Enriched environment enhances β-adrenergic signaling to prevent microglia inflammation by amyloid-β

Environmental enrichment (EE) is a rodent behavioral paradigm that can model the cognitive benefits to humans associated with intellectual activity and exercise. We recently discovered EE's anti-inflammatory protection of brain microglia against soluble oligomers of human amyloid beta-protein (oA beta). Mechanistically, we report that the key factor in microglial protection by EE is chronically enhanced beta-adrenergic signaling. Quantifying microglial morphology and inflammatory RNA profiles revealed that mice in standard housing (SH) fed the beta-adrenergic agonist isoproterenol experienced similar protection of microglia against oA beta-induced inflammation as did mice in EE. Conversely, mice in EE fed the beta-adrenergic antagonist propranolol lost microglial protection against oA beta. Mice lacking beta 1/beta 2-adrenergic receptors showed no protection of microglia by EE. In SH mice, quantification of norepinephrine in hippocampus and interstitial fluid showed that oA disrupted norepinephrine homeostasis, and microglial-specific analysis of beta 2-adrenergic receptors indicated a decreased receptor level. Both features were rescued by EE. Thus, enhanced beta-adrenergic signaling at the ligand and receptor levels mediates potent benefits of EE on microglial inflammation induced by human A beta oligomers invivo.