Influence of Stochastic Gene Expression on the Cell Survival Rheostat after Traumatic Brain Injury

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.

Rapid Accumulation of Endogenous Tau Oligomers in a Rat Model of Traumatic Brain Injury

“…(ipsilateral) side of the brain and oftentimes causes nonlethal cellular changes to the uninjured (contralateral) hemisphere (44). These finding were confirmed by ELISA using T22 and AT8 (Fig.…”

Laser Capture Microdissection of Enriched Populations of Neurons or Single Neurons for Gene Expression Analysis After Traumatic Brain Injury

“…8,10,11,12,13 We were the first investigators to utilize this technique to demonstrate that distinct subregions of the rat hippocampus have gene expression profiles that correlate with their selective vulnerability to injury. Our studies showed that we could quantify gene expression, by qPCR, from as few as 10 laser captured cells and that we could perform genome-wide microarray analysis from as few as 600 captured cells.…”

Randomness in biology

“…It has been described extensively in various contexts and species, in either normal (Raser and O'Shea 2005) or pathological processes (Rojo et al 2011), and its heritability has also been addressed (Ansel et al 2008). It has been proved to be transmissible in a cascade of gene expression (Hooshangi and Weiss 2006), and even, to a certain extent, from one cell generation to another (Kaufmann et al 2007).…”

“…An example of this is given by a recent experimental study on murine brains. This demonstrated that basic stochastic gene expression allows the constitution of different pools of hippocampal neurons, which enhance the survival of certain fractions of them after a traumatic brain injury, which may be seen here as the selection step, and without which the rationale of the overall dynamic does not make sense (Rojo et al 2011).…”