Abstract
Traumatic brain injury (TBI) can occur at any age, from youth to the elderly, and its contribution to age-related neuropathology remains unknown. Few studies have investigated the relationship between age-at-injury and pathophysiology at a discrete biological age. In this study, we report the immunohistochemical analysis of naïve rat brains compared to those subjected to diffuse TBI by midline fluid percussion injury (mFPI) at post-natal day (PND) 17, PND35, 2-, 4-, or 6-months of age. All brains were collected when rats were 10-months of age (n = 6–7/group). Generalized linear mixed models were fitted to analyze binomial proportion and count data with R Studio. Amyloid precursor protein (APP) and neurofilament (SMI34, SMI32) neuronal pathology were counted in the corpus callosum (CC) and primary sensory barrel field (S1BF). Phosphorylated TAR DNA-binding protein 43 (pTDP-43) neuropathology was counted in the S1BF and hippocampus. There was a significantly greater extent of APP and SMI34 axonal pathology and pTDP-43 neuropathology following a TBI compared with naïves regardless of brain region or age-at-injury. However, age-at-injury did determine the extent of dendritic neurofilament (SMI32) pathology in the CC and S1BF where all brain-injured rats exhibited a greater extent of pathology compared with naïve. No significant differences were detected in the extent of astrocyte activation between brain-injured and naïve rats. Microglia counts were conducted in the S1BF, hippocampus, ventral posteromedial (VPM) nucleus, zona incerta, and posterior hypothalamic nucleus. There was a significantly greater proportion of deramified microglia, regardless of whether the TBI was recent or remote, but this only occurred in the S1BF and hippocampus. The proportion of microglia with colocalized CD68 and TREM2 in the S1BF was greater in all brain-injured rats compared with naïve, regardless of whether the TBI was recent or remote. Only rats with recent TBI exhibited a greater proportion of CD68-positive microglia compared with naive in the hippocampus and posterior hypothalamic nucleus. Whilst, only rats with a remote brain-injury displayed a greater proportion of microglia colocalized with TREM2 in the hippocampus. Thus, chronic alterations in neuronal and microglial characteristics are evident in the injured brain despite the recency of a diffuse brain injury.
Highlights
Traumatic brain injury (TBI) is a neurological condition that commonly leads to long-term functional deficits such as impaired memory, cognition, and sensorimotor function [1]
This study investigated whether age-at-injury influenced neuropathology and glial activation at 10-months of age in male rats
The results from this research demonstrate that there was a greater extent of neuropathology and proportion of microglial activation, but not astrogliosis, after a single diffuse
Summary
Traumatic brain injury (TBI) is a neurological condition that commonly leads to long-term functional deficits such as impaired memory, cognition, and sensorimotor function [1]. In conjunction with long-term functional deficits, TBI has been associated with an increased risk of the development of neurodegenerative diseases such as Alzheimer’s disease, chronic traumatic encephalopathy (CTE), multiple sclerosis, and Parkinson’s disease [2]. This chronic presentation of symptoms and increased risk of neurodegenerative disease may be a result of TBI-induced cascades that manifest as enduring neuronal injury and inflammation, as observed both clinically and experimentally [3,4,5]. There is cumulative research in humans and various animal models that demonstrate a TBI at any age can result in long-term sensorimotor, cognitive, and endocrine symptoms in addition to neuropathology and glial activation, but it remains unclear whether age-at-injury affects these outcomes [11,12,13,14,15,16]
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