Abstract
Traumatic brain injury (TBI) is a leading cause of disability and death and survivors often suffer from long-lasting motor impairment, cognitive deficits, anxiety disorders and epilepsy. Few experimental studies have investigated long-term sequelae after TBI and relations between behavioral changes and neural activity patterns remain elusive. We examined these issues in a murine model of TBI combining histology, behavioral analyses and single-photon emission computed tomography (SPECT) imaging of regional cerebral blood flow (CBF) as a proxy for neural activity. Adult C57Bl/6N mice were subjected to unilateral cortical impact injury and investigated at early (15–57 days after lesion, dal) and late (184–225 dal) post-traumatic time points. TBI caused pronounced tissue loss of the parietal cortex and subcortical structures and enduring neurological deficits. Marked perilesional astro- and microgliosis was found at 57 dal and declined at 225 dal. Motor and gait pattern deficits occurred at early time points after TBI and improved over the time. In contrast, impaired performance in the Morris water maze test and decreased anxiety-like behavior persisted together with an increased susceptibility to pentylenetetrazole-induced seizures suggesting alterations in neural activity patterns. Accordingly, SPECT imaging of CBF indicated asymmetric hemispheric baseline neural activity patterns. In the ipsilateral hemisphere, increased baseline neural activity was found in the amygdala. In the contralateral hemisphere, homotopic to the structural brain damage, the hippocampus and distinct cortex regions displayed increased baseline neural activity. Thus, regionally elevated CBF along with behavioral alterations indicate that increased neural activity is critically involved in the long-lasting consequences of TBI.
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We gratefully acknowledge the technical assistance of Tobias Hirnet, Dana Pieter and Wiesia Bobkiewicz (all UMC Mainz, Germany).
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429_2017_1452_MOESM1_ESM.tif
Fig S1 Study design and time lines. (a-c) Time lines for experimental groups (CCI and sham mice, 57 and 225 days survival after CCI) showing sequence and time points of behavioral tasks (a, b) and time points of SPECT and MRI (c). (d) Overview of sample sizes of behavioral tasks, brain histopathology using cresyl violet staining and immunohistochemistry, mRNA expression analysis by qPCR and SPECT and MRI (TIFF 7577 kb)
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Fig S2 TBI induces long-lasting changes in gait patterns. (a-g) Gait pattern analysis (Catwalk) revealed differences between CCI mice and sham mice at 40–42 dal in print position (a), cadence (b), stride length (c) and swing speed (d). At 209–211 dal, CCI mice differed compared to sham mice in swing (e), stance (f), step pattern (g) and cadence (h). Values represent mean ± SEM (early post-traumatic time point; sham: n = 15, CCI: n = 15; late post-traumatic time point; sham: n = 16, CCI: n = 18). *p < 0.05, **p < 0.01, ***p < 0,001, ****p < 0.0001. P values were calculated by Mann–Whitney U test (TIFF 14568 kb)
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Fig S3 TBI induces mild effects on fear conditioning and does not affect swimming speed in the MWM. (a, b) CCI mice exhibited enhanced context-dependent fear conditioning at 42 dal (p = 0.03) but no alterations in cued fear conditioning on 42 days and 212 days after TBI. (c, d) The swimming speed did not differ in CCI mice compared to sham mice. Values from fear-conditioning experiments and swimming speed are expressed as mean ± SEM (42 dal; sham: n = 15, CCI: n = 15; 212 dal; sham: n = 16, CCI: n = 18). *p < 0.05, calculated by Mann–Whitney U test (TIFF 20150 kb)
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Pöttker, B., Stöber, F., Hummel, R. et al. Traumatic brain injury causes long-term behavioral changes related to region-specific increases of cerebral blood flow. Brain Struct Funct 222, 4005–4021 (2017). https://doi.org/10.1007/s00429-017-1452-9
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DOI: https://doi.org/10.1007/s00429-017-1452-9