Obesity Surgery

, Volume 19, Issue 4, pp 475–483 | Cite as

Involvement of the Hippocampus and Neuronal Nitric Oxide Synapse in the Gastric Electrical Stimulation Therapy for Obesity

  • Luo XuEmail author
  • Xiangrong Sun
  • Ming Tang
  • J. D. Z. ChenEmail author
Research Article



Gastric electrical stimulation (GES) has been introduced for treating obesity. However, possible central mechanisms remain to be revealed. Hippocampus has been shown to be involved in the regulation of gastrointestinal functions. Changes in hypothalamic neuronal nitric oxide synthase (nNOS) have been observed in genetically obese rodents. The aim of this study was to investigate the involvement of nNOS with GES in the rodent hippocampus.


The effect of GES on gastric distension (GD) neurons was investigated using four different sets of parameters (GES-A, pulse train of standard parameters; GES-B, reduced on time; GES-C, increased pulse width, and GES-D: reduced pulse frequency), and the expression of nNOS in hippocampus was observed by fluoimmunohistochemistry staining.


CA1 region neurons (90.8%) responded to GD, 50.6% of which showed excitation (GD-E neurons) and 49.4% showed inhibition (GD-I neurons). Most of GD-responsive neurons (63.3%) were excited with GES. The response to GES was associated with stimulation strength, pulse width and frequency. GD-E neurons (62.5%, 76.9%, 100%, and 62.3%) and GD-I (63.6%, 47.1%, 85.7% and 50.0%) showed excitatory responses to GES-A, GES-B, GES-C, and GES-D, respectively (P < 0.05, GES-C vs. others). nNOS immunoreactive (nNOS-IR) positive neurons were observed in hippocampus CA1, CA2-3 regions and the dentate gyrus. The expression of nNOS-IR positive neurons was significantly decreased in CA1 and CA2-3 region (P < 0.05) after GES (para-C) for 2 h.


Excitation of GD-responsive neurons and reduced expression of nNOS in the hippocampus are indicative of the central effect of GES.


Gastric electrical stimulation Obesity Gastric distension sensitive neurons Hippocampus nNOS 



This study was supported by grants from the Oklahoma Center for the Advancement of Science and Technology (HR 02-034R, Dr. J.Z. Chen); The National Natural Science Foundation of China (No. 30470642 and 30670780, Dr. L. Xu) and Qingdao Science and Technique Bureau (05-1-JC-93, Dr. L. Xu).


