这种机制，外部环境对基因表达、突触功能和认知产生持久影响。我们的日常经验强烈影响大脑的结构和功能。积极的经验促进大脑的生长和发育，支持增强学习和记忆，并抵抗焦虑等情绪障碍。虽然这已经众所周知多年，但具体是如何发生的还不清楚。在这里，我们表明，经验的许多积极方面都依赖于一种叫做丝裂原和应激激活蛋白激酶 1（MSK1）的酶。使用 MSK1 突变的雄性小鼠，我们表明 MSK1 是与经验相关的大多数基因表达变化所必需的，扩展了神经元之间通讯的范围，并且对记忆的持久性和学习新任务规则的能力都很重要。
