Repetitive Diffuse Mild Traumatic Brain Injury Causes an Atypical Astrocyte Response and Spontaneous Recurrent Seizures

Shandra, Oleksii; Winemiller, Alexander R.; Heithoff, Benjamin P.; Muñoz‐Ballester, Carmen; George, Kijana K.; Benko, Michael J.; Zuidhoek, Ivan A.; Besser, Michelle N.; Curley, Dallece E.; Edwards, G. Franklin; Mey, A. V. M.; Harrington, A. H.; Kitchen, Jeremy; Robel, Stefanie

doi:10.1093/neuros/nyaa447_413

Cited by 4 publications

(5 citation statements)

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“…Across brain sites and injury stages, we identify astrocytes as a key cell type to the mTBI pathology. Astrocytes are known to play an important role in the acute and chronic responses to mTBI and the resulting changes in gene expression, morphology, proliferation and function are known as astrogliosis [45,82,83]. The diverse functions of astrocytes are central to the mTBI pathogenesis and explain why astrocytes have such massive global transcriptional changes across regions and timepoints.…”

Section: Discussionmentioning

confidence: 99%

Systems spatiotemporal dynamics of traumatic brain injury at single-cell resolution reveals humanin as a therapeutic target

Arneson

Zhang

Ahn

et al. 2022

Cell. Mol. Life Sci.

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Background The etiology of mild traumatic brain injury (mTBI) remains elusive due to the tissue and cellular heterogeneity of the affected brain regions that underlie cognitive impairments and subsequent neurological disorders. This complexity is further exacerbated by disrupted circuits within and between cell populations across brain regions and the periphery, which occur at different timescales and in spatial domains. Methods We profiled three tissues (hippocampus, frontal cortex, and blood leukocytes) at the acute (24-h) and subacute (7-day) phases of mTBI at single-cell resolution. Results We demonstrated that the coordinated gene expression patterns across cell types were disrupted and re-organized by TBI at different timescales with distinct regional and cellular patterns. Gene expression-based network modeling implied astrocytes as a key regulator of the cell–cell coordination following mTBI in both hippocampus and frontal cortex across timepoints, and mt-Rnr2, which encodes the mitochondrial peptide humanin, as a potential target for intervention based on its broad regional and dynamic dysregulation following mTBI. Treatment of a murine mTBI model with humanin reversed cognitive impairment caused by mTBI through the restoration of metabolic pathways within astrocytes. Conclusions Our results offer a systems-level understanding of the dynamic and spatial regulation of gene programs by mTBI and pinpoint key target genes, pathways, and cell circuits that are amenable to therapeutics.

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Section: Discussionmentioning

confidence: 99%

Systems spatiotemporal dynamics of traumatic brain injury at single-cell resolution reveals humanin as a therapeutic target

Arneson

Zhang

Ahn

et al. 2022

Cell. Mol. Life Sci.

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“…However, astrocyte hyperreactivity over the long term may generate a glial scar, which impairs the neuronal interconnections and the synaptic transmission [58,59]. The process of glial scarring includes an increase of the length, density, and area of the astrocytes, characteristic of astrocyte reactivity [60], as well as a shortening of the cytoplasmic projections, hypertrophy, and condensation of the cell soma [61], which were features evident in the fish exposed to CPF and TCF in our study and can be indicative of injury and astrocyte response induced by toxins.…”

Section: Discussionmentioning

confidence: 99%

First study on response of astrocytes in alevines of red-bellied pacu (Piaractus brachypomus) to subchronic exposure to chlorpyrifos and trichlorfon

