The regulation of adult rodent hippocampal neurogenesis by deep brain stimulation

Laboratory investigation

Hiroki Toda M.D., Ph.D. 1 , 2 , Clement Hamani M.D., Ph.D. 1 , Adrian P. Fawcett Ph.D. 3 , William D. Hutchison Ph.D. 3 and Andres M. Lozano M.D., Ph.D. 1
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  • 1 Division of Neurosurgery, Toronto Western Hospital;
  • 3 Department of Physiology, Faculty of Medicine, University of Toronto, Ontario, Canada; and
  • 2 Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan
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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.

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Contributor Notes

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.
  • 1

    Aggleton JP, & Brown MW: Episodic memory, amnesia, and the hippocampal-anterior thalamic axis. Behav Brain Sci 22:425489, 1999

  • 2

    Andrade DM, , Zumsteg D, , Hamani C, , Hodaie M, , Sarkissian S, & Lozano AM, : Long-term follow-up of patients with thalamic deep brain stimulation for epilepsy. Neurology 66:15711573, 2006

    • Search Google Scholar
    • Export Citation
  • 3

    Bain MJ, , Dwyer SM, & Rusak B: Restraint stress affects hippocampal cell proliferation differently in rats and mice. Neurosci Lett 368:710, 2004

    • Search Google Scholar
    • Export Citation
  • 4

    Brown ES, , Woolston D, , Frol A, , Bobadilla L, , Khan DA, & Hanczyc M, : Hippocampal volume, spectroscopy, cognition, and mood in patients receiving corticosteroid therapy. Biol Psychiatry 55:538545, 2004

    • Search Google Scholar
    • Export Citation
  • 5

    Cameron HA, , Tanapat P, & Gould E: Adrenal steroids and N-methyl-D-aspartate receptor activation regulate neurogenesis in the dentate gyrus of adult rats through a common pathway. Neuroscience 82:349354, 1998

    • Search Google Scholar
    • Export Citation
  • 6

    Campbell S, , Marriott M, , Nahmias C, & MacQueen GM: Lower hippocampal volume in patients suffering from depression: a meta-analysis. Am J Psychiatry 161:598607, 2004

    • Search Google Scholar
    • Export Citation
  • 7

    Covolan L, , Ribeiro LT, , Longo BM, & Mello LE: Cell damage and neurogenesis in the dentate granule cell layer of adult rats after pilocarpine- or kainate-induced status epilepticus. Hippocampus 10:169180, 2000

    • Search Google Scholar
    • Export Citation
  • 8

    Deisseroth K, , Singla S, , Toda H, , Monje M, , Palmer TD, & Malenka RC: Excitation-neurogenesis coupling in adult neural stem/progenitor cells. Neuron 42:535552, 2004

    • Search Google Scholar
    • Export Citation
  • 9

    Emsley JG, , Mitchell BD, , Kempermann G, & Macklis JD: Adult neurogenesis and repair of the adult CNS with neural progenitors, precursors, and stem cells. Prog Neurobiol 75:321341, 2005

    • Search Google Scholar
    • Export Citation
  • 10

    Eriksson PS, , Perfilieva E, , Bjork-Eriksson T, , Alborn AM, , Nordborg C, & Peterson DA, : Neurogenesis in the adult human hippocampus. Nat Med 4:13131317, 1998

    • Search Google Scholar
    • Export Citation
  • 11

    Gage FH: Neurogenesis in the adult brain. J Neurosci 22:612613, 2002

  • 12

    Gaulke LJ, , Horner PJ, , Fink AJ, , McNamara CL, & Hicks RR: Environmental enrichment increases progenitor cell survival in the dentate gyrus following lateral fluid percussion injury. Brain Res Mol Brain Res 141:138150, 2005

    • Search Google Scholar
    • Export Citation
  • 13

    Gundersen HJ, , Bagger P, , Bendtsen TF, , Evans SM, , Korbo L, & Marcussen N, : The new stereological tools: disector, fractionator, nucleator and point sampled intercepts and their use in pathological research and diagnosis. APMIS 96:857881, 1988

    • Search Google Scholar
    • Export Citation
  • 14

    Hodaie M, , Wennberg RA, , Dostrovsky JO, & Lozano AM: Chronic anterior thalamus stimulation for intractable epilepsy. Epilepsia 43:603608, 2002

    • Search Google Scholar
    • Export Citation
  • 15

    Kempermann G, , Gast D, , Kronenberg G, , Yamaguchi M, & Gage FH: Early determination and long-term persistence of adult-generated new neurons in the hippocampus of mice. Development 130:391399, 2003

