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

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.

Traumatic Brain Injury Induces Genome-Wide Transcriptomic, Methylomic, and Network Perturbations in Brain and Blood Predicting Neurological Disorders

“…The overall results of our system biology study provide evidence for the impact of TBI on core aspects of gene regulation, which offers critical mechanistic information at the molecular level and can be used as novel elements of diagnosis and treatment. Compared to previous genomic profiling studies of TBI (Von Gertten et al, 2005, Rojo et al, 2011, Samal et al, 2015, Redell et al, 2013, Lipponen et al, 2016), our study differs in the molecular features assessed (gene expression only in previous studies vs. the combination of epigenome, gene expression, and alternative splicing in the current study), network modeling approaches (literature-based networks in previous studies vs data-driven, tissue-specific networks used here), tissues, time points, and TBI severity, which offer unique mechanistic aspects of the TBI pathology.…”

“…1) focusing on the impact of concussive injury on fundamental gene regulatory mechanisms. Unlike previous studies based on microarrays (Von Gertten et al, 2005, Rojo et al, 2011, Samal et al, 2015, Redell et al, 2013) and more recently RNA sequencing (Lipponen et al, 2016) which have reported changes in gene expression in response to TBI, in the current study we leveraged the power of system biology to combine genome-wide transcriptome and DNA methylome analyses in the hippocampus (a main site of cognitive dysfunction in TBI pathology) with modern data-driven gene network modeling approaches, which allowed us to extract information about crucial gene regulatory mechanisms (expression level, alternative splicing, epigenetic regulation) underlying TBI pathogenesis and to model tissue-specific gene-gene interactions which have the power to predict essential regulatory points. Gene networks are graphical models that depict genes as nodes and connections (reflecting regulatory relations or interactions) between genes as edges.…”

Altered gene expression profile in a mouse model of SCN8A encephalopathy

“… a Sources: (Ravizza et al, 2001), b (Tang et al, 2002), c (Elliott et al, 2003), d (Wilson et al, 2005), e (Okamoto et al, 2010), f (Sakaida et al, 2013), g (Almeida-Suhett et al, 2014), h (Samal et al, 2015), i (Zamanian et al, 2012), j (Zhang et al, 2016), k (Rakhade et al, 2005), l (Boer et al, 2010), m (Beaumont et al, 2012) …”

Microglia Responses in Acute and Chronic Neurological Diseases: What Microglia-Specific Transcriptomic Studies Taught (and did Not Teach) Us

“…Although inflammation and up-regulation of inflammatory cytokines is predominant in brain transcriptomic alterations after traumatism (Redell et al, 2013; Samal et al, 2015), to our knowledge, no cell-specific study has been carried out so far to examine gene profile modifications specifically in microglia/monocytes following TBI. There is thus a clear need for such analysis.…”