  1. 1.
    Flegal K, Carroll M, Kuczmarski R, et al. Overweight and obesity in the United States: prevalence and trends, 1960–1994. Int J Obes Relat Metab Disord. 1998;22:38–47.CrossRefGoogle Scholar
  2. 2.
    Eckel R, Krauss R. American Heart Association call to action: obesity as a major risk factor for coronary heart disease. Circulation. 1998;97:2099–100.CrossRefGoogle Scholar
  3. 3.
    Goldstein D. Beneficial health effects of modest weight loss. Int J Obes Relat Metab Disord. 1992;16:397–415.PubMedGoogle Scholar
  4. 4.
    Cigaina V. Gastric pacing as therapy for morbid obesity: preliminary results. Obes Surg. 2002;12:12S–6S.CrossRefGoogle Scholar
  5. 5.
    D’argent J. Gastric electrical stimulation as therapy of morbid obesity: preliminary results from the French study. Obes Surg. 2002;12:21S–5S.CrossRefGoogle Scholar
  6. 6.
    Zou LB, Yamada K, Sasa M, et al. Two phases of behavioral plasticity in rats following unilateral excitotoxic lesion of the hippocampus. Neuroscience. 1999;92:819–26.CrossRefGoogle Scholar
  7. 7.
    Inglis FM, Day JC, Fibiger HC. Enhanced acetylcholine release in hippocampus and cortex during the anticipation and consumption of a palatable meal. Neuroscience. 1994;62:1049–56.CrossRefGoogle Scholar
  8. 8.
    Healy S, Krebs J. Food storing and the hippocampus in Paridae. Brain Behav Evol. 1996;47:195–9.CrossRefGoogle Scholar
  9. 9.
    Guan Y, Tang M, Jiang Z, et al. Excitatory effects of motilin in the hippocampus on gastric motility in rats. Brain Res. 2003;984:33–41.CrossRefGoogle Scholar
  10. 10.
    Xu L, Sun X, Depoortere I, et al. Effect of motilin on the discharge of rat hippocampal neurons responding to gastric distension and its potential mechanism. Peptides. 2008;29:585–92.CrossRefGoogle Scholar
  11. 11.
    Xu L, Sun X, Lu J, et al. Effects of gastric electric stimulation on gastric distention responsive neurons and expressions of CCK in rodent hippocampus. Obesity. 2008;16:951–7.CrossRefGoogle Scholar
  12. 12.
    Isaacson RL. A fuzzy limbic system. Behav Brain Res. 1992;52:129–31.CrossRefGoogle Scholar
  13. 13.
    Seifert W. Neurobiology of the hippocampus. New York: Academic Press; 1983.Google Scholar
  14. 14.
    Palmer R, Moncada S. A novel citrulline-forming enzyme implicated in the formation of nitric oxide by vascular endothelial cells. Biochem Biophys Res Commun. 1989;158:348–52.CrossRefGoogle Scholar
  15. 15.
    Xiong KR, Ma TJ, Guo PS, et al. The projections of nitric oxide synthase (NOS) positive neurons to hippocampus from brainstem and hypothalamus in rat. J Si Chuan Anatomy. 1998;6:69–71.Google Scholar
  16. 16.
    Liu P, Smith PF, Appleton I, et al. Regional variations and age-related changes in nitric oxide synthase and arginase in the sub-regions of the hippocampus. Neuroscience. 2003;119:679–87.CrossRefGoogle Scholar
  17. 17.
    Yamada K, Emson P, Hokfelt T. Immunohistochemical mapping of nitric oxide synthase in the rat hypothalamus and colocalization with neuropeptides. J Chem Neuroanatomy. 1996;10:295–316.CrossRefGoogle Scholar
  18. 18.
    Sadler CJ, Wilding JP. Reduced ventromedial hypothalamic neuronal nitric oxide synthase and increased sensitivity to NOS inhibition in dietary obese rats: further evidence of a role for nitric oxide in the regulation of energy balance. Brain Res. 2004;1016:222–8.CrossRefGoogle Scholar
  19. 19.
    Wang GJ, Yang J, Volkow ND, et al. Gastric stimulation in obese subjects activates the hippocampus and other regions involved in brain reward circuitry. Proc Natl Acad Sci U S A. 2006;103:15641–5.CrossRefGoogle Scholar
  20. 20.
    Paxions G, Watson C. Rat brain in stereotaxic coordinate. London: Academic; 1998.Google Scholar
  21. 21.
    Tang M, Zhang J, Chen JDZ. Central mechanism of gastric electrical stimulation involving neurons in paraventricular nucleus of hypothalamus in rats. Obes Surg. 2006;16:344–52.CrossRefGoogle Scholar
  22. 22.
    Isaacson RL. The Limbic System. New York: Plenum; 1982.CrossRefGoogle Scholar
  23. 23.
