Stochastic fluctuations in gene expression in aging hippocampal neurons could be exacerbated by traumatic brain injury

Abstract

Traumatic brain injury (TBI) is a risk factor for age-related dementia and development of neurodegenerative disorders such as Alzheimer's disease that are associated with cognitive decline. The exact mechanism for this risk is unknown but we hypothesized that TBI is exacerbating age-related changes in gene expression. Here, we present evidence in an animal model that experimental TBI increases age-related stochastic gene expression. We compared the variability in expression of several genes associated with cell survival or death, among three groups of laser capture microdissected hippocampal neurons from aging rat brains. TBI increased stochastic fluctuations in gene expression in both dying and surviving neurons compared to the naïve neurons. Increases in random, stochastic fluctuations in prosurvival or prodeath gene expression could potentially alter cell survival or cell death pathways in aging neurons after TBI which may lead to age-related cognitive decline.

Genetics of Aggression in Alzheimer’s Disease (AD)

“…Remarkably, about 90% of the human body’s total serotonin (and hence TPH biosynthetic systems) are located in the neuroendocrine entero-chromaffin cells in the human gastrointestinal (GI) tract, where it is used to regulate intestinal movements and participate in GI-neural tract signaling; the other 10% is synthesized by serotonergic neurons of the CNS where it functions in the regulation of neurite outgrowth, somatic morphology, growth cone motility, synaptogenesis, and control of dendritic spine shape and density, and behaviorally anger, aggression, mood, body temperature, appetite, sleep, pain and cognition. Serotonin acts via a heterogenic receptor family that includes G protein-coupled receptors and ligand-gated ion channels (New et al, 1998; Craig et al, 2004; Shearer et al, 2016; Wirth et al, 2016). TPH is encoded by two separate enzymes: TPH1 produces serotonin in the pineal gland and entero-chromaffin cells, while TPH2 produces serotonin in the Raphe nuclei of the brain stem and myenteric plexus.…”

“…Other factors that can impact the regulation of gene expression including diurnal regulation, oscillatory aspects, stochastic fluctuations of gene expression and their variable transcriptional regulatory roles add further layers of complexity to our understanding of the role of genetics in the aggression associated with AD. It has recently become apparent that biological mechanisms which drive feedforward loops in NPS-relevant gene expression may have strong influence on attenuating the stochasticity of brain gene expression patterns (Barger, 2016; Shearer et al, 2016). The most recent data on the genetics of aggression in AD demonstrate: (i) that both the timescale of selective gene expression; and (ii) fluctuations in the expression of those genes implicated substantially affect the function and performance of biochemical networks, and these factors further influence gene expression plasticity, especially in the transcription-enriched environment of human neurons (Figure 1; Barger, 2016; Shearer et al, 2016).…”

“…It has recently become apparent that biological mechanisms which drive feedforward loops in NPS-relevant gene expression may have strong influence on attenuating the stochasticity of brain gene expression patterns (Barger, 2016; Shearer et al, 2016). The most recent data on the genetics of aggression in AD demonstrate: (i) that both the timescale of selective gene expression; and (ii) fluctuations in the expression of those genes implicated substantially affect the function and performance of biochemical networks, and these factors further influence gene expression plasticity, especially in the transcription-enriched environment of human neurons (Figure 1; Barger, 2016; Shearer et al, 2016). It is further interesting that this work is a prime example of a remarkable congruency between GWAS-based and DNA-array and transcriptomic-array-based findings which both show similar fluctuations in the expression of gene families important in both aggression and AD.…”

Neurotrauma investigation through spatial omics guided by mass spectrometry imaging: Target identification and clinical applications

“…Following experimental TBI, provided via the fluid‐percussion model on male Sprague‐Dawley rats, Boone et al (2012) found deregulation of the circadian clock genes within the hippocampus. Furthermore, using LCM on samples from the rat hippocampus post‐TBI, it was proven that stochastic gene expression is crucial for predicting whether injured neurons survive or die (Shearer et al, 2016). Accordingly, genomic engineering strategies are being implicated as novel therapeutic methods for the restoration of normal brain functions.…”

Stereotactic Atlas-Guided Laser Capture Microdissection of Brain Regions Affected by Traumatic Injury

“…The ability to laser capture and analyze gene expression in both dying and surviving neurons gives us a greater understanding of the role of stochasticity in gene expression in determining the outcome (neuronal survival) after TBI 6 . LCM techniques have also proven useful for exploring the effects of TBI on hippocampal neurons when comparing young and aging mice 7 or rats 8 .…”