Our research is focused on the role of stress, mediated by glucocorticoids (GCs) acting through its receptor GR, in the pathogenesis of Parkinson’s disease (PD). PD is characterized by motor and non-motor symptoms. GC-GRs not only regulate inflammation but also profoundly modulate mood and cognition. Whether GR functions in glial cells affects mood and cognition in PD is not known. To examine the role of astrocyte GC-GR in PD pathogenesis, we are using mice in which GR gene can be conditionally and specifically inactivated in astrocytes and where we produce region-specific alpha-synuclein pathology. Stereotaxic injection of A53T alpha-synuclein viral vector in SN of control and astrocyte GR mutant mice resulted in greater dopamine neuronal loss with increased glial reactivity in astrocytic GR mutant mice, suggesting astrocyte GR regulates alpha-synuclein- induced neurotoxicity in SN. Interestingly, behavioral analysis showed motor deficit and anxiety-like phenotype in alpha-synuclein injected control but not mutant mice. In depth mood and cognitive analysis was undertaken in control and GR astrocytic mice following alpha-synuclein viral vector injection in VTA. Behavioral analyses for anxiety and depression showed variable differences. In contrast, Novel Object Recognition test for memory showed significant deficit in astrocyte GR mutant mice compared to control mice. In 3-chamber social interaction test, control mice with alpha-synuclein pathology showed decreased sociability, which was not observed in astrocytes GR mutant mice. Overall, these results suggest that astrocyte GR regulates behavioral and memory outcomes in a contrasting manner when alpha-synuclein pathology is provoked in SN or VTA.