    • Search Google Scholar
    • Export Citation
  • 16

    Kempermann G, , Jessberger S, , Steiner B, & Kronenberg G: Milestones of neuronal development in the adult hippocampus. Trends Neurosci 27:447452, 2004

    • Search Google Scholar
    • Export Citation
  • 17

    Kempermann G, , Kuhn HG, & Gage FH: More hippocampal neurons in adult mice living in an enriched environment. Nature 386:493495, 1997

  • 18

    Kerrigan JF, , Litt B, , Fisher RS, , Cranstoun S, , French JA, & Blum DE, : Electrical stimulation of the anterior nucleus of the thalamus for the treatment of intractable epilepsy. Epilepsia 45:346354, 2004

    • Search Google Scholar
    • Export Citation
  • 19

    Komitova M, , Mattsson B, , Johansson BB, & Eriksson PS: Enriched environment increases neural stem/progenitor cell proliferation and neurogenesis in the subventricular zone of stroke-lesioned adult rats. Stroke 36:12781282, 2005

    • Search Google Scholar
    • Export Citation
  • 20

    Lozano AM, , Dostrovsky J, , Chen R, & Ashby P: Deep brain stimulation for Parkinson's disease: disrupting the disruption. Lancet Neurol 1:225231, 2002

    • Search Google Scholar
    • Export Citation
  • 21

    Lu D, , Mahmood A, , Qu C, , Goussev A, , Schallert T, & Chopp M: Erythropoietin enhances neurogenesis and restores spatial memory in rats after traumatic brain injury. J Neurotrauma 22:10111017, 2005

    • Search Google Scholar
    • Export Citation
  • 22

    Madsen TM, , Treschow A, , Bengzon J, , Bolwig TG, , Lindvall O, & Tingstrom A: Increased neurogenesis in a model of electroconvulsive therapy. Biol Psychiatry 47:10431049, 2000

    • Search Google Scholar
    • Export Citation
  • 23

    Malberg JE, & Duman RS: Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment. Neuropsychopharmacology 28:15621571, 2003

    • Search Google Scholar
    • Export Citation
  • 24

    Monje ML, , Toda H, & Palmer TD: Inflammatory blockade restores adult hippocampal neurogenesis. Science 302:17601765, 2003

  • 25

    Moro E, , Esselink RJ, , Xie J, , Hommel M, , Benabid AL, & Pollak P: The impact on Parkinson's disease of electrical parameter settings in STN stimulation. Neurology 59:706713, 2002

    • Search Google Scholar
    • Export Citation
  • 26

    Palmer TD, , Willhoite AR, & Gage FH: Vascular niche for adult hippocampal neurogenesis. J Comp Neurol 425:479494, 2000

  • 27

    Parent JM, & Lowenstein DH: Seizure-induced neurogenesis: are more new neurons good for an adult brain?. Prog Brain Res 135:121131, 2002

    • Search Google Scholar
    • Export Citation
  • 28

    Parent JM, , Yu TW, , Leibowitz RT, , Geschwind DH, , Sloviter RS, & Lowenstein DH: Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J Neurosci 17:37273738, 1997

    • Search Google Scholar
    • Export Citation
  • 29

    Paxinos G, & Watson C: The Rat Brain in Stereotaxic Coordinates ed 4 San Diego, Academic Press, 1998

  • 30

    Santarelli L, , Saxe M, , Gross C, , Surget A, , Battaglia F, & Dulawa S, : Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301:805809, 2003

    • Search Google Scholar
    • Export Citation
  • 31

    Scott BW, , Wojtowicz JM, & Burnham WM: Neurogenesis in the dentate gyrus of the rat following electroconvulsive shock seizures. Exp Neurol 165:231236, 2000

    • Search Google Scholar
    • Export Citation
  • 32

    Tozuka Y, , Fukuda S, , Namba T, , Seki T, & Hisatsune T: GABAergic excitation promotes neuronal differentiation in adult hippocampal progenitor cells. Neuron 47:803815, 2005

    • Search Google Scholar
    • Export Citation
  • 33

    West MJ, , Slomianka L, & Gundersen HJ: Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optical fractionator. Anat Rec 231:482497, 1991

    • Search Google Scholar
    • Export Citation
  • 34

    Winocur G, , Wojtowicz JM, , Sekeres M, , Snyder JS, & Wang S: Inhibition of neurogenesis interferes with hippocampus-dependent memory function. Hippocampus 16:296304, 2006

    • Search Google Scholar
    • Export Citation
  • 35

    Zumsteg D, , Lozano AM, , Wieser HG, & Wennberg RA: Cortical activation with deep brain stimulation of the anterior thalamus for epilepsy. Clin Neurophysiol 117:192207, 2006

    • Search Google Scholar
    • Export Citation

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