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      Low brain endocannabinoids associated with persistent non-goal directed nighttime hyperactivity after traumatic brain injury in mice

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          Abstract

          Traumatic brain injury (TBI) is a frequent cause of chronic headache, fatigue, insomnia, hyperactivity, memory deficits, irritability and posttraumatic stress disorder. Recent evidence suggests beneficial effects of pro-cannabinoid treatments. We assessed in mice levels of endocannabinoids in association with the occurrence and persistence of comparable sequelae after controlled cortical impact in mice using a set of long-term behavioral observations in IntelliCages, motor and nociception tests in two sequential cohorts of TBI/sham mice. TBI mice maintained lower body weights, and they had persistent low levels of brain ethanolamide endocannabinoids (eCBs: AEA, OEA, PEA) in perilesional and subcortical ipsilateral brain tissue (6 months), but rapidly recovered motor functions (within days), and average nociceptive responses were within normal limits, albeit with high variability, ranging from loss of thermal sensation to hypersensitivity. TBI mice showed persistent non-goal directed nighttime hyperactivity, i.e. they visited rewarding and non-rewarding operant corners with high frequency and random success. On successful visits, they made more licks than sham mice resulting in net over-licking. The lower the eCBs the stronger was the hyperactivity. In reward-based learning and reversal learning tasks, TBI mice were not inferior to sham mice, but avoidance memory was less stable. Hence, the major late behavioral TBI phenotype was non-goal directed nighttime hyperactivity and "over-licking" in association with low ipsilateral brain eCBs. The behavioral phenotype would agree with a "post-TBI hyperactivity disorder". The association with persistently low eCBs in perilesional and subcortical regions suggests that eCB deficiency contribute to the post-TBI psychopathology.

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          CB1 cannabinoid receptors and on-demand defense against excitotoxicity.

          Abnormally high spiking activity can damage neurons. Signaling systems to protect neurons from the consequences of abnormal discharge activity have been postulated. We generated conditional mutant mice that lack expression of the cannabinoid receptor type 1 in principal forebrain neurons but not in adjacent inhibitory interneurons. In mutant mice,the excitotoxin kainic acid (KA) induced excessive seizures in vivo. The threshold to KA-induced neuronal excitation in vitro was severely reduced in hippocampal pyramidal neurons of mutants. KA administration rapidly raised hippocampal levels of anandamide and induced protective mechanisms in wild-type principal hippocampal neurons. These protective mechanisms could not be triggered in mutant mice. The endogenous cannabinoid system thus provides on-demand protection against acute excitotoxicity in central nervous system neurons.
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            Modulation of anxiety through blockade of anandamide hydrolysis.

            The psychoactive constituent of cannabis, Delta(9)-tetrahydrocannabinol, produces in humans subjective responses mediated by CB1 cannabinoid receptors, indicating that endogenous cannabinoids may contribute to the control of emotion. But the variable effects of Delta(9)-tetrahydrocannabinol obscure the interpretation of these results and limit the therapeutic potential of direct cannabinoid agonists. An alternative approach may be to develop drugs that amplify the effects of endogenous cannabinoids by preventing their inactivation. Here we describe a class of potent, selective and systemically active inhibitors of fatty acid amide hydrolase, the enzyme responsible for the degradation of the endogenous cannabinoid anandamide. Like clinically used anti-anxiety drugs, in rats the inhibitors exhibit benzodiazepine-like properties in the elevated zero-maze test and suppress isolation-induced vocalizations. These effects are accompanied by augmented brain levels of anandamide and are prevented by CB1 receptor blockade. Our results indicate that anandamide participates in the modulation of emotional states and point to fatty acid amide hydrolase inhibition as an innovative approach to anti-anxiety therapy.
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              Astrocyte roles in traumatic brain injury.

              Astrocytes sense changes in neural activity and extracellular space composition. In response, they exert homeostatic mechanisms critical for maintaining neural circuit function, such as buffering neurotransmitters, modulating extracellular osmolarity and calibrating neurovascular coupling. In addition to upholding normal brain activities, astrocytes respond to diverse forms of brain injury with heterogeneous and progressive changes of gene expression, morphology, proliferative capacity and function that are collectively referred to as reactive astrogliosis. Traumatic brain injury (TBI) sets in motion complex events in which noxious mechanical forces cause tissue damage and disrupt central nervous system (CNS) homeostasis, which in turn trigger diverse multi-cellular responses that evolve over time and can lead either to neural repair or secondary cellular injury. In response to TBI, astrocytes in different cellular microenvironments tune their reactivity to varying degrees of axonal injury, vascular disruption, ischemia and inflammation. Here we review different forms of TBI-induced astrocyte reactivity and the functional consequences of these responses for TBI pathobiology. Evidence regarding astrocyte contribution to post-traumatic tissue repair and synaptic remodeling is examined, and the potential for targeting specific aspects of astrogliosis to ameliorate TBI sequelae is considered.
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                Author and article information

                Contributors
                tegeder@em.uni-frankfurt.de
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                10 September 2020
                10 September 2020
                2020
                : 10
                : 14929
                Affiliations
                [1 ]GRID grid.7839.5, ISNI 0000 0004 1936 9721, Institute of Clinical Pharmacology, Medical Faculty, , Goethe-University Frankfurt, ; Frankfurt, Germany
                [2 ]GRID grid.410607.4, Department of Anesthesiology, , University Medical Center, Johannes Gutenberg-University Mainz, ; Mainz, Germany
                Article
                71879
                10.1038/s41598-020-71879-x
                7483739
                32913220
                e23769a1-3558-4df1-a43d-ae9be8811711
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 25 March 2020
                : 13 July 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: CRC1080, A03
                Award Recipient :
                Categories
                Article
                Custom metadata
                © The Author(s) 2020

                Uncategorized
                circadian rhythms and sleep,cognitive neuroscience,diseases of the nervous system,learning and memory,motor control,reward,sensory processing,somatosensory system,lipids

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