Figure 3.

Putative impact of elevated GC levels on GR function in nigrostriatal and mesolimbic dopaminergic systems in PD. Stress-level elevation of GCs may be an early feature of PD, potentially impacting both motor and nonmotor dopaminergic systems. Mesolimbic dopaminergic circuitry is likely affected through structural and functional changes occurring in D1R MSNs. These changes lead to depression and reduced motivation and social interaction which are key prodromal features of PD. Dopaminergic neurons in VTA are relatively spared in PD. In the nigrostriatal system, high levels of GCs initially protect dopaminergic neurons of substantia nigra through dampening the immune responses, namely, mediated by activated microglia and astrocytes. In the putamen, high stress levels of GCs through GR augment habit learning and may act to prevent the appearance of motor symptoms. With disease progression, GR function is affected, leading to chronic glial and immune activation, which exacerbates dopamine neurodegeneration with significant dopamine depletion in the striatum. Changes in GR activity may also affect striatal D1 and D2R MSNs further participating in the appearance of clinical motor symptoms.