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Aerobic Exercise Induces Alternative Splicing of Neurexins in Frontal Cortex.

ABSTRACT: Aerobic exercise (AE) is known to produce beneficial effects on brain health by improving plasticity, connectivity, and cognitive functions, but the underlying molecular mechanisms are still limited. Neurexins (Nrxns) are a family of presynaptic cell adhesion molecules that are important in synapsis formation and maturation. In vertebrates, three-neurexin genes (NRXN1, NRXN2, and NRXN3) have been identified, each encoding for α and β neurexins, from two independent promoters. Moreover, each Nrxns gene (1-3) has several alternative exons and produces many splice variants that bind to a large variety of postsynaptic ligands, playing a role in trans-synaptic specification, strength, and plasticity. In this study, we investigated the impact of a continuous progressive (CP) AE program on alternative splicing (AS) of Nrxns on two brain regions: frontal cortex (FC) and hippocampus. We showed that exercise promoted Nrxns1-3 AS at splice site 4 (SS4) both in α and β isoforms, inducing a switch from exon-excluded isoforms (SS4-) to exon-included isoforms (SS4+) in FC but not in hippocampus. Additionally, we showed that the same AE program enhanced the expression level of other genes correlated with synaptic function and plasticity only in FC. Altogether, our findings demonstrated the positive effect of CP AE on FC in inducing molecular changes underlying synaptic plasticity and suggested that FC is possibly a more sensitive structure than hippocampus to show molecular changes.

SUBMITTER: Innocenzi E

PROVIDER: S-EPMC8261640 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Aerobic Exercise Induces Alternative Splicing of Neurexins in Frontal Cortex.

Innocenzi Elisa E Cariati Ida I De Domenico Emanuela E Tiberi Erika E D'Arcangelo Giovanna G Verdile Veronica V Paronetto Maria Paola MP Tancredi Virginia V Barchi Marco M Rossi Pellegrino P Sette Claudio C Grimaldi Paola P

Journal of functional morphology and kinesiology 20210531 2

Aerobic exercise (AE) is known to produce beneficial effects on brain health by improving plasticity, connectivity, and cognitive functions, but the underlying molecular mechanisms are still limited. Neurexins (Nrxns) are a family of presynaptic cell adhesion molecules that are important in synapsis formation and maturation. In vertebrates, three-neurexin genes (NRXN1, NRXN2, and NRXN3) have been identified, each encoding for α and β neurexins, from two independent promoters. Moreover, each <i>N ...[more]

PMID: 34072692

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Project description:Aims: Recent research suggests that aerobic exercise can be performed safely within the first week following a concussion injury and that early initiation of exercise may speed recovery. To better understand the physiological changes during a concussion, we tested the hypothesis that mild-to-intense exercise testing can be performed within days immediately following injury, and can be used to discern differences between the concussed and normal healthy state. Thus, the purpose was to observe the cerebral hemodynamic responses to incremental exercise testing performed acutely post-concussion in high-performance athletes. Methods: This study was a within- and between-experimental design, with seven male university ice hockey teams participating. A subgroup of five players acted as control subjects (CON) and was tested at the same time as the 14 concussed (mTBI) players on Day 2, 4, and 7 post-concussion. A 5-min resting baseline and 5-min exercise bouts of mild (EX1), moderate (EX2), and high (EX3) intensity exercise were performed on a cycle ergometer. Near-infrared spectroscopy was used to monitor pre-frontal cortex oxy-haemoglobin (HbO2), deoxy-haemoglobin (HHb), and total blood volume (tHb) changes. Results: ANOVA compared differences between testing days and groups, and although large percentage changes in HbO2 (20-30%), HHb (30-40%), and tHb (30-40%) were recorded, no significant (p ? 0.05) differences in cerebral hemodynamics occurred between mTBI vs. CON during aerobic exercise testing on any day post-injury. Furthermore, there was a linear relationship between exercise intensity vs. cerebral hemodynamics during testing for each day (r 2 = 0.83-0.99). Conclusion: These results demonstrate two novel findings: (1) mild-to-intense aerobic exercise testing can be performed safely as early as Day 2 post-concussion injury in a controlled laboratory environment; and (2) evidence-based objective measures such as cerebral hemodynamics can easily be collected using near-infrared spectroscopy (NIRS) to monitor physiological changes during the first-week post-injury. This research has important implications for monitoring physiological recovery post-injury and establishing new rehabilitation guidelines.

Project description:BackgroundThe vast majority of genes in the genome are multi-exonic, and are alternatively spliced during transcription, resulting in multiple isoforms for each gene. For some genes, different mRNA isoforms may have differential expression levels or be involved in different pathways. Bulk tissue RNA-seq, as a widely used technology for transcriptome quantification, measures the total expression (TE) levels of each gene across multiple isoforms in multiple cell types for each tissue sample. With recent developments in precise quantification of alternative splicing events for each gene, we propose to study the effects of alternative splicing variation on gene-gene correlation effects. We adopted a variance-component model for testing the TE-TE correlations of one gene with a co-expressed gene, accounting for the effects of splicing variation and splicing-by-TE interaction of one gene on the other.ResultsWe analyzed data from the Genotype-Tissue Expression (GTEx) project (V8). At the 5% FDR level, 38,146 pairs of genes out of ∼10 M examined pairs from GTEx lung tissue showed significant TE-splicing interaction effects, implying isoform-specific and/or sample-specific TE-TE correlations. Additional analysis across 13 GTEx brain tissues revealed strong tissue-specificity of TE-splicing interaction effects. Moreover, we showed that accounting for splicing variation across samples could improve the reproducibility of results and could reduce potential confounding effects in studying co-expressed gene pairs with bulk tissue data. Many of those gene pairs had correlation effects specific to only certain isoforms and would otherwise be undetected. By analyzing gene-gene co-expression variation within functional pathways accounting for splicing, we characterized the patterns of the "hub" genes with isoform-specific regulatory effects on multiple other genes.ConclusionsWe showed that splicing variation of a gene may interact with TE of the gene and affect the TE of co-expressed genes, resulting in substantial tissue-specific inter-sample variability in gene-gene correlation effects. Accounting for TE-splicing interaction effects could reduce potential confounding effects and improve the robustness of estimation when estimating gene-gene correlations from bulk tissue expression data.

Dataset Information

Aerobic Exercise Induces Alternative Splicing of Neurexins in Frontal Cortex.

Publications

Aerobic Exercise Induces Alternative Splicing of Neurexins in Frontal Cortex.

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