Diacylglycerol Lipase-β Knockout Mice Display a Sex-Dependent Attenuation of Traumatic Brain Injury-Induced Mortality with No Impact on Memory or Other Functional Consequences
| Autor: | Jason Newton, Terry L. Smith, Lesley D. O'Brien, Linda L. Phillips, Sarah Spiegel, Aron H. Lichtman, Giulia Donvito, Benjamin F. Cravatt, Thomas M. Reeves |
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| Rok vydání: | 2021 |
| Předmět: |
Male
medicine.medical_specialty Elevated plus maze Diacylglycerol lipase Traumatic brain injury Morris water navigation task Mice Internal medicine Brain Injuries Traumatic Animals Medicine Pharmacology (medical) Neuroinflammation Original Research Mice Knockout Pharmacology biology Microglia business.industry medicine.disease Endocannabinoid system Lipoprotein Lipase Endocrinology medicine.anatomical_structure Complementary and alternative medicine Neuroinflammatory Diseases Knockout mouse biology.protein Female business |
| Zdroj: | Cannabis Cannabinoid Res |
| ISSN: | 2378-8763 2578-5125 |
| Popis: | Background: The endogenous cannabinoid system modulates inflammatory signaling in a variety of pathological states, including traumatic brain injury (TBI). The selective expression of diacylglycerol lipase-β (DAGL-β), the 2-arachidonylglycerol biosynthetic enzyme, on resident immune cells of the brain (microglia) and the role of this pathway in neuroinflammation, suggest that this enzyme may contribute to TBI-induced neuroinflammation. Accordingly, we tested whether DAGL-β(−/−) mice would show a protective phenotype from the deleterious consequences of TBI on cognitive and neurological motor functions. Materials and Methods: DAGL-β(−/−) and -β(+/+) mice were subjected to the lateral fluid percussion model of TBI and assessed for learning and memory in the Morris water maze (MWM) Fixed Platform (reference memory) and Reversal (cognitive flexibility) tasks, as well as in a cued MWM task to infer potential sensorimotor/motivational deficits. In addition, subjects were assessed for motor behavior (Rotarod and the Neurological Severity Score assays) and in the light/dark box and the elevated plus maze to infer whether these manipulations affected anxiety-like behavior. Finally, we also examined whether brain injury disrupts the ceramide/sphingolipid lipid signaling system and if DAGL-β deletion offers protection. Results: TBI disrupted all measures of neurological motor function and reduced body weight, but did not affect body temperature or performance in common assays used to infer anxiety. TBI also impaired performance in MWM Fixed Platform and Reversal tasks, but did not affect cued MWM performance. Although no differences were found between DAGL-β(−/−) and -β(+/+) mice in any of these measures, male DAGL-β(−/−) mice displayed an unexpected survival-protective phenotype, which persisted at increased injury severities. In contrast, TBI did not elicit mortality in female mice regardless of genotype. TBI also produced significant changes in sphingolipid profiles (a family of lipids, members of which have been linked to both apoptotic and antiapoptotic pathways), in which DAGL-β deletion modestly altered levels of select species. Conclusions: These findings indicate that although DAGL-β does not play a necessary role in TBI-induced cognitive and neurological function, it appears to contribute to the increased vulnerability of male mice to TBI-induced mortality, whereas female mice show high survival rates irrespective of DAGL-β expression. |
| Databáze: | OpenAIRE |
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