Repetitive mild traumatic brain injury (r-mTBI) can induce neurological damage many years after the cessation of injury, increasing the risk for ADRD. No disease-modifying treatment strategies have been developed to mitigate the long-term consequences of r-mTBI. There is an urgent need to advance our current understanding of the cellular mechanisms driving the cascade of secondary injury events, as this could lead to the identification and development of novel therapeutics. Astrocytes play an important role in these secondary injury events. After acute insult, they undergo a dramatic transcriptomic and morphological transformation. Reactive astrocytes can be polarized into different states adopting neuroprotective or neurotoxic properties that can influence brain recovery. Neuroprotective astrocytes can serve to create a physical barrier to limit the spread of damage, preventexcitotoxicity, boost metabolic support for neurons, and release trophic factors to promote neurorepair. While neurotoxic astrocytes can take a dual role of neuroinflammation and glial scar formation that inhibits axonal regeneration and promotes neuronal damage, and this can be accompanied by loss of their constitutive supportive roles. Our knowledge of the mechanisms that regulate astrocyte phenotypes and responses in the healthy brain or after brain injury is lacking. To address this, we established a mouse model of r-mTBI that recapitulates many of the features of human TBI and thus represents a translationally relevant preclinical platform. Using this model, we generated a molecular library of astroglia gene profiles, at a range of timepoints post-injury that provides a unique and detailed time-course of the astroglia response to TBI. Particularly, we reveal deficits in cellular metabolism, oxidative stress and a proinflammatory signature of astroglia, which appears to be influenced by the loss of constitutive PPAR? signaling in astrocytes. PPARγ is highly expressed in glial cells and plays a vital constitutive role in regulating cell metabolism, bioenergetics, cell survival and immune function. Treatment with a PPARγ agonist has shown efficacy in restoring behavioral outcomes and rescuing astroglia pathobiology in our r-mTBI model. Because multiple cell types express PPARγ receptors, PPARγ ligands lack the specificity needed to target astroglia specific PPARγ signaling in vivo. In this proposal, we plan to clarify the constitutive role of PPARγ in regulating astroglial responses in the healthy brain and in the context of TBI, and demonstrate whether astroglia specific PPARγ activation mitigates TBI mediated astroglia activation, inflammation, neurodegeneration and functional outcomes. We will achieve this by utilizing a tamoxifen inducible mouse model that specifically targets PPARγ activation in astrocytes. We will induce PPARγ activation inastrocytes using three therapeutic time-windows (i.e., pre-injury, early and delayed), and examine functional and pathobiological ...