Journal of Neural Transmission

, Volume 120, Issue 7, pp 1027–1038 | Cite as

Effects of leptin on pedunculopontine nucleus (PPN) neurons

  • Paige Beck
  • Francisco J. Urbano
  • D. Keith Williams
  • Edgar Garcia-RillEmail author
Translational Neurosciences - Original Article


Leptin, a hormone that regulates appetite and energy expenditure, is increased in obese individuals, although these individuals often exhibit leptin resistance. Obesity is characterized by sleep/wake disturbances, such as excessive daytime sleepiness, increased REM sleep, increased nighttime arousals, and decreased percentage of total sleep time. Several studies have shown that short sleep duration is highly correlated with decreased leptin levels in both animal and human models. Arousal and rapid eye movement (REM) sleep are regulated by the cholinergic arm of the reticular activating system, the pedunculopontine nucleus (PPN). The goal of this project was to determine the role of leptin in the PPN, and thus in obesity-related sleep disorders. Whole-cell patch-clamp recordings were conducted on PPN neurons in 9- to 17-day-old rat brainstem slices. Leptin decreased action potential (AP) amplitude, AP frequency, and h-current (I H). These findings suggest that leptin causes a blockade of Na+ channels. Therefore, we conducted an experiment to test the effects of leptin on Na+ conductance. To determine the average voltage dependence of this conductance, results from each cell were equally weighted by expressing conductance as a fraction of the maximum conductance in each cell. I Na amplitude was decreased in a dose-dependent manner, suggesting a direct effect of leptin on these channels. The average decrease in Na+ conductance by leptin was ~40 %. We hypothesize that leptin normally decreases activity in the PPN by reducing I H and I Na currents, and that in states of leptin dysregulation (i.e., leptin resistance) this effect may be blunted, therefore causing increased arousal and REM sleep drive, and ultimately leading to sleep-related disorders.


Arousal Hyperpolarization-activated cation current Sodium current 



This work was supported by USPHS awards F31 HL10842 (to PB), R01 NS020246, and by core facilities of the Center for Translational Neuroscience supported by P20 GM104325 (to EGR). In addition, Dr. Urbano was supported by FONCyT, Agencia Nacional de Promoción Científica y Tecnológica ( BID 1728 OC.AR. PICT 2008-2019 and PIDRI-PRH 2007 None of the authors have a conflict of interest.


