In Parkinson’s disease, nigrostriatal degeneration is associated with striatal astrocytes activation. However, the possible causal relationships between striatal astrocytosis and nigrostriatal degeneration remain unclear. Our central hypothesis is that corticostriatal alterations may act as a top-down stressor for retrograde nigrostriatal neurodegeneration (Foffani and Obeso, Neuron 2018). Here we tested whether chronically increasing corticostriatal activity and/or overexpressing corticostriatal alpha-synuclein may induce striatal astrocytosis in mice.Glutamatergic corticostriatal neurons in the left primary sensorimotor cortex of wild-type mice were transfected with adenoviruses expressing excitatory DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) and/or human alpha-synuclein. The ability of DREADD activation to increase corticostriatal activity was verified via in vivo extracellular electrophysiology in anesthetized animals. Mice behavior was monitored through weekly open field tests. Viral transfection, protein expression and striatal effects of chronic cortical manipulations were analyzed through post-mortem immunohistochemistry. The primary immunohistochemical outcome measure was the expression GFAP, a sensitive marker of striatal astrocytosis in animal models of nigrostriatal degenerationElectrophysiological examinations confirmed that systemic administration of clozapine-N-oxide tonically increased the activity of the targeted corticostriatal neurons. Behavioral observations revealed that chronic corticostriatal overactivity and/or alpha-synuclein overexpression induced a myoclonus-like behavior, suggestive of pathological corticostriatal hyperexcitability. Immunohistochemical analysis demonstrated that both corticostriatal manipulations induced a robust increase of GFAP expression in the ipsilateral dorso-medial posterior striatum.Results suggest that excessive corticostriatal activity and corticostriatal alpha-synuclein overexpression by themselves act as top-down stressors, inducing striatal astrocytosis. Maintaining this top-down stress over the long term may play a role in shaping nigrostriatal degeneration.