TY - JOUR
T1 - Traumatic axonopathy in spinal tracts after impact acceleration head injury
T2 - Ultrastructural observations and evidence of SARM1-dependent axonal degeneration
AU - Alexandris, Athanasios S.
AU - Lee, Youngrim
AU - Lehar, Mohamed
AU - Alam, Zahra
AU - Samineni, Pranav
AU - Tripathi, Sunil J.
AU - Ryu, Jiwon
AU - Koliatsos, Vassilis E.
N1 - Funding Information:
V.E.K received funding from the National Eye Institute ( RO1EY028039 ), the National Institute of Neurological Disorders and Stroke ( R01NS114397 ), the Department of Defense ( W81XWH-14-0396 ), and from generous gifts from the Kate Sidran Family foundation . In all cases, the funding agencies were not involved in the acquisition, analysis, interpretation and/or presentation/reporting of data.
Publisher Copyright:
© 2022 The Authors
PY - 2023/1
Y1 - 2023/1
N2 - Traumatic axonal injury (TAI) and the associated axonopathy are common consequences of traumatic brain injury (TBI) and contribute to significant neurological morbidity. It has been previously suggested that TAI activates a highly conserved program of axonal self-destruction known as Wallerian degeneration (WD). In the present study, we utilize our well-established impact acceleration model of TBI (IA-TBI) to characterize the pathology of injured myelinated axons in the white matter tracks traversing the ventral, lateral, and dorsal spinal columns in the mouse and assess the effect of Sterile Alpha and TIR Motif Containing 1 (Sarm1) gene knockout on acute and subacute axonal degeneration and myelin pathology. In silver-stained preparations, we found that IA-TBI results in white matter pathology as well as terminal field degeneration across the rostrocaudal axis of the spinal cord. At the ultrastructural level, we found that traumatic axonopathy is associated with diverse types of axonal and myelin pathology, ranging from focal axoskeletal perturbations and focal disruption of the myelin sheath to axonal fragmentation. Several morphological features such as neurofilament compaction, accumulation of organelles and inclusions, axoskeletal flocculation, myelin degeneration and formation of ovoids are similar to profiles encountered in classical examples of WD. Other profiles such as excess myelin figures and inner tongue evaginations are more typical of chronic neuropathies. Stereological analysis of pathological axonal and myelin profiles in the ventral, lateral, and dorsal columns of the lower cervical cord (C6) segments from wild type and Sarm1 KO mice at 3 and 7 days post IA-TBI (n = 32) revealed an up to 90% reduction in the density of pathological profiles in Sarm1 KO mice after IA-TBI. Protection was evident across all white matter tracts assessed, but showed some variability. Finally, Sarm1 deletion ameliorated the activation of microglia associated with TAI. Our findings demonstrate the presence of severe traumatic axonopathy in multiple ascending and descending long tracts after IA-TBI with features consistent with some chronic axonopathies and models of WD and the across-tract protective effect of Sarm1 deletion.
AB - Traumatic axonal injury (TAI) and the associated axonopathy are common consequences of traumatic brain injury (TBI) and contribute to significant neurological morbidity. It has been previously suggested that TAI activates a highly conserved program of axonal self-destruction known as Wallerian degeneration (WD). In the present study, we utilize our well-established impact acceleration model of TBI (IA-TBI) to characterize the pathology of injured myelinated axons in the white matter tracks traversing the ventral, lateral, and dorsal spinal columns in the mouse and assess the effect of Sterile Alpha and TIR Motif Containing 1 (Sarm1) gene knockout on acute and subacute axonal degeneration and myelin pathology. In silver-stained preparations, we found that IA-TBI results in white matter pathology as well as terminal field degeneration across the rostrocaudal axis of the spinal cord. At the ultrastructural level, we found that traumatic axonopathy is associated with diverse types of axonal and myelin pathology, ranging from focal axoskeletal perturbations and focal disruption of the myelin sheath to axonal fragmentation. Several morphological features such as neurofilament compaction, accumulation of organelles and inclusions, axoskeletal flocculation, myelin degeneration and formation of ovoids are similar to profiles encountered in classical examples of WD. Other profiles such as excess myelin figures and inner tongue evaginations are more typical of chronic neuropathies. Stereological analysis of pathological axonal and myelin profiles in the ventral, lateral, and dorsal columns of the lower cervical cord (C6) segments from wild type and Sarm1 KO mice at 3 and 7 days post IA-TBI (n = 32) revealed an up to 90% reduction in the density of pathological profiles in Sarm1 KO mice after IA-TBI. Protection was evident across all white matter tracts assessed, but showed some variability. Finally, Sarm1 deletion ameliorated the activation of microglia associated with TAI. Our findings demonstrate the presence of severe traumatic axonopathy in multiple ascending and descending long tracts after IA-TBI with features consistent with some chronic axonopathies and models of WD and the across-tract protective effect of Sarm1 deletion.
KW - Corticospinal tract
KW - Electron microscopy
KW - Microglia
KW - Myelin
KW - Neurodegeneration
KW - Neuropathy
KW - Oligodendrocyte
KW - Traumatic axonal injury
KW - Wallerian degeneration
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UR - http://www.scopus.com/inward/citedby.url?scp=85140457428&partnerID=8YFLogxK
U2 - 10.1016/j.expneurol.2022.114252
DO - 10.1016/j.expneurol.2022.114252
M3 - Article
C2 - 36244414
AN - SCOPUS:85140457428
SN - 0014-4886
VL - 359
JO - Experimental Neurology
JF - Experimental Neurology
M1 - 114252
ER -