Influence of stochastic gene expression on the cell survival rheostat after traumatic brain injury

Daniel R. Rojo, Donald Prough, Michael T. Falduto, Deborah R. Boone, Maria Micci, Kristen M. Kahrig, Jeanna M. Crookshanks, Arnaldo Jimenez, Tatsuo Uchida, Jeremy C. Cowart, Bridget Hawkins, Marcela Avila, Douglas Dewitt, Helen Hellmich

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Experimental evidence suggests that random, spontaneous (stochastic) fluctuations in gene expression have important biological consequences, including determination of cell fate and phenotypic variation within isogenic populations. We propose that fluctuations in gene expression represent a valuable tool to explore therapeutic strategies for patients who have suffered traumatic brain injury (TBI), for which there is no effective drug therapy. We have studied the effects of TBI on the hippocampus because TBI survivors commonly suffer cognitive problems that are associated with hippocampal damage. In our previous studies we separated dying and surviving hippocampal neurons by laser capture microdissection and observed unexplainable variations in post-TBI gene expression, even though dying and surviving neurons were adjacent and morphologically identical. We hypothesized that, in hippocampal neurons that subsequently are subjected to TBI, randomly increased pre-TBI expression of genes that are associated with neuroprotection predisposes neurons to survival; conversely, randomly decreased expression of these genes predisposes neurons to death. Thus, to identify genes that are associated with endogenous neuroprotection, we performed a comparative, high-resolution transcriptome analysis of dying and surviving hippocampal neurons in rats subjected to TBI. We found that surviving hippocampal neurons express a distinct molecular signature - increased expression of networks of genes that are associated with regeneration, cellular reprogramming, development, and synaptic plasticity. In dying neurons we found decreased expression of genes in those networks. Based on these data, we propose a hypothetical model in which hippocampal neuronal survival is determined by a rheostat that adds injury-induced genomic signals to expression of pro-survival genes, which pre-TBI varies randomly and spontaneously from neuron to neuron. We suggest that pharmacotherapeutic strategies that co-activate multiple survival signals and enhance self-repair mechanisms have the potential to shift the cell survival rheostat to favor survival and therefore improve functional outcome after TBI.

Original languageEnglish (US)
Article numbere23111
JournalPLoS One
Volume6
Issue number8
DOIs
StatePublished - 2011

Fingerprint

Gene expression
Neurons
cell viability
Brain
Cell Survival
neurons
Cells
brain
Gene Expression
gene expression
Genes
Survival
Microdissection
Traumatic Brain Injury
Laser Capture Microdissection
Drug therapy
Neuronal Plasticity
Gene Regulatory Networks
Gene Expression Profiling
hippocampus

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Influence of stochastic gene expression on the cell survival rheostat after traumatic brain injury. / Rojo, Daniel R.; Prough, Donald; Falduto, Michael T.; Boone, Deborah R.; Micci, Maria; Kahrig, Kristen M.; Crookshanks, Jeanna M.; Jimenez, Arnaldo; Uchida, Tatsuo; Cowart, Jeremy C.; Hawkins, Bridget; Avila, Marcela; Dewitt, Douglas; Hellmich, Helen.

In: PLoS One, Vol. 6, No. 8, e23111, 2011.

Research output: Contribution to journalArticle

Rojo, DR, Prough, D, Falduto, MT, Boone, DR, Micci, M, Kahrig, KM, Crookshanks, JM, Jimenez, A, Uchida, T, Cowart, JC, Hawkins, B, Avila, M, Dewitt, D & Hellmich, H 2011, 'Influence of stochastic gene expression on the cell survival rheostat after traumatic brain injury', PLoS One, vol. 6, no. 8, e23111. https://doi.org/10.1371/journal.pone.0023111
Rojo, Daniel R. ; Prough, Donald ; Falduto, Michael T. ; Boone, Deborah R. ; Micci, Maria ; Kahrig, Kristen M. ; Crookshanks, Jeanna M. ; Jimenez, Arnaldo ; Uchida, Tatsuo ; Cowart, Jeremy C. ; Hawkins, Bridget ; Avila, Marcela ; Dewitt, Douglas ; Hellmich, Helen. / Influence of stochastic gene expression on the cell survival rheostat after traumatic brain injury. In: PLoS One. 2011 ; Vol. 6, No. 8.
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