Conditioned Contextual Freezing is A Neurobehavioral Biomarker of Axonal Injury Indicated by Reduced Fractional Anisotropy in A Mouse Model of Blast-Induced Mild Traumatic Brain Injury

Abstract

Mild traumatic brain injury (TBI) is an important public health problem generated by closed head injury. This study is focused on the impact of blast-induced mild TBI on auditory trace and delay fear conditioning, models of declarative and non-declarative memory, respectively, and the correlation of conditioned freezing and fractional anisotropy, a measure of axonal state. A supersonic helium pressure wave was generated by a shock tube to blast 8-week-old male mice on Day 1 for 1.4 msec with an incident pressure of 16 psi, corresponding to a reflected pressure of 56.9 psi at the mouse head. On Day 3, the mice were subjected to auditory trace- or delay-fear conditioning. On Day 4, contextual freezing in the trained context, and precue and cued freezing in a novel context were determined. After cardiac perfusion on Day 5, ex vivo images were obtained with diffusion tensor imaging at 14.1 Tesla. We observed that delay fear conditioning prevented or reversed the decrease in fractional anisotropy in both the medial and lateral corpus callosum suggesting axonal stabilization of potentially behavioral therapeutic significance. Moderately strong and statistically significant Pearson correlations were found between fractional anisotropy and contextual freezing in the medial and lateral corpus callosum of blasted and sham-blasted delay- or trace-fear conditioned mice. Thus, contextual freezing is a neurobehavioral biomarker for axonal injury in mild TBI and is a reliable and high-throughput behavioral assay for the evaluation of potential therapeutics to treat mild TBI.

Hippocampal-Dependent Cognitive Dysfunction following Repeated Diffuse Rotational Brain Injury in Male and Female Mice

“…[75][76][77] Deficits on the DFC context test in male mice have been reported following fluid percussion injury, [76][77][78][79][80] repetitive CBI, 39,70,75 and blast neurotrauma. 74 Neural underpinnings of cognitive dysfunction following CHIMERA No pathology was found here to account for the behavioral deficits observed. No inflammation as measured by GFAP staining was found in the HP, nor were there any observable gross H&E differences between injured and sham-treated mice.…”

“…In a recent study assessing the effects of blast TBI, Weiss and colleagues demonstrated reduced freezing after injury to the cue in a TFC paradigm as well as decreased freezing in the context test, which showed negative correlation with fractional anisotropy values in the CC. 74 More often reported are results following experimental TBI and delay fear conditioning (DFC), in which the foot shock co-terminates with the auditory cue. The context test in the DFC paradigm is hippocampal-dependent, and contextual FC is often utilized as a specific behavioral test of hippocampal function.…”

“… 75-77 Deficits on the DFC context test in male mice have been reported following fluid percussion injury, 76–80 repetitive CBI, 39 , 70 , 75 and blast neurotrauma. 74 …”

Diffusion Tensor Imaging-Based Studies at the Group-Level Applied to Animal Models of Neurodegenerative Diseases

“…Notably, the alteration in radial anisotropy displayed the largest effect size and were directly correlated with histological measures of axonal damage (Li et al, 2013 ; Tu et al, 2016 ; also in rat models). FA maps have demonstrated substantial microstructural abnormalities also in case of experimental blast injury in mouse (Rubovitch et al, 2011 ; Hutchinson et al, 2018 ; Venkatasubramanian et al, 2020 ; Weiss et al, 2020 ) as well as in rat models (Budde et al, 2013 ; Begonia et al, 2014 ; Kamnaksh et al, 2014 ; Zhuo et al, 2015 ; Tang et al, 2017 ; Badea et al, 2018 ; Missault et al, 2019 ; Mohamed et al, 2020 ; San Martín Molina et al, 2020 ). DTI appeared sensitive enough to detect changes even in mild TBI models (Hylin et al, 2013 ; Takeuchi et al, 2013 ; Long et al, 2015 ; Li et al, 2016 ; Herrera et al, 2017 ; Kikinis et al, 2017 ; Wendel et al, 2018 ; Hoogenboom et al, 2019 ) and in distant locations within the brain up to 1 year after injury (Pischiutta et al, 2018 ).…”

“…Similar alterations have been detected in rat models of repeated TBI (Calabrese et al, 2014 ; Singh et al, 2016 ; Wright et al, 2016 ; Qin et al, 2018 ; Kao et al, 2019 ) as well as in juvenile rat (Fidan et al, 2018 ; Wortman et al, 2018 ; Wright et al, 2018 ) or mouse (Rodriguez-Grande et al, 2018 ; Clément et al, 2020 ) cohorts subject to TBI. A few studies have applied ex-vivo DTI to obtain high-resolution maps of axonal disruption upon TBI, both in mouse (Weiss et al, 2020 ) and in rat (Donovan et al, 2014 ; Laitinen et al, 2015 ) models of brain trauma.…”