CHIMERA repetitive mild traumatic brain injury induces chronic behavioural and neuropathological phenotypes in wild-type and APP/PS1 mice

Abstract

BackgroundThe annual incidence of traumatic brain injury (TBI) in the United States is over 2.5 million, with approximately 3–5 million people living with chronic sequelae. Compared with moderate-severe TBI, the long-term effects of mild TBI (mTBI) are less understood but important to address, particularly for contact sport athletes and military personnel who have high mTBI exposure. The purpose of this study was to determine the behavioural and neuropathological phenotypes induced by the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA) model of mTBI in both wild-type (WT) and APP/PS1 mice up to 8 months post-injury.MethodsMale WT and APP/PS1 littermates were randomized to sham or repetitive mild TBI (rmTBI; 2 × 0.5 J impacts 24 h apart) groups at 5.7 months of age. Animals were assessed up to 8 months post-injury for acute neurological deficits using the loss of righting reflex (LRR) and Neurological Severity Score (NSS) tasks, and chronic behavioural changes using the passive avoidance (PA), Barnes maze (BM), elevated plus maze (EPM) and rotarod (RR) tasks. Neuropathological assessments included white matter damage; grey matter inflammation; and measures of Aβ levels, deposition, and aducanumab binding activity.ResultsThe very mild CHIMERA rmTBI conditions used here produced no significant acute neurological or motor deficits in WT and APP/PS1 mice, but they profoundly inhibited extinction of fear memory specifically in APP/PS1 mice over the 8-month assessment period. Spatial learning and memory were affected by both injury and genotype. Anxiety and risk-taking behaviour were affected by injury but not genotype. CHIMERA rmTBI induced chronic white matter microgliosis, axonal injury and astrogliosis independent of genotype in the optic tract but not the corpus callosum, and it altered microgliosis in APP/PS1 amygdala and hippocampus. Finally, rmTBI did not alter long-term tau, Aβ or amyloid levels, but it increased aducanumab binding activity.ConclusionsCHIMERA is a useful model to investigate the chronic consequences of rmTBI, including behavioural abnormalities consistent with features of post-traumatic stress disorder and inflammation of both white and grey matter. The presence of human Aβ greatly modified extinction of fear memory after rmTBI.Electronic supplementary materialThe online version of this article (10.1186/s13195-018-0461-0) contains supplementary material, which is available to authorized users.

From biomechanics to pathology: predicting axonal injury from patterns of strain after traumatic brain injury

“…Other animal models [e.g. fluid-percussion or rotational acceleration models such as CHIMERA (closed-head impact model of engineered rotational acceleration)] might be more suitable to investigate axonal injuries ( Cheng et al , 2019 ; Desai et al , 2020 ). These models would allow a direct quantitative analysis of primary axonal damage in the first hours after injury and in turn a better comparison to the strain predictions, as both seem tightly connected directly after injury.…”

Penetrating Ballistic-Like Brain Injury Leads to MicroRNA Dysregulation, BACE1 Upregulation, and Amyloid Precursor Protein Loss in Lesioned Rat Brain Tissues

“…Lastly, the later steps in APP processing rely upon PSEN1/2 variants within the active γ-secretase complex may be responsible for extensive and sustained Aβ-40/42 peptide generation and seeding after action upon APP by BACE1. APP and its peptides are often studied in TBI rodent models that carry the mutated PSEN transgenes (Cheng et al, 2019) in an effort to show direct relationships to early onset dementia (Gotz et al, 2018). These mutations are rare and indicate that analysis in wild type models, as in this study, are increasingly important.…”

Risk-Based Decision Making: A Systematic Scoping Review of Animal Models and a Pilot Study on the Effects of Sleep Deprivation in Rats

“…For the purpose of this review, we operationalise decision making as actively selecting one from several options [ 2 ], and we restricted to decision-making involving risk (i.e., unknown outcome). The following types of experiments (with examples) were thus excluded from this review: tasks without an active choice (e.g., single-option response tasks [ 82 ], progressive ratio tasks [ 83 , 84 ] or Pavlovian autoshaping [ 85 ]), delay discounting tasks without an uncertain component [ 86 ], naturalistic responses to alarm cues [ 87 ], risk taking outside the laboratory [ 88 ], time spent on open arms of an elevated maze [ 89 , 90 ] or parts of other devices [ 91 , 92 ], risk-based decision making including social components (e.g., social risk taking comparing selfish and social choices in Non-Human Primates (NHPs) [ 93 ] and collective decision making on risky or safe options in ants [ 94 ]), and self-administration studies of addiction [ 95 ]. Also excluded was the rodent slot machine task [ 96 , 97 , 98 ].…”