The role of PPARγ in microglia pathobiologyafter exposure to repetitive mild traumatic brain injury

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Exposure to repetitive mild traumatic brain injury (r-mTBI) can induce neurological damage many years following the cessation of injury, contributing to an increased risk for neurodegenerative disease in later life. To date, no suitable treatment strategies have been developed to rescue the persistent and long-term negative consequences of r-mTBI. A greater emphasis should therefore be placed on understanding the underlying pathobiological mechanisms driving the long-term neurological deficits after r-mTBI, as this could lead to the identification of novel therapeutic targets. Neuroinflammation is a common feature of human and preclinical animal models of TBI. The factors governing the propagation and persistence of neuroinflammatory responses in the chronic sequelae of TBI remain elusive. We have established a mouse model of r-mTBI that recapitulates many of the features of human TBI and thus represents a translationally relevant preclinical platform for such studies. From this model we have generated a molecular library of microglia gene profiles at a range of timepoints post-injury that provides a unique and detailed time-course of the microglial neuroinflammatory response to r-mTBI. Particularly, we observed deficits in energy bioenergetics, altered glucose and lipid metabolism, and a pro-inflammatory signature at chronic timepoints, which appeared to be driven by the loss of constitutive PPAR𝛾𝛾 signaling in microglia. PPAR𝛾𝛾 is expressed in multiple cell types and plays a critical role in regulating glucose and lipid metabolism, energy bioenergetics and inflammation. Treatment with a PPAR𝛾𝛾 agonist has shown efficacy in restoring behavioral and microglial pathobiological consequences in our r- mTBI model. However, because multiple cell types express PPARγ receptors, pharmacological PPARγ ligands lack the specificity needed to target microglial PPARγ signaling in vivo. In this new application, we plan to clarify the constitutive role of PPARγ in regulating brain microglial cell responses in the context of TBI and demonstrate whether microglia specific PPARγ activation mitigates TBI mediated neuroinflammation and subsequent neurodegeneration in our r-mTBI model. We will compare TBI-dependent responses in the presence or absence of PPARγ activation to reveal microglial specific targets that correlate with favorable outcomes after r-mTBI and represent novel therapeutic targets. We will achieve this by utilizing a tamoxifen inducible mouse model that specifically targets PPARγ activation in microglia. We will induce PPARγ activation in microglia using a pre-injury tamoxifen treatment paradigm, and examine functional and pathobiological outcomes, and glial cell transcriptomic profiles at 3 and 6 mo post-injury. Our goal is to clarify the role of PPARγ as a master regulator of microglial pathobiology in the chronic sequelae of r-mTBI, and to identify unique gene signatures and reparative mechanisms in microglia induced by PPAR𝛾𝛾 activation that can be explored as novel microglial specific targets, not only in TBI but other neurodegenerative diseases where neuroinflammation is a critical contributor.