Abstract
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.SIGNIFICANCE STATEMENT 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.
Highlights
Experience exerts a profound influence on the structure and function of the mammalian brain (Kolb and Whishaw, 1998)
mitogen- and stress-activated protein kinase 1 (MSK1) is necessary for the full extent of experiencedependent enhancement of cognition To confirm that our enrichment protocol had tangible effects on animal behavior, we initially assessed the influence of enrichment on locomotor function and anxiety, the latter of which in particular is sensitive to enrichment (Rogers et al, 2019)
While standard housed mice of both genotypes performed at comparable levels (Fig. 2B), there was a significant effect of enrichment that was reflected in significantly improved performance in WT mice, but not in the MSK1 KD animals (Fig. 2B)
Summary
Experience exerts a profound influence on the structure and function of the mammalian brain (Kolb and Whishaw, 1998). While this was predicted by early physiologists (von Bernhardi et al, 2017), it was the pioneering work of Donald Hebb in the. 1940s that first demonstrated the enhanced cognitive abilities of rats raised in the stimulating environment of his home compared with their counterparts reared in a laboratory (Hebb, 1947, 1949). L. Privitera’s present address: Centre for Discovery Brain Sciences, Edinburgh EH8 9JZ, UK, and School of Medicine, University of Dundee, Ninewells Hospital, Dundee, DD1 9SY, UK. L. Morè’s present address: School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston, PR1 2HE, UK
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