Neurons have unique roles for lipids that are distinct from other cell types and are equipped with specialized machinery for regulating intracellular lipid metabolism. Although it is widely appreciated that the lipid composition of neurons is criticl for human development and defects in lipid metabolism result in severe and debilitating neurological disease, there is a dearth of understanding about how neurons regulate intracellular lipid metabolism at a fundamental level. Using tissue specific transgenic and knockout mouse models we have discovered that neurons regulate fatty acid flux and prevent lipotoxicity by hydrolyzing long chain acyl-CoAs to free fatty acid and CoA. This is mediated by the neuron-specific Acyl-CoA Thioesterase 7 (ACOT7). The loss of ACOT7 in mice and humans results in behavioral deficits and neurodegenerative disease. We have developed a new model describing the coordinated metabolism of fatty acids within the nervous system between neurons and astrocytes. We hypothesize that this is mediated by acyl-CoA hydrolysis within the neuron and fatty acid ?-oxidation within the astrocyte. Because of the critical importance of fatt acids to brain function and pathophysiology, a deeper understanding of fatty acid metabolism in the nervous system is greatly needed. The studies described herein will detail these fundamental unanswered questions. To test these hypotheses we propose two specific aims: 1) Determine the neuroprotective role and regulation of ACOT7. 2) Determine the roles and requirements for brain fatty acid oxidation. The long-term goal of this project is to elucidate the molecular mechanisms employed by the nervous system to regulate the metabolism of fatty acids. The expectation is that our proposed studies will describe new mechanisms for how fatty acid metabolism is regulated in the nervous system and more broadly, advance our understanding of the role of lipid homeostasis in neurological disease.