Glucocorticoids (GCs), the adrenal steroid hormones released during stress, can have an array of adverse effects in the nervous system, including disruption of hippocampal-dependent plasticity and cognition. Of relevance to this proposal, GCs can also compromise the ability of hippocampal and cortical neurons to survive an array of necrotic neurological insults. Amid this picture of deleterious effects, there is the accepted paradigm in which GCs are seemingly protective in the context of necrotic insults, namely concerning the well-known anti-inflammatory effects of the hormone. There has been a growing appreciation for the extent to which inflammation can worsen the neurotoxicity of necrotic insults, and the anti-inflammatory capacity of GCs has long been exploited pharmacologically to protect against circumstances of post-insult edema. This proposal is therefore designed to address this paradox of how and why GCs can have adverse effects on neuronal survival given the well-accepted anti-inflammatory effects of the hormone.The purpose of this project is to better understand when GCs are classically anti-inflammatory, and when unexpected pro-inflammatory effects occur in the challenged nervous system, and to explore the mechanisms underlying such unexpected effects. This represents an innovative and fascinating question (i.e., understanding how a signaling molecule such as GCs can have diametrically opposite and simultaneous effects. At the same time, understanding this phenomenon is of great potential clinical relevance, given the common use of GCs.