Deep Brain Stimulation of the Medial Septal Nucleus Induces Expression of a Virally Delivered Reporter Gene in Dentate Gyrus

Anton Fomenko; Darrin J Lee; Chris McKinnon; Eun Jung Lee; Mitchell L de Snoo; Elise Gondard; Clemens Neudorfer; Clement Hamani; Andres M Lozano; Lorraine V Kalia; Suneil K Kalia

doi:10.3389/fnins.2020.00463

Deep Brain Stimulation of the Medial Septal Nucleus Induces Expression of a Virally Delivered Reporter Gene in Dentate Gyrus

Front Neurosci. 2020 May 12:14:463. doi: 10.3389/fnins.2020.00463. eCollection 2020.

Authors

Anton Fomenko¹, Darrin J Lee², Chris McKinnon¹, Eun Jung Lee¹, Mitchell L de Snoo¹, Elise Gondard¹, Clemens Neudorfer¹, Clement Hamani³, Andres M Lozano^{1

4}, Lorraine V Kalia^{1

4}, Suneil K Kalia^{1

2}

Affiliations

¹ Krembil Research Institute, University Health Network, Toronto, ON, Canada.
² Department of Neurological Surgery and USC Neurorestoration Center, Keck School of Medicine of USC, Los Angeles, CA, United States.
³ Division of Neurosurgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.
⁴ Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, University of Toronto, Toronto, ON, Canada.

Abstract

Background: 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.

Objective: This 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.

Methods: Rats 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.

Results: No 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.

Conclusion: We 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.

Keywords: deep brain stimulation; gene expression; hippocampus; medial septal nucleus; neuromodulation; viral vector.