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Acute Response of the Hippocampal Transcriptome Following Mild Traumatic Brain Injury After Controlled Cortical Impact in the Rat

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Abstract

We have previously demonstrated that mild controlled cortical impact (mCCI) injury to rat cortex causes indirect, concussive injury to underlying hippocampus and other brain regions, providing a reproducible model for mild traumatic brain injury (mTBI) and its neurochemical, synaptic, and behavioral sequelae. Here, we extend a preliminary gene expression study of the hippocampus-specific events occurring after mCCI and identify 193 transcripts significantly upregulated, and 21 transcripts significantly downregulated, 24 h after mCCI. Fifty-three percent of genes altered by mCCI within 24 h of injury are predicted to be expressed only in the non-neuronal/glial cellular compartment, with only 13 % predicted to be expressed only in neurons. The set of upregulated genes following mCCI was interrogated using Ingenuity Pathway Analysis (IPA) augmented with manual curation of the literature (190 transcripts accepted for analysis), revealing a core group of 15 first messengers, mostly inflammatory cytokines, predicted to account for >99 % of the transcript upregulation occurring 24 h after mCCI. Convergent analysis of predicted transcription factors (TFs) regulating the mCCI target genes, carried out in IPA relative to the entire Affymetrix-curated transcriptome, revealed a high concordance with TFs regulated by the cohort of 15 cytokines/cytokine-like messengers independently accounting for upregulation of the mCCI transcript cohort. TFs predicted to regulate transcription of the 193-gene mCCI cohort also displayed a high degree of overlap with TFs predicted to regulate glia-, rather than neuron-specific genes in cortical tissue. We conclude that mCCI predominantly affects transcription of non-neuronal genes within the first 24 h after insult. This finding suggests that early non-neuronal events trigger later permanent neuronal changes after mTBI, and that early intervention after mTBI could potentially affect the neurochemical cascade leading to later reported synaptic and behavioral dysfunction.

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Notes

  1. Downregulated genes were only sparsely represented in the overall first-messenger IPA analysis, and were therefore not considered further for correlation of first-messenger mCCI-response genes and first-messenger-related transcription factors.

Abbreviations

CCI:

Controlled cortical impact

mCCI:

Mild controlled cortical injury

mTBI:

Mild traumatic brain injury

IPA:

Ingenuity Pathway Analysis

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Acknowledgments

We thank Chang-Mei Hsu for expert technical assistance in preparation of RNA for microarray and qRT-PCR analysis. This work was supported by the NIMH Intramural Research Program Project Z01 MH002386-22.

Conflict of Interest

The authors have nothing to disclose.

Author information

Authors and Affiliations

  1. Section on Molecular Neuroscience, Laboratory of Cellular and Molecular Regulation, National Institute of Mental Health, Building 49, Room 5A-38, 9000 Rockville Pike, Bethesda, MD, 20892, USA

    Babru B. Samal, Cameron K. Waites & Lee E. Eiden

  2. Department of Anatomy, Physiology and Genetics, F. Edward Hebert School of Medicine, Bethesda, MD, USA

    Camila Almeida-Suhett & Maria F. M. Braga

  3. Unit on Synapse Development and Plasticity, National Institute of Mental Health, Bethesda, MD, USA

    Zheng Li

  4. Department of Neurology, F. Edward Hebert School of Medicine Uniformed Services University of the Health Sciences, Bethesda, MD, USA

    Ann M. Marini

  5. 4005 Louisiana St #3, San Diego, CA, USA

    Nihar R. Samal

  6. Microarray Core, National Human Genome Research Institute, Bethesda, MD, USA

    Abdel Elkahloun

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  1. Babru B. Samal
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  2. Cameron K. Waites
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  3. Camila Almeida-Suhett
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  4. Zheng Li
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  8. Maria F. M. Braga
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  9. Lee E. Eiden
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Correspondence to Lee E. Eiden.

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Samal, B.B., Waites, C.K., Almeida-Suhett, C. et al. Acute Response of the Hippocampal Transcriptome Following Mild Traumatic Brain Injury After Controlled Cortical Impact in the Rat. J Mol Neurosci 57, 282–303 (2015). https://doi.org/10.1007/s12031-015-0626-2

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  • DOI: https://doi.org/10.1007/s12031-015-0626-2

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