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Neurodegeneration in the somatosensory cortex after experimental diffuse brain injury.

ABSTRACT: Disruption and consequent reorganization of central nervous system circuits following traumatic brain injury may manifest as functional deficits and behavioral morbidities. We previously reported axotomy and neuronal atrophy in the ventral basal (VB) complex of the thalamus, without gross degeneration after experimental diffuse brain injury in adult rats. Pathology in VB coincided with the development of late-onset aberrant behavioral responses to whisker stimulation, which lead to the current hypothesis that neurodegeneration after experimental diffuse brain injury includes the primary somatosensory barrel cortex (S1BF), which receives projection of VB neurons and mediates whisker somatosensation. Over 28 days after midline fluid percussion brain injury, argyrophilic reaction product within superficial layers and layer IV barrels at 1 day progresses into the cortex to subcortical white matter by 7 days, and selective inter-barrel septa and subcortical white matter labeling at 28 days. Cellular consequences were determined by stereological estimates of neuronal nuclear volumes and number. In all cortical layers, neuronal nuclear volumes significantly atrophied by 42-49% at 7 days compared to sham, which marginally attenuated by 28 days. Concomitantly, the number of healthy neurons was reduced by 34-45% at 7 days compared to sham, returning to control levels by 28 days. Progressive neurodegeneration, including argyrophilic reaction product and neuronal nuclear atrophy, indicates injury-induced damage and reorganization of the reciprocal thalamocortical projections that mediate whisker somatosensation. The rodent whisker barrel circuit may serve as a discrete model to evaluate the causes and consequences of circuit reorganization after diffuse brain injury.

SUBMITTER: Lifshitz J

PROVIDER: S-EPMC3536493 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Neurodegeneration in the somatosensory cortex after experimental diffuse brain injury.

Lifshitz Jonathan J Lisembee Amanda M AM

Brain structure & function 20110520 1

Disruption and consequent reorganization of central nervous system circuits following traumatic brain injury may manifest as functional deficits and behavioral morbidities. We previously reported axotomy and neuronal atrophy in the ventral basal (VB) complex of the thalamus, without gross degeneration after experimental diffuse brain injury in adult rats. Pathology in VB coincided with the development of late-onset aberrant behavioral responses to whisker stimulation, which lead to the current h ...[more]

PMID: 21597967

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Project description:Transcranial magnetic stimulation (TMS) over human primary somatosensory cortex (S1) does not produce immediate outputs. Researchers must therefore rely on indirect methods for TMS coil positioning. The "gold standard" is to use individual functional and structural magnetic resonance imaging (MRI) data, but the majority of studies don't do this. The most common method to locate the hand area of S1 (S1-hand) is to move the coil posteriorly from the hand area of primary motor cortex (M1-hand). Yet, S1-hand is not directly posterior to M1-hand. We localized the index finger area of S1-hand (S1-index) experimentally in four ways. First, we reanalyzed functional MRI data from 20 participants who received vibrotactile stimulation to their 10 digits. Second, to assist the localization of S1-hand without MRI data, we constructed a probabilistic atlas of the central sulcus from 100 healthy adult MRIs and measured the likely scalp location of S1-index. Third, we conducted two experiments mapping the effects of TMS across the scalp on tactile discrimination performance. Fourth, we examined all available neuronavigation data from our laboratory on the scalp location of S1-index. Contrary to the prevailing method, and consistent with systematic review evidence, S1-index is close to the C3/C4 electroencephalography (EEG) electrode locations on the scalp, ~7-8 cm lateral to the vertex, and ~2 cm lateral and 0.5 cm posterior to the M1-hand scalp location. These results suggest that an immediate revision to the most commonly used heuristic to locate S1-hand is required. The results of many TMS studies of S1-hand need reassessment. NEW & NOTEWORTHY Noninvasive human brain stimulation requires indirect methods to target particular brain areas. Magnetic stimulation studies of human primary somatosensory cortex have used scalp-based heuristics to find the target, typically locating it 2 cm posterior to the motor cortex. We measured the scalp location of the hand area of primary somatosensory cortex and found that it is ~2 cm lateral to motor cortex. Our results suggest an immediate revision of the prevailing method is required.

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.

Project description:BACKGROUND:Thalamic dysfunction has been implicated in overall chronic neurological dysfunction after traumatic brain injury (TBI), however little is known about the underlying histopathology. In experimental diffuse TBI (dTBI), we hypothesize that persisting histopathological changes in the ventral posteromedial (VPM) nucleus of the thalamus is indicative of progressive circuit reorganization. Since circuit reorganization in the VPM impacts the whisker sensory system, the histopathology could explain the development of hypersensitivity to whisker stimulation by 28days post-injury; similar to light and sound hypersensitivity in human TBI survivors. METHODS:Adult, male Sprague-Dawley rats underwent craniotomy and midline fluid percussion injury (FPI) (moderate severity; 1.8-2.0atm) or sham surgery. At 1d, 7d, and 28days post-FPI (d FPI) separate experiments confirmed the cytoarchitecture (Giemsa stain) and evaluated neuropathology (silver stain), activated astrocytes (GFAP), neuron morphology (Golgi stain) and microglial morphology (Iba-1) in the VPM. RESULTS:Cytoarchitecture was unchanged throughout the time course, similar to previously published data; however, neuropathology and astrocyte activation were significantly increased at 7d and 28d and activated microglia were present at all time points. Neuron morphology was dynamic over the time course with decreased dendritic complexity (fewer branch points; decreased length of processes) at 7d FPI and return to sham values by 28d FPI. CONCLUSIONS:These data indicate that dTBI results in persisting thalamic histopathology out to a chronic time point. While these changes can be indicative of either adaptive (recovery) or maladaptive (neurological dysfunction) circuit reorganization, they also provide a potential mechanism by which maladaptive circuit reorganization could contribute to the development of chronic neurological dysfunction. Understanding the processes that mediate circuit reorganization is critical to the development of future therapies for TBI patients.

Dataset Information

Neurodegeneration in the somatosensory cortex after experimental diffuse brain injury.

Publications

Neurodegeneration in the somatosensory cortex after experimental diffuse brain injury.

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