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- W2891501311 abstract "Abstract In traumatic brain injury (TBI) the initial injury phase is followed by a secondary phase that contributes to neurodegeneration. Yet the mechanisms leading to neuropathology in vivo remain to be elucidated. To address this question, we developed a Drosophila head-specific model for TBI, which we term Drosophila Closed Head Injury (dCHI), where well-controlled, non-penetrating strikes are directly delivered to the head of unanesthetized flies. This assay recapitulates many TBI phenotypes, including increased mortality, impaired motor control, fragmented sleep, and increased neuronal cell death. To discover novel mediators of TBI, we used glial targeted translating ribosome affinity purification in combination with RNA sequencing. We detected significant changes in the transcriptome at various times after TBI including in genes involved in innate immunity within 24 hours after TBI. To test the in vivo functional role of these changes, we examined TBI-dependent behavior and lethality in mutants of the master immune regulator NF-κB and found that while lethality effects were still evident, changes in sleep and motor function were substantially reduced. These studies validate a new head-specific model for TBI in Drosophila and identify glial immune pathways as candidate in vivo mediators of TBI effects. Traumatic brain injury (TBI) is one of the leading causes of death and disability in the developed world [1-3]. Yet the underlying mechanisms that lead to long term physical, emotional, and cognitive impairment remain unclear. Unlike in most forms of trauma, a large percentage of people killed by traumatic brain injuries do not die immediately but rather days or weeks after the insult [4]. TBI consists of a primary and a secondary phase. The primary brain injury is the result of an external mechanical force, resulting in damaged blood vessels, axonal shearing [5], cell death, disruption of the blood– brain barrier, edema, and the release of damage associated molecular patterns (DAMPs) and excitotoxic agents [6]. In response, local glia and infiltrating immune cells upregulate cytokines (tumor necrosis factor α) and interleukins (IL-6 and IL-1β) that drive post-traumatic neuroinflammation [7-10]. This secondary injury develops over a much longer time course, ranging from hours to months after the initial injury and is the result of a complex cascade of metabolic, cellular and molecular processes [11-13]. Neuroinflammation is beneficial when it is promoting clearance of debris and regeneration [14] but can become harmful, mediating neuronal death, progressive neurodegeneration, and neurodegenerative disorders [15-18]. The mechanisms underlying these opposing outcomes are largely unknown, but are thought to depend of the location and timing of the neuroinflammatory response [19, 20]. It remains to be determined what the relative roles of TBI-induced neuroinflammation and other TBI-induced changes are in mediating short and long-term impairments in brain function in vivo. To study the mechanisms that mediate TBI pathology in vivo over time, we employ the fruit fly Drosophila melanogaster , a model organism well suited to understanding the in vivo genetics of brain injury. Despite considerable morphological differences between flies and mammals, the fly brain operates on similar principles through a highly conserved repertoire of neuronal signaling proteins, including a large number of neuronal cell adhesion receptors, synapse-organizing proteins, ion channels and neurotransmitter receptors, and synaptic vesicle-trafficking proteins [21]. This homology makes Drosophila a fruitful model to study neurodegenerative disorders [22], including ALS [23], Alzheimer’s disease [24], Huntington’s disease [25] and Parkinson’s disease [26]. Trauma-induced changes in glial gene expression are a highly conserved feature of both mammalian [27, 28] and Drosophila glia [29-32] (reviewed in [33]). In Drosophila , glia are able to perform immune-related functions [32, 34]. Ensheathing glia can act as phagocytes and contribute to the clearance of degenerating axons from the fly brain [29, 31, 35]. The Drosophila innate immune system is highly conserved with that of mammals and consists primarily of the Toll, Immunodeficiency (Imd) and Janus Kinase protein and the Signal Transducer and Activator of Transcription (JAK-STAT) pathways, which together combat fungal and bacterial infections [36, 37]. Dysregulation of cerebral innate immune signaling in Drosophila glial cells can lead to neuronal dysfunction and degeneration [38, 39], suggesting that changes in glia cells could underlie secondary injury mechanisms in our Drosophila model of TBI. Existing Drosophila TBI models [40, 41] deliver impacts to the entire body, not just the head, and thus, one cannot definitively attribute ensuing phenotypes to TBI. To remove the confound of bodily injury, we have developed a novel, head-specific Drosophila model for TBI, Drosophila Closed Head Injury (dCHI). Here we show that by delivering precisely controlled, non-penetrating strikes to an unanesthetized fly’s head, we can induce cell death and increased mortality in a dose-dependent manner. In addition, TBI results in impaired motor control and decreased, fragmented sleep. Impaired motor control persists for many days after TBI while the sleep phenotype disappears after three days. These TBI-induced behavioral phenotypes do not occur in mutants lacking the master immune regulator NF-κB Relish ( Rel ), even though TBI-induced mortality is greatly induced in these mutants. In wild type flies, TBI results in changes in glial gene expression, where many immune related genes are upregulated 24 hours after injury. Together, these results establish a platform where powerful Drosophila genetics can be utilized to study the complex cascade of secondary injury mechanisms that occur after TBI in order to genetically disentangle its beneficial and detrimental effects." @default.
