Tip60 HAT action mediates Environmental Enrichment induced cognitive restoration

Environmental stimuli provide neurons in the brain with instructive information that shapes synaptic connections to impact cognitive ability. As such, environmental enrichment (EE) conditions have profound beneficial effects for reinstating cognitive ability in neuropathological conditions such as Alzheimer's disease (AD). While EE benefits involve epigenetic gene control mechanisms that comprise histone acetylation, the select HATs involved remain largely unknown. I have shown that Tip60 HAT action controls activity-dependent cognition linked neuronal processes that include synaptic plasticity, axonal transport and epigenetically regulates transcriptional profiles of genes enriched for these functions. Here, I examine a role for Tip60 HAT action in mediating activity- dependent adaptations to EE. The mushroom body (MB) in the Drosophila brain is a superb model to study cognitive processes in vivo as it displays homology to human circuits corresponding to the hippocampus and as such, functions in learning and memory (L&M). Here, I show that misregulation of Tip60 in the fly MB results in memory defects in these flies. AD flies also exhibit memory impairment, consistent with their inability to learn. Remarkably, excess Tip60 rescues both L&M defects in AD flies. Morphological analysis of the MB revealed that EE induced MB axonal outgrowth while Tip60 deficient flies showed a defect in such beneficial EE axonal enhancement. These defects correlated with attenuation of the transcriptional profile of certain activity-dependent cognition linked genes induced in response to EE. Our results implicate Tip60 as a critical mediator of EE-induced benefits, and provide insight into non-invasive behavioral and epigenetic treatments for cognitive deficits in neurological disorders.