2022

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Background and Aim: Organophosphate pesticides (OPs) used in agricultural production pose environmental and public health risks whenever non-target organisms are exposed to them. Oxon-type OPs, such as trichlorfon (TCF) and chlorpyrifos (CPF), are frequently used in Colombia and have been detected in water bodies in the vicinity of croplands; however, their effect on aquatic organisms, especially fish, is largely unknown. The neurotoxicity of OPs includes inhibition of esterase enzymes, neuronal damage, and increased glial reactivity. This study aimed to assess the astrocytic response in the brain tissue of juvenile red-bellied pacu (Piaractus brachypomus) exposed to TCF and CPF. Materials and Methods: A 25-day subchronic assay was conducted in which juvenile red-bellied pacu were exposed to CPF and TCF. After 25 days of exposure, the fish were killed and brain samples were collected and processed for immunohistochemistry to assess the morphology and reactivity of astrocytes; glial acidic fibrillary protein was used as a biomarker. Results: The brain samples from animals under subchronic exposure to OPs for 25 days showed higher cellular density as well as changes in astrocyte phenotype characterized by shortening of cytoplasmic projections, hypertrophy, and ameboid morphology compared to those from nonexposed animals. Similarly, astrocyte hyperreactivity was detected in the optic tectum and medial longitudinal fasciculus of the exposed group. Conclusion: Immunoreactivity of brain glial cells under subchronic exposure to OPs measured through immunohistochemical tests as well as OPs-induced neuropathology may be useful as a biomarker for monitoring environmental pollution. The results also indicate that P. brachypomus is a suitable biomonitoring model for studying neurotoxicological and neurodegenerative diseases.

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“…EEG and video analysis. EEG data were analyzed using a Matlab [45] automated algorithm and manually in BioPac's AcqKnowledge software (Goleta, CA, USA). We used five criteria to identify seizures.…”

Section: Animalsmentioning

confidence: 99%

“…1C). Using an automated MatLab algorithm [45], each EEG event was manually confirmed together with a video review. We demonstrate that 37% of all mice tested were PTE + , with a higher incidence seen in mice whose histopathology showed evidence of hippocampal damage or displacement and categorized as severe (Fig.…”

Section: Murine Cci-induced Pte Is Associated With Injury Severity An...mentioning

confidence: 99%

Atypical Neurogenesis, Astrogliosis, and Excessive Hilar Interneuron Loss Are Associated With the Development of Post-Traumatic Epilepsy

Basso¹,

Shandra²,

Volanth³

et al. 2023

Preprint

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Background: Traumatic brain injury (TBI) remains a significant risk factor for post-traumatic epilepsy (PTE). The pathophysiological mechanisms underlying the injury-induced epileptogenesis are under under investigation. The dentate gyrus, a structure highly susceptible to injury, and has been implicated in the evolution of seizure development. Methods: Utilizing the murine unilateral focal control cortical impact (CCI) injury, we evaluated seizure onset using 24/7 EEG video analysis at 2-4 months post-injury. Cellular changes in the dentate gyrus and hilus of the hippocampus were quantified by non-biased stereology and Imaris image analysis to evaluate Prox1-positive cell migration, astrocyte branching and morphology, as well as neuronal loss at four months post-injury. Isolation of region-specific astrocytes and RNA-seq was performed to determine differential gene expression in PTE+ vs. PTE- that may comport with the epileptogenic process. Results: CCI injury resulted in 37% PTE+-incidence, which increased with injury severity and hippocampal damage. Histological assessments uncovered a significant loss of hilar interneurons that coincided with aberrant migration of Prox1-positive granule cells and reduced astroglial branching in PTE+ compared to PTE- mice. We uniquely identified Cst3 as a PTE+-specific gene signature in astrocytes across all brain regions. Conclusions: These findings suggest that epileptogenesis may emerge following TBI due to distinct aberrant cellular remodeling events and key molecular changes in the dentate gyrus of the hippocampus.

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Repetitive Diffuse Mild Traumatic Brain Injury Causes an Atypical Astrocyte Response and Spontaneous Recurrent Seizures

Cited by 4 publications

References 0 publications

Systems spatiotemporal dynamics of traumatic brain injury at single-cell resolution reveals humanin as a therapeutic target

Systems spatiotemporal dynamics of traumatic brain injury at single-cell resolution reveals humanin as a therapeutic target

First study on response of astrocytes in alevines of red-bellied pacu (Piaractus brachypomus) to subchronic exposure to chlorpyrifos and trichlorfon

Atypical Neurogenesis, Astrogliosis, and Excessive Hilar Interneuron Loss Are Associated With the Development of Post-Traumatic Epilepsy

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