Abstract
BackgroundMechanisms of deep brain stimulation (DBS) remain controversial, and spatiotemporal control of brain-wide circuits remains elusive. Adeno-associated viral (AAV) vectors have emerged as vehicles for spatiotemporal expression of exogenous transgenes in several tissues, including specific nuclei in the brain. Coupling DBS with viral vectors to modulate exogenous transgene expression remains unexplored.ObjectiveThis study examines whether DBS of the medial septal nucleus (MSN) can regulate gene expression of AAV-transduced neurons in a brain region anatomically remote from the stimulation target: the hippocampal dentate gyrus.MethodsRats underwent unilateral hippocampal injection of an AAV vector with c-Fos promoter-driven expression of TdTomato (TdT), followed by MSN electrode implantation. Rodents received no stimulation, 7.7 Hz (theta), or 130 Hz (gamma) DBS for 1 h one week after surgery. In a repeat stimulation experiment, rodents received either no stimulation, or two 1 h MSN DBS over 2 weeks.ResultsNo significant differences in hippocampal TdT expression between controls and acute MSN DBS were found. With repeat DBS we found c-Fos protein expression was induced and we could detect increased TdT with either gamma or theta stimulation.ConclusionWe demonstrate that viral vector-mediated gene expression can be regulated spatially and temporally using DBS. Control of gene expression by DBS warrants further investigation into stimulation-responsive promoters for clinical applications.
Highlights
Deep brain stimulation (DBS) is a standard treatment for medication-refractory movement disorders such as Parkinson’s disease and essential tremor (Kalia et al, 2013; Lozano et al, 2017)
After associated viral (AAV) gene delivery into the dentate gyrus of the hippocampus, we detected reporter green fluorescent protein (GFP) expression widely distributed in neurons within the DG (Figure 3)
We first tested whether single 1 h medial septal nucleus (MSN) DBS at theta frequency (7.7 Hz) or gamma frequency (130 Hz) could induce c-Fos promoter driven expression of the TdT gene following AAV gene delivery to the DG. Using this single 1 h stimulation paradigm we found no difference (p = 0.1308, ANOVA) in percentage of dentate gyrus TdT positive cells out of constitutively expressive GFP cells, among unstimulated controls, 7.7 Hz DBS, or 130 Hz DBS 1 week after electrode implantation (Figure 4)
Summary
Mechanisms of deep brain stimulation (DBS) remain controversial, and spatiotemporal control of brain-wide circuits remains elusive. Adeno-associated viral (AAV) vectors have emerged as vehicles for spatiotemporal expression of exogenous transgenes in several tissues, including specific nuclei in the brain. Coupling DBS with viral vectors to modulate exogenous transgene expression remains unexplored
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