Prolonged hippocampal cell death following closed-head traumatic brain injury in rats

Abstract

Traumatic brain injury (TBI) leads to enduring cognitive disorders. Although recent evidence has shown that controlled cortical impact in a rodent may induce memory deficits with prolonged cell death in the dentate gyrus (DG) of the hippocampus, few studies have reported long-term chronic hippocampal cell death following 'closed-head' TBI (cTBI), the predominant form of human TBI. Therefore, the aim of this study was to quantify terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)(+) apoptotic hippocampal cells as well as hippocampal cells with hallmark morphological features of degenerating cells in a chronic setting of cTBI in rats. TUNEL assays and Cresyl violet staining were performed using 6-month post-TBI fixed hippocampal sections. Evidence of prolonged hippocampal cell death was shown by the presence of a significantly increased number of TUNEL(+) cells in the cornu ammonis 1-3 (CA1-CA3) and DG of the hippocampus compared with intact controls. In addition, Cresyl violet staining indicated a significantly elevated number of cells with the degenerative morphological features in all hippocampal subregions (CA1-CA3, hilus, and DG). These results suggest that prolonged cell death may occur in multiple regions of the hippocampus following cTBI.

Mild Traumatic Brain Injury Produces Neuron Loss That Can Be Rescued by Modulating Microglial Activation Using a CB2 Receptor Inverse Agonist

“…However, additional analysis and the use of cell-type specific markers would be required to determine if there was any loss of interneurons and/or any preferential loss of a specific subpopulation(s) of projection neurons from cortex or striatum (Reiner et al, 1998 ; Hattox and Nelson, 2007 ; DeFelipe et al, 2013 ; Deng et al, 2015 ). Prior studies have reported that projection neurons in cortex and striatum are vulnerable to TBI (Maxwell et al, 2010 ; Bales et al, 2011 ), but interneurons, at least those in the hippocampus, have been reported to also be vulnerable to TBI (Lowenstein et al, 1992 ; Hicks et al, 1993 ; Smith et al, 1997 ; Tsuda et al, 2016 ).…”

Diurnal Variation Induces Neurobehavioral and Neuropathological Differences in a Rat Model of Traumatic Brain Injury

“…These morphological changes suggest a daytime pre-pro-inflammatory microenvironment in the cortex or variations in microglia-mediated inflammatory-immune responses. In the hippocampus, heterogeneity in the cellular response for the CA1, CA2/3, and DG regions after TBI has been described in controlled cortical impact models and in a closed head injury model ( Grady et al, 2003 ; Anderson et al, 2005 ; Mao et al, 2013 ; Tsuda et al, 2016 ), the latter of which is similar to our TBI model. However, none of these previous models considered the effect of diurnal variations at the time of TBI.…”

Diminished Dentate Gyrus Filtering of Cortical Input Leads to Enhanced Area Ca3 Excitability after Mild Traumatic Brain Injury

“…121 The complex DG interneuron network has also been shown to experience shifts in intrinsic excitability and synaptic inputs after TBI. 4,[31][32][33][34]120,122,123 Thus, an imbalance in excitatory/inhibitory neurotransmission throughout the DG after injury most likely contributes to the breakdown of DG filter function.…”