Experience recruits MSK1 to expand the dynamic range of synapses and enhance cognition
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ABSTRACT:
PROVIDER: PRJNA627668 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11597363_1.fastq.gz | Fastqsanger.gz | |||
| SRR11597363_2.fastq.gz | Fastqsanger.gz | |||
| SRR11597364_1.fastq.gz | Fastqsanger.gz | |||
| SRR11597364_2.fastq.gz | Fastqsanger.gz | |||
| SRR11597365_1.fastq.gz | Fastqsanger.gz |
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Project description: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 harbouring an inactivating mutation of mitogen- and stress-activated protein kinase 1 (MSK1), a BDNF-activated enzyme downstream of the 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 LTP and 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.
2020-05-10 | GSE149210 | GEO
Project description: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.
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Project description:Positive experiences, such as social interaction, cognitive training and physical exercise, have been shown to ameliorate some of the harms to cognition associated with ageing. Animal models of positive interventions, commonly known as environmental enrichment, strongly influence neuronal morphology and synaptic function and enhance cognitive performance. While the profound structural and functional benefits of enrichment have been appreciated for decades, little is known as to how the environment influences neurons to respond and adapt to these positive sensory experiences. We show that adult and aged male wild-type mice that underwent a 10-week environmental enrichment protocol demonstrated improved performance in a variety of behavioural tasks, including those testing spatial working and spatial reference memory, and an enhancement in hippocampal LTP. Aged animals in particular benefitted from enrichment, performing spatial memory tasks at levels similar to healthy adult mice. Many of these benefits, including in gene expression, were absent in mice with a mutation in an enzyme, MSK1, which is activated by BDNF, a growth factor implicated in rodent and human cognition. We conclude that enrichment is beneficial across the lifespan and that MSK1 is required for the full extent of these experience-induced improvements of cognitive abilities, synaptic plasticity and gene expression.
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Project description:MSK1 is required for the beneficial synaptic and cognitive effects of enriched experience across the lifespan
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Project description:Analysis of alterations in the hippocampus transcriptome caused by deletion of Mitogen Stress activated Kinase 1 (MSK1). MAPK signaling has been implicated in a wide range of neuronal processes, including development, plasticity and viability. One of the principal downstream targets of both the ERK/MAPK pathway and the p38 MAPK pathway is Mitogen Stress activated Kinase 1 (MSK1). Here, we sought to understand the role that MSK1 plays in neuroprotection against excitotoxic stimulation in the hippocampus. To this end, we utilized a MSK1 null mouse line, cell viability assays and array-based profiling approaches. Here we show that MSK1 is broadly expressed within the major neuronal cell layers of the hippocampus and that status epilepticus (SE) drives acute induction of MSK1 activation. In response to the SE paradigm, MSK1 KO mice exhibited a striking increase in vulnerability to pilocarpine-evoked cell death within the CA1 and CA3 cell layers. Further, cultured MSK1 null neurons exhibited a heighted level of NMDA-evoked excitotoxicity relative to WT neurons, as assessed using the LDH assay. Given these findings, we examined the hippocampal transcriptional profile of MSK1 null mice. Affymetrix array profiling revealed that with MSK1 deletion a total of 115 genes showed significant changes (> 1.25-fold) in expression. Notably, functional analysis indicated that a subset of these genes contribute to neuroprotective signaling networks. Together, these data provide important new insights into the mechanism by which the MAPK/MSK1 signaling cassette confers neuroprotection against excitotoxic insults. Approaches designed to upregulate or mimic the functional effects of MSK1 may prove beneficial against an array of degenerative processes resulting from excitotoxic insults. MAPK signaling has been implicated in a wide range of neuronal processes, including development, plasticity and viability. One of the principal downstream targets of both the ERK/MAPK pathway and the p38 MAPK pathway is Mitogen Stress activated Kinase 1 (MSK1). Here, we sought to understand the role that MSK1 plays in neuroprotection against excitotoxic stimulation in the hippocampus. To this end, we utilized a MSK1 null mouse line, cell viability assays and array-based profiling approaches. Here we show that MSK1 is broadly expressed within the major neuronal cell layers of the hippocampus and that status epilepticus (SE) drives acute induction of MSK1 activation. In response to the SE paradigm, MSK1 KO mice exhibited a striking increase in vulnerability to pilocarpine-evoked cell death within the CA1 and CA3 cell layers. Further, cultured MSK1 null neurons exhibited a heighted level of NMDA-evoked excitotoxicity relative to WT neurons, as assessed using the LDH assay. Given these findings, we examined the hippocampal transcriptional profile of MSK1 null mice. Affymetrix array profiling revealed that with MSK1 deletion a total of 115 genes showed significant changes (> 1.25-fold) in expression. Notably, functional analysis indicated that a subset of these genes contribute to neuroprotective signaling networks. Together, these data provide important new insights into the mechanism by which the MAPK/MSK1 signaling cassette confers neuroprotection against excitotoxic insults. Approaches designed to upregulate or mimic the functional effects of MSK1 may prove beneficial against an array of degenerative processes resulting from excitotoxic insults.
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Project description:The postsynaptic density (PSD) of excitatory synapses contains a highly organized protein network with thousands of proteins and is key node in the regulation of synaptic plasticity. To gain new mechanistic insight into experience-induced changes in the PSD, we examined the global dynamics of the hippocampal PSD proteome and phosphoproteome in mice following 4 different types of experience. Mice were trained using an inhibitory avoidance (IA) task and hippocampal PSD fractions were isolated from individual mice to investigate molecular mechanisms underlying experience-dependent remodeling of synapses. We developed a new strategy to identify and quantify the relatively low level of site-specific phosphorylation of PSD proteome from the hippocampus, by using a modified iTRAQ-based TiSH protocol. In the PSD, we identified 3,938 proteins and 2,761 phosphoproteins in the sequential strategy covering a total of 4,968 unique protein groups (at least 2 peptides including an unique peptide). On the phosphoproteins, we identified a total of 6,188 unambiguous phosphosites (75% site localization probability)
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Project description:For many breast cancer (BCa) patients, symptomatic bone metastases appear after years or even decades of latency. How metastatic cells disseminate, and how micrometastatic lesions remain dormant and undetectable yet initiate colonization, are major questions in cancer research. Here we identify and functionally analyse a molecular mechanism involved in bone metastatic latency of estrogen receptor–positive (ER)+ BCa. We developed an in vivo loss-of-function, genome-wide shRNA screening to identify genes relevant for long-latent relapse in BCa. This screen revealed the kinase MSK1 as an important regulator of metastatic dormancy. Importantly, low MSK1 expression associates with early metastasis in ER+ BCa patients. Reduced MSK1 levels impaired cellular differentiation and increased the bone homing and growth capacity of metastatic cells. MSK1 modulates chromatin status at promoters to regulate the expression of luminal differentiation genes, including those for the GATA-3 and FOXA1 transcription factors, which prevent the progression of ER+ BCa towards metastasis. Our results identify the regulation of luminal cell differentiation by MSK1 via modulation of chromatin remodelling to be a key mechanism for controlling metastatic dormancy in BCa. We propose that MSK1 could be a useful marker for stratifying BCa patients as high- or low-risk for early relapse, allowing patients to receive appropriate treatments.
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