- W2891501311 created "2018-09-27" @default.
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- W2891501311 date "2018-09-20" @default.
- W2891501311 modified "2023-09-26" @default.
- W2891501311 title "Glial immune-related pathways as mediators of closed head TBI effects on behavior in <i>Drosophila</i>" @default.
- W2891501311 cites W1114726613 @default.
- W2891501311 cites W1487697945 @default.
- W2891501311 cites W1511996564 @default.
- W2891501311 cites W1595377383 @default.
- W2891501311 cites W166433223 @default.
- W2891501311 cites W1745005559 @default.
- W2891501311 cites W1769448430 @default.
- W2891501311 cites W1771972286 @default.
- W2891501311 cites W1822745879 @default.
- W2891501311 cites W1876773427 @default.
- W2891501311 cites W1965495835 @default.
- W2891501311 cites W1969203830 @default.
- W2891501311 cites W1972677800 @default.
- W2891501311 cites W1976316003 @default.
- W2891501311 cites W1976897228 @default.
- W2891501311 cites W1977951553 @default.
- W2891501311 cites W1979050144 @default.
- W2891501311 cites W1984737307 @default.
- W2891501311 cites W1985252982 @default.
- W2891501311 cites W1986918091 @default.
- W2891501311 cites W1988094797 @default.
- W2891501311 cites W1988610853 @default.
- W2891501311 cites W1988808659 @default.
- W2891501311 cites W1990514899 @default.
- W2891501311 cites W1993981485 @default.
- W2891501311 cites W1995572922 @default.
- W2891501311 cites W1997576057 @default.
- W2891501311 cites W2001068966 @default.
- W2891501311 cites W2002068275 @default.
- W2891501311 cites W2002216056 @default.
- W2891501311 cites W2004666307 @default.
- W2891501311 cites W2005401338 @default.
- W2891501311 cites W2005758956 @default.
- W2891501311 cites W2008325147 @default.
- W2891501311 cites W2011356417 @default.
- W2891501311 cites W2011647197 @default.
- W2891501311 cites W2012338377 @default.
- W2891501311 cites W2018067227 @default.
- W2891501311 cites W2021668479 @default.
- W2891501311 cites W2022001110 @default.
- W2891501311 cites W2031242418 @default.
- W2891501311 cites W2034123113 @default.
- W2891501311 cites W2034901682 @default.
- W2891501311 cites W2035181561 @default.
- W2891501311 cites W2039521726 @default.
- W2891501311 cites W2048137511 @default.
- W2891501311 cites W2048438139 @default.
- W2891501311 cites W2053685560 @default.
- W2891501311 cites W2055807373 @default.
- W2891501311 cites W2056213320 @default.
- W2891501311 cites W2060279158 @default.
- W2891501311 cites W2067448822 @default.
- W2891501311 cites W2069473378 @default.
- W2891501311 cites W2070093243 @default.
- W2891501311 cites W2074344918 @default.
- W2891501311 cites W2075008638 @default.
- W2891501311 cites W2075782105 @default.
- W2891501311 cites W2077812845 @default.
- W2891501311 cites W2077927847 @default.
- W2891501311 cites W2083102961 @default.
- W2891501311 cites W2083462524 @default.
- W2891501311 cites W2085262393 @default.
- W2891501311 cites W2088196319 @default.
- W2891501311 cites W2088329771 @default.
- W2891501311 cites W2089631463 @default.
- W2891501311 cites W2091838922 @default.
- W2891501311 cites W2092348144 @default.
- W2891501311 cites W2095491556 @default.
- W2891501311 cites W2095916445 @default.
- W2891501311 cites W2097795961 @default.
- W2891501311 cites W2099369953 @default.
- W2891501311 cites W2100404048 @default.
- W2891501311 cites W2102549002 @default.
- W2891501311 cites W2102791000 @default.
- W2891501311 cites W2103868159 @default.
- W2891501311 cites W2113033488 @default.
- W2891501311 cites W2117775547 @default.
- W2891501311 cites W2119717666 @default.
- W2891501311 cites W2121749695 @default.
- W2891501311 cites W2122277738 @default.
- W2891501311 cites W2125174305 @default.
- W2891501311 cites W2127634810 @default.
- W2891501311 cites W2129999356 @default.
- W2891501311 cites W2132505635 @default.
- W2891501311 cites W2135623011 @default.