The Ca2+-calmodulin (Ca2+-CaM) dependent protein kinase kinase-2 (CaMKK2) is the core component of a signalling pathway in neurons that regulates appetite, mood and whole-body energy metabolism. We recently discovered that, in addition to being activated by Ca2+-CaM, CaMKK2 is also activated by fatty acid metabolites (palmitoyl -CoA). Emerging evidence indicates that fatty acids released from skeletal muscle during exercise can act centrally in the brain to enhance mood, and may provide a molecular mechanism to explain the long-established relationship between exercise and positive mental health. To explore these concepts further, we have generated a CaMKK2 G551L knock in (KI) mouse containing a mutation that renders it insensitive to fatty acid activation. CaMKK2 is the main driver of brain-derived neurotrophic factor (BDNF) expression in neurons, which promotes mood stability and protects against anxiety and depression. BDNF expression is increased in response to exercise, however the molecular mechanisms that link the two are unclear. Our knock-in mice are a uniquely powerful model to determine whether CaMKK2 is the key factor that drives the positive mental effects of exercise. Therefore, the main aims of the project were: i) Determine the effects of exercise training on BDNF expression in brain in Wild-type (C57Bl/6 -WT) and G551L KI mice; ii) Determine the effects of exercise training on anxiety and depressive-like behaviours in WT and G551L KI mice.This project will employ a range of state-of-the-art techniques including mouse behavioural tests, neuroimaging, RNAscope, mouse exercise protocols, metabolic assays, and metabolomics.
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