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.

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 Alzheimer’s 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; Alzheimer’s disease

Project description:The problem of traumatic brain injury (TBI) heterogeneity has been a critical barrier to successful translation of therapies in the field. TBI heterogeneity exists in the patient substrate pre-injury (genetics, sex, comorbidities), external injury characteristics (severity, mechanism), and resultant post-injury host response that is responsible for deleterious secondary injury processes (seizures, neuroinflammation, neurodegeneration) and repair/regeneration. Identification of final common molecular pathways and signatures that integrate this vast heterogeneity could be valuable for guiding biomarkers, therapeutic targets, and predictive enrichment. In this study, we present the first large-scale searchable murine single-cell atlas of the transcriptomic response to TBI in 339,357 cells as a foundational step in molecularly deconstructing TBI heterogeneity. We identify 23 cell types with massive heterogeneity in the single-cell response across extrinsicand intrinsic factors, that has been underestimated. Majority of response to TBI was unique to individual cell populations with minimal overlap even within a single injury-model thus highlighting the importance of cell-level resolution. Through this effort, we report novel cell-specific targets and a previously unrecognized role for specific microglial and ependymal subtypes in post-TBI pathophysiology that is highly variable depending on the extrinsic and intrinsic factors studied. One ependymal subtype was a hub of neuroinflammatory signaling after contusional-TBI, particularly related to Il-1b. A single microglial-lineage along pseudotime (comprising 3 microglial subtypes) was a key mediator of host-response after TBI, and shared features with disease associated microglia noted in Alzheimer’s disease and other neurodegenerative disorders, potentially providing a link between TBI and accelerated neurodegeneration. One microglial subtype within this lineage emerged as a key target – it was the only cell type of all 23 that retained persistent and marked gene expression changes 6 months post contusional-TBI. We identify sexually dimorphic gene expression and pathway vulnerabilities with cell-specific differences in both immune and non-immune biological processes. These likely contribute to sex-based outcome and warrant further study to facilitate discovery of cell- and sex-specific druggable targets. Active changes in brain regions distal from the site of primary TBI impact included infiltration of specific microglial populations as well as cell-specific transcriptomic changes in several genes and inflammatory processes distinct from both the peri-contusional and naïve signatures. This atlas validates several known contributors in TBI pathophysiology, and also identifies previously unrecognized targets and avenues for further research. Beyond our presented exemplar analyses (including pathways of clinical interest like sulfonylurea-receptor-1), the companion searchable atlas serves as a foundation for countless future efforts to understand cell-specific heterogeneity after TBI (https://shiny.crc.pitt.edu/cerebri/) as well as numerous other neurological diseases with overlapping pathophysiology.

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Thyroid Hormone T4 Mitigates Traumatic Brain Injury by Dynamically Remodeling Cell Type Specific Genes, Pathways, and Networks in Hippocampus and Frontal Cortex

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