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The Effects of Voluntary Physical Exercise-Activated Neurotrophic Signaling in Rat Hippocampus on mRNA Levels of Downstream Signaling Molecules

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Abstract

Physical exercise results in the increased expression of neurotrophic factors and the subsequent induction of signal transduction cascades with a positive impact on neuronal functions. In this study, we used a voluntary physical exercise rat model to determine correlations in hippocampus mRNA expression of the neurotropic factors Bdnf, VegfA, and Igf1; their receptors TrkB, Igf1R, VegfR1, and VegfrR2; and downstream signal transducers Creb, Syn1, and Vgf. In hippocampi of physically exercised rats, the mRNA expression levels of Bdnf transcript 4 (Bdnf-t4), VegfA, and Igf1, as well as VegfR1, TrkB, Creb, Vgf, and Syn1, were increased. Bdnf-t4 mRNA expression positively correlated with mRNA expression of Creb, Vgf, and Syn1 in hippocampi of exercised rats. A correlation between Bdnf-t4 and Syn1 mRNA expression was also observed in hippocampi of sedentary rats. Igf1 and VegfA mRNA expression was positively correlated in hippocampi of both exercised and sedentary rats. But, neither Igf1 nor VegfA mRNA expression was correlated with the expression of Bdnf-t4 or the expression of the signal transducers Creb, Syn1, and Vgf. In hippocampi of exercised rats, Creb mRNA expression was positively correlated with TrkB, Syn1, and Vgf mRNA expression and with the correlation between Creb and Vgf mRNA expression also observed in hippocampi of sedentary rats. To examine for causality of the in vivo observed correlated mRNA expression levels between Bdnf-t4 and the other examined transcripts, we used nuclease-deactivated CRISPR-Cas9 fused with VP64 to induce mRNA expression of endogenous Bdnf-t4 in rat PC12 cells. Following Bdnf-t4 mRNA induction, we observed increased Creb mRNA expression. This in vitro result is in accordance with the in vivo results and supports that under specified conditions, an increase in Creb mRNA expression can be a downstream signal transduction event due to induction of endogenous Bdnf mRNA expression.

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Abbreviations

Bdnf:

Brain-derived neurotrophic factor

Bdnf–t4 :

Bdnf transcript 4

Creb:

cAMP-response-element binding protein

CRISPR:

Clustered regularly interspaced short palindromic repeats

Cas9:

CRISPR associated protein 9

dCas9:

nuclease deficient Cas9

Igf1:

Insulin-like growth factor 1

Igf1R:

Insulin-like growth factor 1 receptor

NE:

Norepinephrine

Ngf:

Nerve growth factor

p75NTR:

p75 neurotrophin receptor

PI3K:

Phosphatidylinositol-3 kinase

RT:

Reverse transcriptase

RT-qPCR:

RT quantitative PCR

SEM:

Standard error of the mean

sgRNA:

Short guide RNA

Syn1:

Synapsin 1

TrkB:

Tropomyosin receptor kinase B

TrkB.tk+:

Full-length TrkB receptor

TrkB.t1:

Truncated TrkB receptor

VegfA:

Vascular endothelial growth factor A

VegfR:

Vascular endothelial growth factor receptor

VIP:

Vasoactive intestinal peptide

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Acknowledgements

This work was supported by the Lundbeck Foundation (R100-A9606).

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Authors and Affiliations

  1. Department of Biomedicine, Aarhus University, 8000, Aarhus C, Denmark

    Christina A. E. Solvsten, Tina F. Daugaard, Yonglun Luo, Frank de Paoli, Jane H. Christensen & Anders L. Nielsen

  2. The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark

    Jane H. Christensen & Anders L. Nielsen

  3. Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark

    Jane H. Christensen

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  1. Christina A. E. Solvsten
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  2. Tina F. Daugaard
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  3. Yonglun Luo
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  4. Frank de Paoli
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  5. Jane H. Christensen
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  6. Anders L. Nielsen
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Contributions

CS, FDP, JHC, and ALN conceived and designed the study. CS and TFD performed the biological experiments. YL guided the implementation of CRISPR-dCas9 technology. CS analyzed the results for rat hippocampi and TFD and ALN analyzed the results for CRISPR-dCas9 experiments. CS and ALN drafted the manuscript and all authors approved the final version of the manuscript.

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Correspondence to Anders L. Nielsen.

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Solvsten, C.A.E., Daugaard, T.F., Luo, Y. et al. The Effects of Voluntary Physical Exercise-Activated Neurotrophic Signaling in Rat Hippocampus on mRNA Levels of Downstream Signaling Molecules. J Mol Neurosci 62, 142–153 (2017). https://doi.org/10.1007/s12031-017-0918-9

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