Cerebellar mitochondrial dysfunction and concomitant multi-system fatty acid oxidation defects are sufficient to discriminate PTSD-like and resilient male mice.

Autor:	Preston G; Department of Clinical Genomics, Mayo Clinic, 200 1st St. SW, Rochester, MN, 55905, USA.; Hayward Genetics Center, Tulane University School of Medicine, 1430 Tulane Ave., New Orleans, LA, 70112, USA., Emmerzaal T; Department of Clinical Genomics, Mayo Clinic, 200 1st St. SW, Rochester, MN, 55905, USA.; Department of Anatomy, Radboudumc, Geert Grooteplein Zuid 10, 6525, GA, Nijmegen, Netherlands., Kirdar F; Hayward Genetics Center, Tulane University School of Medicine, 1430 Tulane Ave., New Orleans, LA, 70112, USA., Schrader L; Department of Cell and Molecular Biology, Tulane University, 6823 St Charles Ave, New Orleans, LA, 70118, USA., Henckens M; Department of Cognitive Neurosciences, Radboudumc, Geert Grooteplein Zuid 10, 6525, GA, Nijmegen, Netherlands., Morava E; Department of Clinical Genomics, Mayo Clinic, 200 1st St. SW, Rochester, MN, 55905, USA., Kozicz T; Department of Clinical Genomics, Mayo Clinic, 200 1st St. SW, Rochester, MN, 55905, USA.
Jazyk:	angličtina
Zdroj:	Brain, behavior, & immunity - health [Brain Behav Immun Health] 2020 Jul 08; Vol. 6, pp. 100104. Date of Electronic Publication: 2020 Jul 08 (Print Publication: 2020).
DOI:	10.1016/j.bbih.2020.100104
Abstrakt:	The impact of trauma on mental health is complex with poorly understood underlying mechanisms. Mitochondrial dysfunction is increasingly implicated in psychopathologies and mood disorders, including post-traumatic stress disorder (PTSD). We hypothesized that defects in mitochondrial energy metabolism in the cerebellum, an emerging region of interest in the pathobiology of mood disorders, would be associated with PTSD-like symptomatology, and that PTSD-like symptomatology would correlate with the activities of the mitochondrial electron transport chain (mtETC) and fatty acid oxidation (FAO) pathways. We assayed mitochondrial energy metabolism and fatty acid profiling using targeted metabolomics in mice exposed to a recently developed paradigm for PTSD-induction. 48 wild type male FVB.129P2 mice were exposed to a trauma, and PTSD-like and resilient animals were identified using behavioral profiling. Mice displaying PTSD-like symptomatology displayed reduced mtETC complex activities in the cerebellum, and cerebellar mtETC complex activity negatively correlated with PTSD-like symptomatology. PTSD-like animals also displayed fatty acid profiles consistent with FAO dysfunction in both cerebellum and plasma. Machine learning analysis of all biochemical measures in this cohort of animals also identified plasma acetylcarnitine, along with reduced activity of cerebellar complex I and IV as well as succinate:cytochrome c oxidoreductase as state predictive discriminators of PTSD-symptomatology. Our data also suggest that trauma-induced impaired mtETC function in the cerebellum and concomitant impaired multi-system fatty acid oxidation are candidate drivers of PTSD-like behavior in mice. These bioenergetic and metabolic changes may offer an informative window into the underlying biology and highlight novel potential targets for diagnostics and therapeutic interventions in PTSD. Competing Interests: No Authors have any conflicts of interest to disclose. (© 2020 The Authors.)
Databáze:	MEDLINE
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