  1. Adamantidis A, Carter MC, de Lecea L (2010) Optogenetic deconstruction of sleep-wake circuitry in the brain. Front Mol Neurosci 2:31. doi: 10.3389/neuro.02.031.2009 PubMedCrossRefGoogle Scholar
  2. Ahima RS, Flier JS (2000) Leptin. Annu Rev Physiol 62:413–437. doi: 10.1146/annurev.physiol.62.1.413 PubMedCrossRefGoogle Scholar
  3. Ahima RS, Bjorbaek C, Osei S, Flier JS (1999) Regulation of neuronal and glial proteins by leptin: implications for brain development. Endocrinology 140(6):2755–2762PubMedCrossRefGoogle Scholar
  4. Aldabal L, Bahammam AS (2011) Metabolic, endocrine, and immune consequences of sleep deprivation. Open Respir Medicine J 5:31–43. doi: 10.2174/1874306401105010031 CrossRefGoogle Scholar
  5. Beccuti G, Pannain S (2011) Sleep and obesity. Curr Opin Clin Nutr Metab Care 14(4):402–412. doi: 10.1097/MCO.0b013e3283479109 PubMedCrossRefGoogle Scholar
  6. Carter ME, Brill J, Bonnavion P, Huguenard JR, Huerta R, de Lecea L (2012) Mechanism for hypocretin-mediated sleep-to-wake transitions. Proc Natl Acad Sci USA 109(39):E2635–E2644. doi: 10.1073/pnas.1202526109 PubMedCrossRefGoogle Scholar
  7. Cottrell EC, Cripps RL, Duncan JS, Barrett P, Mercer JG, Herwig A, Ozanne SE (2009) Developmental changes in hypothalamic leptin receptor: relationship with the postnatal leptin surge and energy balance neuropeptides in the postnatal rat. Am J Physiol Regul Integr Comp Physiol 296(3):R631–R639. doi: 10.1152/ajpregu.90690.2008 PubMedCrossRefGoogle Scholar
  8. Crill WE (1996) Persistent sodium current in mammalian central neurons. Annu Rev Physiol 58:349–362. doi: 10.1146/ PubMedCrossRefGoogle Scholar
  9. Datta S, Desarnaud F (2010) Protein kinase A in the pedunculopontine tegmental nucleus of rat contributes to regulation of rapid eye movement sleep. J Neurosci Off J Soc Neurosci 30(37):12263–12273. doi: 10.1523/jneurosci.1563-10.2010 CrossRefGoogle Scholar
  10. Desarnaud F, Macone BW, Datta S (2011) Activation of extracellular signal-regulated kinase signaling in the pedunculopontine tegmental cells is involved in the maintenance of sleep in rats. J Neurochem 116(4):577–587. doi: 10.1111/j.1471-4159.2010.07146.x PubMedCrossRefGoogle Scholar
  11. Dixon JB, Dixon ME, Anderson ML, Schachter L, O’Brien PE (2007) Daytime sleepiness in the obese: not as simple as obstructive sleep apnea. Obesity (Silver Spring, MD) 15(10):2504–2511. doi: 10.1038/oby.2007.297 CrossRefGoogle Scholar
  12. Durakoglugil M, Irving AJ, Harvey J (2005) Leptin induces a novel form of NMDA receptor-dependent long-term depression. J Neurochem 95(2):396–405. doi: 10.1111/j.1471-4159.2005.03375.x PubMedCrossRefGoogle Scholar
  13. Elmquist JK, Bjorbaek C, Ahima RS, Flier JS, Saper CB (1998) Distributions of leptin receptor mRNA isoforms in the rat brain. J Comp Neurol 395(4):535–547PubMedCrossRefGoogle Scholar
  14. Gan Y, Zhang Y, Digirolamo DJ, Jiang J, Wang X, Cao X, Zinn KR, Carbone DP, Clemens TL, Frank SJ (2010) Deletion of IGF-I receptor (IGF-IR) in primary osteoblasts reduces GH-induced STAT5 signaling. Mol Endocrinol (Baltimore, MD) 24(3):644–656. doi: 10.1210/me.2009-0357 CrossRefGoogle Scholar
  15. Garcia-Rill E (1997) Disorders of the reticular activating system. Med Hypotheses 49(5):379–387PubMedCrossRefGoogle Scholar
  16. Garcia-Rill E (2009) Sleep and arousal states: reticular activating system. New Encycl Neurosci 8:137–143CrossRefGoogle Scholar
  17. Garcia-Rill E, Charlesworth A, Heister D, Ye M, Hayar A (2008) The developmental decrease in REM sleep: the role of transmitters and electrical coupling. Sleep 31(5):673–690PubMedGoogle Scholar
  18. Herold KF, Hemmings HC Jr (2012) Sodium channels as targets for volatile anesthetics. Front Pharmacol 3:50. doi: 10.3389/fphar.2012.00050 PubMedCrossRefGoogle Scholar
