Blast traumatic brain injury induced cognitive deficits are attenuated by pre- or post-injury treatment with the glucagon-like peptide-1 receptor agonist, exendin-4 [Day 3 dataset]
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ABSTRACT: Blast traumatic brain injury (B-TBI) affects military and civilian personnel. Presently there are no approved drugs for blast brain injury. Exendin-4, administered subcutaneously, was evaluated as a pre-treatment (48 hours) and post-injury treatment (2 hours) on neurodegeneration, behaviors and gene expressions in a murine open field model of blast injury. B-TBI induced neurodegeneration, changes in cognition and genes expressions linked to dementia disorders. Exendin-4, administered pre- or post-injury ameliorated B-TBI-induced neurodegeneration at 72 hours, memory deficits from days 7-14 and attenuated genes regulated by blast at day 14 post-injury. The present data suggest shared pathological processes between concussive and B-TBI, with endpoints amenable to beneficial therapeutic manipulation by exendin-4. B-TBI-induced dementia-related gene pathways and cognitive deficits in mice somewhat parallel epidemiological studies of Barnes and co-workers who identified a greater risk in US military veterans who experienced diverse TBIs, for dementia in later life.
Project description:Traumatic brain injury dysregulates microRNA expression in the brain. We hypothesized that injury-induced epigenetic changes contribute to neurodegeneration and learning and memory deficits after TBI. These changes may provide a mechanistic explanation for neuropsychiatric comorbidities in TBI patients. Our objective is to compare and contrast the effects of several neuroprotective drugs (JM6, PMI-006 and E33-estrogen) on the TBI-induced changes in microRNA expression in the hippocampus, a region of the brain that is critical for learning and memory. We will also study if different neuroprotective drugs have similar effects on common microRNAs which may cooperatively regulate a common set of gene targets. 3 biological samples each of Naïve, Sham control, TBI and TBI plus JM6, TI plus PMI-006, and TBI plus E33 rat hippocampi were obtained 24 hr post-sham injury or TBI, stored in RNA later and sent to GenUs Biosystems for microRNA microarray analysis.
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:Traumatic brain injury dysregulates microRNA expression in the brain. We hypothesized that injury-induced epigenetic changes contribute to neurodegeneration and learning and memory deficits after TBI. These changes may provide a mechanistic explanation for neuropsychiatric comorbidities in TBI patients. Our objective is to compare and contrast the effects of several neuroprotective drugs (JM6, PMI-006 and E33-estrogen) on the TBI-induced changes in microRNA expression in the hippocampus, a region of the brain that is critical for learning and memory. We will also study if different neuroprotective drugs have similar effects on common microRNAs which may cooperatively regulate a common set of gene targets.
Project description:Traumatic brain injury (TBI) alters and dysregulates the expression of thousands of genes in the brain. Since some of the most common problems in TBI patients are learning and memory deficits, we are studying the effects of TBI on the hippocampus, a region of the brain which is essential for learning and memory and which is known to be particularly vulnerable to TBI. We are interested in understanding how potential neuroprotective drugs alter the TBI-induced gene expression profile. The objective of this study is to elucidate and compare the differential gene expression profiles in the hippocampus of naive, sham-control, TBI and TBI plus drug treated rats. JM6, PMI-006 and E33 are three compounds with neuroprotective, anti-inflammatory and anti-oxidative effects. Our goal is to determine if different neuroprotective compounds have similar effects on common gene targets. These genes and the cell signaling pathways linked to them would then be the target of new therapeutic strategies for TBI. Rats were prepared for fluid percussion traumatic brain injury or sham injury (naïve rats had no anesthesia and were not handled in any way and gene expression in their brains serve as baseline data) and 24 hr post-injury, hippocampi were obtained, and stored in RNA later. Total RNA was isolated, quantitified and used for Agilent microarray analysis at GenUs Biosystems. Each group of naive, sham control, TBI and TBI plus JM6, TBI plus PMI-006 and TBI plus E33 (estrogen) has three biological replicates.
Project description:To gain insight into the biological functions of the highly expressed GLP-1R in Brunner’s glands, transcriptome analyses were conducted in male GLP-1R-/- and wild-type control mice. Analyses were performed 6 hours after a single s.c. dose of exendin-4 (1.0mg/kg s.c.), following 18 hours of two doses of exendin-4 (1.0 mg/kg s.c., administered at 0 and 9 hours), and in untreated controls. Brunner’s glands were isolated by laser capture micro dissection and extracted total RNA was used for microarray profiling.
Project description:Compared to patients with no TBI history, patients with a TBI history at least one month before infectious encephalitis have an increased risk of mortality, epilepsy, and dementia or delirium. Those with a history of TBI have an increased risk of various outcomes, including mortality, epilepsy, and dementia. Bulk RNA sequencing of the hippocampus from mice subjected to CCI injury and VEEV infection demonstrated that key pathways, specifically those involved in granzyme-mediated cell death, were enriched compared to VEEV infection alone.
Project description:Traumatic brain injuries (TBI) of varied types are common across all populations and can cause visual problems. For military personnel in combat settings, injuries from blast exposures (bTBI) are prevalent and arise from a myriad of different situations. To model these diverse conditions, we are one of several groups modeling bTBI using mice in varying ways. Here, we report a refined analysis of retinal ganglion cell (RGC) damage in male C57BL/6J mice exposed to a blast-wave in an enclosed chamber. Ganglion cell layer thickness, RGC density (BRN3A and RBPMS immunoreactivity), cellular density of ganglion cell layer (hematoxylin and eosin staining), and axon numbers (paraphenylenediamine staining) were quantified at timepoints ranging from 1 to 17-weeks. RNA sequencing was performed at 1-week and 5-weeks post-injury. Earliest indices of damage, evident by 1-week post-injury, are a loss of RGC marker expression, damage to RGC axons, and increase in glial markers expression. Blast exposure caused a loss of RGC somas and axons-with greatest loss occurring by 5-weeks post-injury. While indices of glial involvement are prominent early, they quickly subside as RGCs are lost. The finding that axonopathy precedes soma loss resembles pathology observed in mouse models of glaucoma, suggesting similar mechanisms.
Project description:Lipofuscin is an autofluorescent (AF) pigment formed by lipids and misfolded proteins that accumulates in post-mitotic cells with advanced age. Here we immunophenotyped microglia in the brain of old C57BL/6 mice (>18 months-old) and demonstrate that in comparison to young mice, one third of old microglia are AF, characterized by profound changes in lipid and iron content, phagocytic activity, and oxidative stress. Pharmacological depletion of microglia in old mice eliminated the AF microglia following repopulation and reversed microglial dysfunction. Age-related neurological deficits and neurodegeneration after traumatic brain injury (TBI) were attenuated in old mice lacking AF microglia. Furthermore, hyperphagocytic activity and lipid accumulation in microglia persisted for up to one year after TBI, was modified by Apoe4 genotype, and chronically driven by phagocyte-mediated oxidative stress. Thus, AF may reflect a pathological state in aging microglia associated with hyperphagocytosis and inflammatory neurodegeneration that can be further accelerated by TBI.
Project description:Primary blast-induced mild traumatic brain injury (mTBI) represents a common injury experienced during modern warfare. With virtually no apparent physical damage or symptoms presented, an effective source with minimum-invasion for mTBI biomarker discovery is required. In this study, we measure the transcriptomic sensitivity of the hair follicles in relation to the severity of primary blast-derived TBI.