    Davidson TL, Kanoski SE, Walls EK, et al. Memory inhibition and energy regulation. Physiol Behav. 2005;86:731–46.CrossRefGoogle Scholar
  24. 24.
    Clifton PG, Vickers SP, Somerville EM. Little and often: ingestive behavior patterns following hippocampal lesions in rats. Behav Neurosci. 1998;112:502–11.CrossRefGoogle Scholar
  25. 25.
    Hamm RJ, Pike BR, Phillips LL, et al. Impaired gustatory neophobia following traumatic brain injury in rats. J Neurotraum. 1995;12:307–14.CrossRefGoogle Scholar
  26. 26.
    Jeanningros R. Modulation of lateral hypothalamic single unit activity by gastric and intestinal distension. J Auton Nerv Syst. 1984;11:1–11.CrossRefGoogle Scholar
  27. 27.
    Zhang X, Renehan WE, Fogel R. Neurons in the vagal complex of the rat respond to mechanical and chemical stimulation of the gastrointestinal tract. Am J Physiol. 1998;274:331–41.Google Scholar
  28. 28.
    Ueta Y, Kannan H, Yamashita H. Inhibition of vasopressin secreting neurons of the paraventricular nucleus by gastric distension in rats. J UOEH. 1986;8:429–35.CrossRefGoogle Scholar
  29. 29.
    Renaud LP, Tang M, McCann MJ. Cholecystokinin decreases and gastric distension activates oxytocinergic cells in rat hypothalamus. Am J Physiol. 1989;253:661–5.Google Scholar
  30. 30.
    Suemori K, Kobashi M, Adachi A. Effects of gastric distension and electrical stimulation of dorsomedial medulla on neurons in parabrachial nucleus of rats. J Auton Nerv Syst. 1994;48:1–229.CrossRefGoogle Scholar
  31. 31.
    Ouyang H, Xing J, Chen JD. Tachygastria induced by gastric electrical stimulation is mediated via alpha- and beta-adrenergic pathway and inhibits antral motility in dogs. Neurogastroenterol Motil. 2005;17:846–53.CrossRefGoogle Scholar
  32. 32.
    Xu X, Zhu H, Chen JD. Pyloric electrical stimulation reduces food intake by inhibiting gastric motility in dogs. Gastroenterology. 2005;128:43–50.CrossRefGoogle Scholar
  33. 33.
    Yao S, Ke M, Wang Z, et al. Retrograde gastric pacing reduces food intake and delays gastric emptying in humans: a potential therapy for obesity? Dig Dis Sci. 2005;50:1569–75.CrossRefGoogle Scholar
  34. 34.
    Zhu HB, Chen JDZ. Implantable gastric stimulation inhibits gastric motility via sympathetic pathway in dogs. Obes Surg. 2005;15:95–100.CrossRefGoogle Scholar
  35. 35.
    Lin ZY, McCallum RW, Schirmer BD, et al. Effects of pacing parameters on entrainment of gastric slow waves in patients with gastroparesis. Am J Physiol. 1998;274:G186–91.CrossRefGoogle Scholar
  36. 36.
    Familoni B, Abell T, Nemoto D, et al. Efficacy of electrical stimulation at frequencies higher than basal rate in canine stomach. Dig Dis Sci. 1997;42:892–7.CrossRefGoogle Scholar
  37. 37.
    McCallum RW, Chen JD, Lin Z, et al. Gastric pacing improves emptying and symptoms in patients with gastroparesis. Gastroenterology. 1998;114:456–61.CrossRefGoogle Scholar
  38. 38.
    Lin Z, Sarosiek FI, McCallum RW. Effects of high-frequency gastric electrical stimulation on gastric myoelectric acitivity in gastroparetic patients. Neurogastroenterol Motil. 2004;16:205–12.CrossRefGoogle Scholar
  39. 39.
    Chen JDZ, Qian L, Quyang H, et al. Enteric neuromuscular disorders and pain group. Gastric electrical stimulation with short pulses reduces vomiting but not dysrhythmias in dogs. Gastroenterol. 2003;124:401–9.CrossRefGoogle Scholar
  40. 40.
    Chen J, Ke M, Lin X, et al. Cisapride provides symptomatic relief in functional dyspepsia associated with gastric myoelectrical abnormality. Aliment Pharmacol Ther. 2000;14:1041–7.CrossRefGoogle Scholar
  41. 41.
    Chang HK, Jang MH, Lim BV, et al. Administration of Ginseng radix decreases nitric oxide synthase expression in the hippocampus of streptozotocin-induced diabetic rats. Am J Chin Med. 2004;32:497–507.CrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media, LLC 2008

Authors and Affiliations

  1. 1.Department of PathophysiologyMedical College of Qingdao UniversityQingdaoPeople’s Republic of China
  2. 2.Division of GastroentoerlogyUniversity of Texas Medical BranchGalvestonUSA

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