The regulation of adult rodent hippocampal neurogenesis by deep brain stimulation

Laboratory investigation

Restricted access

Object

To examine the influence of deep brain stimulation on hippocampal neurogenesis in an adult rodent model.

Methods

Rats were anesthetized and treated for 1 hour with electrical stimulation of the anterior nucleus of the thalamus (AN) or sham surgery. The animals were injected with 5′-bromo-2′-deoxyuridine (BrdU) 1–7 days after surgery and killed 24 hours or 28 days later. The authors counted the BrdU-positive cells in the dentate gyrus (DG) of the hippocampus. To investigate the fate of these cells, they also stained sections for doublecortin, NeuN, and GFAP and analyzed the results with confocal microscopy. In a second set of experiments they assessed the number of DG BrdU-positive cells in animals treated with corticosterone (a known suppressor of hippocampal neurogenesis) and sham surgery, corticosterone and AN stimulation, or vehicle and sham surgery.

Results

Animals receiving AN high-frequency stimulation (2.5 V, 90 μsec, 130 Hz) had a 2- to 3-fold increase in the number of DG BrdU-positive cells compared with nonstimulated controls. This increase was not seen with stimulation at 10 Hz. Most BrdU-positive cells assumed a neuronal cell fate. As expected, treatment with corticosterone significantly reduced the number of DG BrdU-positive cells. This steroid-induced reduction of neurogenesis was reversed by AN stimulation.

Conclusions

High-frequency stimulation of the AN increases the hippocampal neurogenesis and restores experimentally suppressed neurogenesis. Interventions that increase hippocampal neurogenesis have been associated with enhanced behavioral performance. In this context, it may be possible to use electrical stimulation to treat conditions associated with impairment of hippocampal function.

Abbreviations used in this paper:AN = anterior nucleus of the thalamus; BrdU = 5′-bromo-2′-deoxyuridine; DBS = deep brain stimulation; DCX = doublecortin; DG = dentate gyrus of the hippocampus; GFAP = glial fibrillary acidic protein; HFS = high frequency stimulation; NeuN = neuron-specific nuclear protein; TUNEL = terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling.

Article Information

Address correspondence to: Andres M. Lozano, M.D., Ph.D., Division of Neurosurgery, Toronto Western Hospital, 399 Bathurst Street WW 4-447, Toronto, Ontario M5T2S8, Canada. email: lozano@uhnres.utoronto.ca.

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    High-frequency stimulation of the AN increases hippocampal neurogenesis. A and B: Photomicrographs of DG sections from animals that underwent sham surgery (A) or AN HFS (B), showing increased expression of the immediate early gene Zif/268 at 3 hours after stimulation. C: Graphic illustration of the timing of BrdU administration and death. Injections of BrdU were administered at variable time points from postoperative Day 1 to Day 7 (indicated in the figure by ×) and the animals were killed 24 hours or 4 weeks later (indicated by solid black circles). D: Graph showing the relationship between the number of BrdU-positive cells in DG sections and time after last BrdU injection in the AN HFS (dark bars) and sham surgery (light bars) groups. Animals that received AN HFS had a 2- to 3-fold increase in the number of BrdU-positive cells in the granule cell layer and subgranular zone of the DG compared with nonstimulated controls. E–H: Photomicrographs of DG sections from animals that underwent sham surgery (E and G) or AN HFS (F and H) and were killed 24 hours (E and F) or 28 days (G and H) after BrdU injections (BrdU-positive cells are stained red). I: Graph showing the relationship between the number of BrdU-positive cells and timing of BrdU injection. The maximum number of labeled cells was seen in sections from animals that received BrdU 3 and 5 days after stimulation in the AN HFS (dark bars) and the sham surgery (light bars) groups. J: Graph showing that the effect of AN stimulation was frequency dependent. While rats treated with stimulation at 50 Hz and 130 Hz had a significant increase in the number of BrdU-positive cells, stimulation at 10 Hz did not have such an effect. Scale bars = 200 μm (B and H). Values in the graphs represent the mean number of BrdU-positive cells (± standard error of the mean) per group of animals. *Statistically significant difference in comparison with controls.

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    High-frequency stimulation of the AN increases the number of neural progenitor cells in the subgranular zone of the DG. The BrdU-positive cells (red) coexpressed DCX (blue in A), NeuN (green in A, C), and GFAP (blue in C) in animals treated with AN HFS. The proportion of BrdU cells coexpressing these markers was similar in animals treated with AN HFS or in nonstimulated controls (B and D). In animals killed 24 hours after BrdU administration, approximately 85% of the DG BrdU-positive cells were also immunoreactive for DCX (B). At long term (28 days after the BrdU injections), almost 50% of the DG BrdU-positive cells coexpressed NeuN, with a small number coexpressing DCX or GFAP (D). Scale bars = 10 μm (A and C). Values in the graphs represent the mean number of BrdU-positive cells (± standard error of the mean) per group of animals.

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    High-frequency stimulation of the AN reverses corticosteroid suppression of neurogenesis in the hippocampus. A and B: Photomicrographs of the DG from animals that were undergoing an 8-day course of corticosterone and had been treated with either sham surgery (A) or AN HFS (B). C and D: Corresponding bar graphs showing the number of BrdU-positive cells in the sham surgery plus vehicle (control), sham surgery plus corticosterone (corticosterone), and corticosterone plus AN stimulation groups at 24 hours (C) and 28 days after the last BrdU injection. Animals killed 24 hours (A–C) or 28 days (D) after BrdU injections had a significant increase in the number of BrdU-positive cells (red in A and B) after AN HFS. Scale bar = 200 μm. Values in the graphs represent the mean number of BrdU-positive cells (± standard error of the mean) per group of animals. *Statistically significant difference compared with controls.

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