  19. Jouvet-Mounier D, Astic L, Lacote D (1970) Ontogenesis of the states of sleep in rat, cat, and guinea pig during the first postnatal month. Dev Psychobiol 2(4):216–239. doi: 10.1002/dev.420020407 PubMedCrossRefGoogle Scholar
  20. Kamondi A, Williams JA, Hutcheon B, Reiner PB (1992) Membrane properties of mesopontine cholinergic neurons studied with the whole-cell patch-clamp technique: implications for behavioral state control. J Neurophysiol 68(4):1359–1372PubMedGoogle Scholar
  21. Kezunovic N, Urbano FJ, Simon C, Hyde J, Smith K, Garcia-Rill E (2011) Mechanism behind gamma band activity in the pedunculopontine nucleus. Eur J Neurosci 34(3):404–415. doi: 10.1111/j.1460-9568.2011.07766.x PubMedCrossRefGoogle Scholar
  22. Kobayashi T, Good C, Mamiya K, Skinner RD, Garcia-Rill E (2004) Development of REM sleep drive and clinical implications. J Appl Physiol (Bethesda, MD: 1985) 96(2):735–746. doi: 10.1152/japplphysiol.00908.2003 CrossRefGoogle Scholar
  23. Krebs DL, Hilton DJ (2000) SOCS: physiological suppressors of cytokine signaling. J Cell Sci 113(Pt 16):2813–2819PubMedGoogle Scholar
  24. Leonard CS, Llinas R (1994) Serotonergic and cholinergic inhibition of mesopontine cholinergic neurons controlling REM sleep: an in vitro electrophysiological study. Neuroscience 59(2):309–330PubMedCrossRefGoogle Scholar
  25. Lindsley DB, Bowden JW, Magoun HW (1949) Effect upon the EEG of acute injury to the brain stem activating system. Electroencephalogr Clin Neurophysiol 1(4):475–486PubMedGoogle Scholar
  26. Luthi A, McCormick DA (1998) H-current: properties of a neuronal and network pacemaker. Neuron 21(1):9–12PubMedCrossRefGoogle Scholar
  27. Moruzzi G, Magoun HW (1995) Brain stem reticular formation and activation of the EEG. 1949. J Neuropsychiatry Clin Neurosci 7(2):251–267PubMedGoogle Scholar
  28. Niswender KD, Morton GJ, Stearns WH, Rhodes CJ, Myers MG Jr, Schwartz MW (2001) Intracellular signalling. Key enzyme in leptin-induced anorexia. Nature 413(6858):794–795. doi: 10.1038/35101657 PubMedCrossRefGoogle Scholar
  29. O’Malley D, Irving AJ, Harvey J (2005) Leptin-induced dynamic alterations in the actin cytoskeleton mediate the activation and synaptic clustering of BK channels. FASEB J Off Publ Fed Am Soc Exp Biol 19(13):1917–1919. doi: 10.1096/fj.05-4166fje Google Scholar
  30. Roffwarg HP, Muzio JN, Dement WC (1966) Ontogenetic development of the human sleep-dream cycle. Science (New York, NY) 152(3722):604–619. doi: 10.1126/science.152.3722.604 CrossRefGoogle Scholar
  31. Rutters F, Gonnissen HK, Hursel R, Lemmens SG, Martens EA, Westerterp-Plantenga MS (2012) Distinct associations between energy balance and the sleep characteristics slow wave sleep and rapid eye movement sleep. Int J Obes. doi: 10.1038/ijo.2011.250 Google Scholar
  32. Sah N, Rajput SK, Singh JN, Meena CL, Jain R, Sikdar SK, Sharma SS (2011) l-pGlu-(2-propyl)-l-His-l-ProNH(2) attenuates 4-aminopyridine-induced epileptiform activity and sodium current: a possible action of new thyrotropin-releasing hormone analog for its anticonvulsant potential. Neuroscience 199:74–85. doi: 10.1016/j.neuroscience.2011.10.008 PubMedCrossRefGoogle Scholar
  33. Sahu A (2011) Intracellular leptin-signaling pathways in hypothalamic neurons: the emerging role of phosphatidylinositol-3 kinase-phosphodiesterase-3B-cAMP pathway. Neuroendocrinology 93(4):201–210. doi: 10.1159/000326785 PubMedCrossRefGoogle Scholar
  34. Shanley LJ, Irving AJ, Rae MG, Ashford ML, Harvey J (2002a) Leptin inhibits rat hippocampal neurons via activation of large conductance calcium-activated K+ channels. Nat Neurosci 5(4):299–300. doi: 10.1038/nn824 PubMedCrossRefGoogle Scholar
