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The meningeal transciptional response to traumatic brain injury and aging [scRNA-seq]

ABSTRACT: Emerging evidence suggests that the meningeal compartment plays instrumental roles in various neurological disorders and can modulate neurodevelopment and behavior. While this has sparked great interest in the meninges, we still lack fundamental knowledge about meningeal biology. Here, we utilized high-throughput RNA sequencing (RNA-seq) techniques to investigate the transcriptional response of the meninges to traumatic brain injury (TBI) and aging in the sub-acute and chronic time frames. Using single-cell RNA sequencing (scRNA-seq), we first explored how mild TBI affects the cellular and transcriptional landscape in the meninges in young mice at one week post-injury. Then, using bulk RNA sequencing, we assessed the differential long-term outcomes between young and aged mice following a TBI. In our scRNA-seq studies, we found that mild head trauma leads to an activation of type I interferon (IFN) signature genes in meningeal macrophages as well as the mobilization of multiple distinct sub-populations of meningeal macrophages expressing hallmarks of either classically activated or wound healing macrophages. We also revealed that dural fibroblasts in the meningeal compartment are highly responsive to TBI, and pathway analysis identified differential expression of genes linked to various neurodegenerative diseases. For reasons that remain poorly understood, the elderly are especially vulnerable to head trauma, where even mild injuries can lead to rapid cognitive decline and devastating neuropathology. To better understand the differential outcomes between the young and the elderly following brain injury, we performed bulk RNA-seq on young and aged meninges from mice that had received a mild TBI or Sham treatment 1.5 months prior. Notably, we found that aging alone induced massive upregulation of meningeal genes involved in antibody production by B cells and type I IFN signaling. Following injury, the meningeal transcriptome had largely returned to its pre-injury signature in young mice. In stark contrast, aged TBI mice still exhibited massive upregulation of immune-related genes and markedly reduced expression of genes involved in extracellular matrix remodeling and maintenance of cellular junctions. Overall, these findings illustrate the dynamic and complex transcriptional response of the meninges to mild head trauma. Moreover, we also reveal how aging modulates the meningeal response to TBI.

ORGANISM(S): Mus musculus

PROVIDER: GSE206940 | GEO | 2022/12/22

REPOSITORIES: GEO

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Project description:Emerging evidence suggests that the meningeal compartment plays instrumental roles in various neurological disorders and can modulate neurodevelopment and behavior. While this has sparked great interest in the meninges, we still lack fundamental knowledge about meningeal biology. Here, we utilized high-throughput RNA sequencing (RNA-seq) techniques to investigate the transcriptional response of the meninges to traumatic brain injury (TBI) and aging in the sub-acute and chronic time frames. Using single-cell RNA sequencing (scRNA-seq), we first explored how mild TBI affects the cellular and transcriptional landscape in the meninges in young mice at one week post-injury. Then, using bulk RNA sequencing, we assessed the differential long-term outcomes between young and aged mice following a TBI. In our scRNA-seq studies, we found that mild head trauma leads to an activation of type I interferon (IFN) signature genes in meningeal macrophages as well as the mobilization of multiple distinct sub-populations of meningeal macrophages expressing hallmarks of either classically activated or wound healing macrophages. We also revealed that dural fibroblasts in the meningeal compartment are highly responsive to TBI, and pathway analysis identified differential expression of genes linked to various neurodegenerative diseases. For reasons that remain poorly understood, the elderly are especially vulnerable to head trauma, where even mild injuries can lead to rapid cognitive decline and devastating neuropathology. To better understand the differential outcomes between the young and the elderly following brain injury, we performed bulk RNA-seq on young and aged meninges from mice that had received a mild TBI or Sham treatment 1.5 months prior. Notably, we found that aging alone induced massive upregulation of meningeal genes involved in antibody production by B cells and type I IFN signaling. Following injury, the meningeal transcriptome had largely returned to its pre-injury signature in young mice. In stark contrast, aged TBI mice still exhibited massive upregulation of immune-related genes and markedly reduced expression of genes involved in extracellular matrix remodeling and maintenance of cellular junctions. Overall, these findings illustrate the dynamic and complex transcriptional response of the meninges to mild head trauma. Moreover, we also reveal how aging modulates the meningeal response to TBI.

