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Reorganization of Thalamic Inputs to Lesioned Cortex Following Experimental Traumatic Brain Injury.

ABSTRACT: Traumatic brain injury (TBI) disrupts thalamic and cortical integrity. The effect of post-injury reorganization and plasticity in thalamocortical pathways on the functional outcome remains unclear. We evaluated whether TBI causes structural changes in the thalamocortical axonal projection terminals in the primary somatosensory cortex (S1) that lead to hyperexcitability. TBI was induced in adult male Sprague Dawley rats with lateral fluid-percussion injury. A virus carrying the fluorescent-tagged opsin channel rhodopsin 2 transgene was injected into the ventroposterior thalamus. We then traced the thalamocortical pathways and analyzed the reorganization of their axonal terminals in S1. Next, we optogenetically stimulated the thalamocortical relays from the ventral posterior lateral and medial nuclei to assess the post-TBI functionality of the pathway. Immunohistochemical analysis revealed that TBI did not alter the spatial distribution or lamina-specific targeting of projection terminals in S1. TBI reduced the axon terminal density in the motor cortex by 44% and in S1 by 30%. A nematic tensor-based analysis revealed that in control rats, the axon terminals in layer V were orientated perpendicular to the pial surface (60.3°). In TBI rats their orientation was more parallel to the pial surface (5.43°, difference between the groups p < 0.05). Moreover, the level of anisotropy of the axon terminals was high in controls (0.063) compared with TBI rats (0.045, p < 0.05). Optical stimulation of the sensory thalamus increased alpha activity in electroencephalography by 312% in controls (p > 0.05) and 237% (p > 0.05) in TBI rats compared with the baseline. However, only TBI rats showed increased beta activity (33%) with harmonics at 5 Hz. Our findings indicate that TBI induces reorganization of thalamocortical axonal terminals in the perilesional cortex, which alters responses to thalamic stimulation.

SUBMITTER: Ndode-Ekane XE

PROVIDER: S-EPMC8231773 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Morphometric changes in cortical thickness (CT), cortical surface area (CSA), and cortical volume (CV) can reflect pathological changes after acute mild traumatic brain injury (mTBI). Most previous studies focused on changes in CT, CSA, and CV in subacute or chronic mTBI, and few studies have examined changes in CT, CSA, and CV in acute mTBI. Furthermore, acute mTBI patients typically show transient cognitive impairment, and few studies have reported on the relationship between cerebral morphological changes and cognitive function in patients with mTBI. This prospective cohort study included 30 patients with acute mTBI (15 males, 15 females, mean age 33.7 years) and 27 matched healthy controls (12 males, 15 females, mean age 37.7 years) who were recruited from the Second Xiangya Hospital of Central South University between September and December 2019. High-resolution T1-weighted images were acquired within 7 days after the onset of mTBI. The results of analyses using FreeSurfer software revealed significantly increased CSA and CV in the right lateral occipital gyrus of acute-stage mTBI patients compared with healthy controls, but no significant changes in CT. The acute-stage mTBI patients also showed reduced executive function and processing speed indicated by a lower score in the Digital Symbol Substitution Test, and reduced cognitive ability indicated by a longer time to complete the Trail Making Test-B. Both increased CSA and CV in the right lateral occipital gyrus were negatively correlated with performance in the Trail Making Test part A. These findings suggest that cognitive deficits and cortical alterations in CSA and CV can be detected in the acute stage of mTBI, and that increased CSA and CV in the right lateral occipital gyrus may be a compensatory mechanism for cognitive dysfunction in acute-stage mTBI patients. This study was approved by the Ethics Committee of the Second Xiangya Hospital of Central South University, China (approval No. 086) on February 9, 2019.

Project description:Following traumatic brain injury (TBI), activation of microglia and peripherally derived inflammatory macrophages occurs in association with tissue damage. This neuroinflammatory response may have beneficial or detrimental effects on neuronal survival, depending on the functional polarization of these cells along a continuum from M1-like to M2-like activation states. The mechanisms that regulate M1-like and M2-like activation after TBI are not well understood, but appear in part to reflect the redox state of the lesion microenvironment. NADPH oxidase (NOX2) is a critical enzyme system that generates reactive oxygen species in microglia/macrophages. After TBI, NOX2 is strongly up-regulated in M1-like, but not in M2-like polarized cells. Therefore, we hypothesized that NOX2 drives M1-like neuroinflammation and contributes to neurodegeneration and loss of neurological function after TBI. In the present studies we inhibited NOX2 activity using NOX2-knockout mice or the selective peptide inhibitor gp91ds-tat. We show that NOX2 is highly up-regulated in infiltrating macrophages after injury, and that NOX2 deficiency reduces markers of M1-like activation, limits tissue loss and neurodegeneration, and improves motor recovery after moderate-level control cortical injury (CCI). NOX2 deficiency also promotes M2-like activation after CCI, through increased IL-4Rα signaling in infiltrating macrophages, suggesting that NOX2 acts as a critical switch between M1- and M2-like activation states after TBI. Administration of gp91ds-tat to wild-type CCI mice starting at 24h post-injury reduces deficits in cognitive function and increased M2-like activation in the hippocampus. Collectively, our data indicate that increased NOX2 activity after TBI drives M1-like activation that contributes to inflammatory-mediated neurodegeneration, and that inhibiting this pathway provides neuroprotection, in part by altering M1-/M2-like balance towards the M2-like neuroinflammatory response.

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Reorganization of Thalamic Inputs to Lesioned Cortex Following Experimental Traumatic Brain Injury.

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