  35. Shanley LJ, O’Malley D, Irving AJ, Ashford ML, Harvey J (2002b) Leptin inhibits epileptiform-like activity in rat hippocampal neurones via PI 3-kinase-driven activation of BK channels. J Physiol 545(Pt 3):933–944PubMedCrossRefGoogle Scholar
  36. Shouse MN, Siegel JM (1992) Pontine regulation of REM sleep components in cats: integrity of the pedunculopontine tegmentum (PPT) is important for phasic events but unnecessary for atonia during REM sleep. Brain Res 571(1):50–63PubMedCrossRefGoogle Scholar
  37. Simon C, Kezunovic N, Ye M, Hyde J, Hayar A, Williams DK, Garcia-Rill E (2010) Gamma band unit activity and population responses in the pedunculopontine nucleus. J Neurophysiol 104(1):463–474. doi: 10.1152/jn.00242.2010 PubMedCrossRefGoogle Scholar
  38. Spiegel K, Knutson K, Leproult R, Tasali E, Van Cauter E (2005) Sleep loss: a novel risk factor for insulin resistance and Type 2 diabetes. J Appl Physiol (Bethesda, MD: 1985) 99(5):2008–2019. doi: 10.1152/japplphysiol.00660.2005 CrossRefGoogle Scholar
  39. Steriade M, Datta S, Pare D, Oakson G, Curro Dossi RC (1990) Neuronal activities in brain-stem cholinergic nuclei related to tonic activation processes in thalamocortical systems. J Neurosci Off J Soc Neurosci 10(8):2541–2559Google Scholar
  40. Storm JF (1987) Action potential repolarization and a fast after-hyperpolarization in rat hippocampal pyramidal cells. J Physiol 385:733–759PubMedGoogle Scholar
  41. Taheri S, Lin L, Austin D, Young T, Mignot E (2004) Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index. PLoS Med 1(3):e62. doi: 10.1371/journal.pmed.0010062 PubMedCrossRefGoogle Scholar
  42. Takakusaki K, Kitai ST (1997) Ionic mechanisms involved in the spontaneous firing of tegmental pedunculopontine nucleus neurons of the rat. Neuroscience 78(3):771–794PubMedCrossRefGoogle Scholar
  43. Taylor CP (1993) Na+ currents that fail to inactivate. Trends Neurosci 16(11):455–460PubMedCrossRefGoogle Scholar
  44. Udagawa J, Hatta T, Hashimoto R, Otani H (2007) Roles of leptin in prenatal and perinatal brain development. Congenit Anom 47(3):77–83. doi: 10.1111/j.1741-4520.2007.00150.x CrossRefGoogle Scholar
  45. Urbano FJ, Kezunovic N, Hyde J, Simon C, Beck P, Garcia-Rill E (2012) Gamma band activity in the reticular activating system. Front Neurol 3:6. doi: 10.3389/fneur.2012.00006 PubMedCrossRefGoogle Scholar
  46. Vgontzas AN, Bixler EO, Tan TL, Kantner D, Martin LF, Kales A (1998) Obesity without sleep apnea is associated with daytime sleepiness. Arch Intern Med 158(12):1333–1337PubMedCrossRefGoogle Scholar
  47. Yang MJ, Wang F, Wang JH, Wu WN, Hu ZL, Cheng J, Yu DF, Long LH, Fu H, Xie N, Chen JG (2010a) PI3 K integrates the effects of insulin and leptin on large-conductance Ca2+-activated K+ channels in neuropeptide Y neurons of the hypothalamic arcuate nucleus. Am J Physiol Endocrinol Metab 298(2):E193–E201. doi: 10.1152/ajpendo.00155.2009 PubMedCrossRefGoogle Scholar
  48. Yang RH, Wang WT, Hou XH, Hu SJ, Chen JY (2010b) Ionic mechanisms of the effects of sleep deprivation on excitability in hippocampal pyramidal neurons. Brain Res 1343:135–142. doi: 10.1016/j.brainres.2010.05.019 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2012

Authors and Affiliations

  • Paige Beck
    • 1
  • Francisco J. Urbano
    • 2
  • D. Keith Williams
    • 1
  • Edgar Garcia-Rill
    • 1
    Email author
  1. 1.Department of Neurobiology and Developmental Sciences, Center for Translational NeuroscienceUniversity of Arkansas for Medical SciencesLittle RockUSA
  2. 2.IFIBYNE, CONICETUniversity of Buenos AiresBuenos AiresArgentina

Personalised recommendations