Project description:Warfare has long been associated with traumatic brain injury (TBI) in militarized zones. Common forms of TBI can be caused by a physical insult to the head-brain or by the effects of a high velocity blast shock wave generated by the detonation of an explosive device. While both forms of trauma are distinctly different regarding the mechanism of trauma induction, there are striking similarities in the cognitive and emotional status of survivors. Presently, proven effective therapeutics for the treatment of either form of TBI are unavailable. To be able to develop efficacious therapies, studies involving animal models of physical- and blast-TBI are required to identify possible novel or existing medicines that may be of value in the management of clinical events. We examined indices of cognition and anxiety-like behavior and the hippocampal gene transcriptome of mice subjected to both forms of TBI. We identified common behavioral deficits and gene expression regulations, in addition to unique injury-specific forms of gene regulation. Molecular pathways presented a pattern similar to that seen in gene expression. Interestingly, pathways connected to AlzheimerM-bM-^@M-^Ys disease displayed a markedly different form of regulation depending on the type of TBI. While these data highlight similarities in behavioral outcomes after trauma, the divergence in hippocampal transcriptome observed between models suggests that, at the molecular level, the TBIs are quite different. These models may provide tools to help define therapeutic approaches for the treatment of physical- and blast-TBIs. Based upon observations of increasing numbers of personnel displaying TBI related emotional and behavioral changes in militarized zones, the development of efficacious therapies will become a national if not a global priority. Keywords: Physical-traumatic brain injury; Blast-traumatic brain injury; Cognitive dysfunction; Gene expression; Molecular pathway(s); Neurodegeneration; Stem cells; AlzheimerM-bM-^@M-^Ys disease A mild physical-TBI was induced using a concussive head trauma device described previously (Milman et al., 2005; Zohar et al., 2003). Briefly, mice were lightly anesthetized (Isoflurane) and placed under the weight-drop concussive head trauma instrument. The device consisted of a metal tube (inner diameter 13 mm), placed vertically over the mouse head. A metal weight (30 g) was dropped from the top of the tube (80 cm) and struck the skull at the right side temporal area between the corner of the eye and the ear. A sponge supported the head, allowing some antero-posterior motion without any rotational head movement at the moment of the impact. Experimental conditions used to create a mild low-level blast-TBI and the subsequent model characterization, have been described in detail elsewhere (Rubovitch et al., 2011). In brief, mice were anaesthetized with a combination of ketamine (100 mg/kg) and xylazine (10 mg/kg). Once the animals were fully anaesthetized they were placed at a defined distance from a detonation source, in this case 7 meters. Pressure sensors were used to measure the explosion shock wave pressure (PSI) generated by the detonation (Free-Field ICPM-BM-. Blast Pressure Sensor; PCB Piezoelectronics, Depew, NY, USA, Model 137). At 7 meters from the source of the detonation, the animals were exposed to a maximum of a 2.5 PSI (17.2 kPa) pressure shock wave. Immediately after the induction of the injury, mice were placed back in their cages. Once the animals had recovered from the anesthesia, basic neurological assessments were undertaken to identify any acute neurological dysfunction. Only animals exhibiting no evidence of acute neurological damage post injury were subsequently used in further experiments. Sham treated mouse groups were treated identically; however, they were not exposed to physical- or blast-TBI. Mouse hippocampus tissues were randomly selected from the larger library of samples generated from the behavioral experiments and the numbers utilized in the gene expression study were as follows: sham, n = 5: physical-TBI, n = 4; blast-TBI, n = 7.

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The meningeal transciptional response to traumatic brain injury and aging [scRNA-seq]

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