Subthalamic nucleus deep brain stimulation induces nigrostriatal dopaminergic plasticity in a stable rat model of Parkinson's disease.

OBJECTIVE: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been a highly effective treatment option for middle to late stage Parkinson's disease for decades. Though, the underlying mechanisms of action, particularly effects on the cellular level, remain in part unclear. In the context of identifying disease-modifying effects of STN-DBS by prompting cellular plasticity in midbrain dopaminergic systems, we analyzed neuronal tyrosine hydroxylase and c-Fos expression in the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA). METHODS: We applied 1 week of continuous unilateral STN-DBS in a group of stable 6-hydroxydopamine (6-OHDA) hemiparkinsonian rats (STNSTIM) in comparison to a 6-OHDA control group (STNSHAM). Immunohistochemistry identified NeuN+, tyrosine hydroxylase+ and c-Fos+ cells within the SNpc and VTA. RESULTS: After 1 week, rats in the STNSTIM group had 3.5-fold more tyrosine hydroxylase+ neurons within the SNpc (P = 0.010) but not in the VTA compared to sham controls. There was no difference in basal cell activity as indicated by c-Fos expression in both midbrain dopaminergic systems. CONCLUSION: Our data support a neurorestorative effect of STN-DBS in the nigrostriatal dopaminergic system already after 7 days of continuous STN-DBS in the stable Parkinson's disease rat model without affecting basal cell activity.

Serial Gene Expression Profiling of Neural Stem Cells Shows Transcriptome Switch by Long-Term Physioxia from Metabolic Adaption to Cell Signaling Profile.

Oxygen is an essential factor in the cellular microenvironment with pivotal effects on neural development with a particular sensitivity of midbrain neural stem cells (NSCs) to high atmospheric oxygen tension. However, most experiments are still performed at atmospheric O2 levels (21%, normoxia), whereas mammalian brain tissue is physiologically exposed to substantially lower O2 tensions around 3% (physioxia). We here performed serial Affymetrix gene array analyses to detect expression changes in mouse fetal NSCs from both midbrain and cortical tissues when kept at physioxia compared to normoxia. We identified more than 400 O2-regulated genes involved in cellular metabolism, cell proliferation/differentiation, and various signaling pathways. NSCs from both regions showed a low number but high conformity of regulated genes (9 genes in midbrain vs. 34 in cortical NSCs; 8 concordant expression changes) after short-term physioxia (2 days) with metabolic processes and cellular processes being the most prominent GO categories pointing to cellular adaption to lower oxygen levels. Gene expression profiles changed dramatically after long-term physioxia (13 days) with a higher number of regulated genes and more diverse expression patterns when comparing the two NSC types (338 genes in midbrain vs. 121 in cortical NSCs; 75 concordant changes). Most prominently, we observed a reduction of hits in metabolic processes but an increase in biological regulation and signaling pointing to a switch towards signaling processes and stem cell maintenance. Our data may serve as a basis for identifying potential signaling pathways that maintain stem cell characteristics in cortical versus midbrain physioxic stem cell niches.