title: Activation of brain-derived neurotrophic factor-tropomyosin receptor kinase B signaling in the pedunculopontine tegmental nucleus: a novel mechanism for the homeostatic regulation of rapid eye movement sleep.
abstract: Rapid eye movement (REM) sleep dysregulation is a symptom of many neuropsychiatric disorders, yet the mechanisms of REM sleep homeostatic regulation are not fully understood. We have shown that, after REM sleep deprivation, the pedunculopontine tegmental nucleus (PPT) plays a critical role in the generation of recovery REM sleep. In this study, we used multidisciplinary techniques to show a causal relationship between brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling in the PPT and the development of REM sleep homeostatic drive. Rats were randomly assigned to conditions of unrestricted sleep or selective REM sleep deprivation (RSD) with PPT microinjections of vehicle control or a dose of a TrkB receptor inhibitor (2, 3, or 4 nmol K252a or 4 nmol ANA-12). On experimental days, rats received PPT microinjections and their sleep-wake physiological signals were recorded for 3 or 6 h, during which selective RSD was performed in the first 3 h. At the end of all 3 h recordings, rats were killed and the PPT was dissected out for BDNF quantification. Our results show that K252a and ANA-12 dose-dependently reduced the homeostatic responses to selective RSD. Specifically, TrkB receptor inhibition reduced REM sleep homeostatic drive and limited REM sleep rebound. There was also a dose-dependent suppression of PPT BDNF up-regulation, and regression analysis revealed a significant positive relationship between REM sleep homeostatic drive and the level of PPT BDNF expression. These data provide the first direct evidence that activation of BDNF-TrkB signaling in the PPT is a critical step for the development of REM sleep homeostatic drive.
authors.affiliation: Department of Anesthesiology, Graduate School of Medicine, The University of Tennessee, Knoxville, Tennessee, USA.|Department of Psychology, College of Arts and Sciences, The University of Tennessee, Knoxville, Tennessee, USA.
authors.forename: Abigail K
authors.initials: AK
authors.lastname: Barnes
authors.affiliation: Department of Anesthesiology, Graduate School of Medicine, The University of Tennessee, Knoxville, Tennessee, USA.|Department of Psychology, College of Arts and Sciences, The University of Tennessee, Knoxville, Tennessee, USA.
authors.forename: Richa
authors.initials: R
authors.lastname: Koul-Tiwari
authors.affiliation: Department of Anesthesiology, Graduate School of Medicine, The University of Tennessee, Knoxville, Tennessee, USA.|Department of Psychology, College of Arts and Sciences, The University of Tennessee, Knoxville, Tennessee, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Garner
authors.affiliation: Department of Anesthesiology, Graduate School of Medicine, The University of Tennessee, Knoxville, Tennessee, USA.|Department of Psychology, College of Arts and Sciences, The University of Tennessee, Knoxville, Tennessee, USA.
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Geist
authors.affiliation: Department of Anesthesiology, Graduate School of Medicine, The University of Tennessee, Knoxville, Tennessee, USA.|Department of Psychology, College of Arts and Sciences, The University of Tennessee, Knoxville, Tennessee, USA.|Program in Comparative and Experimental Medicine, The University of Tennessee, Knoxville, Tennessee, USA.
authors.forename: Subimal
authors.initials: S
authors.lastname: Datta
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D026121:Indole Alkaloids / Q000494:pharmacology; D008297:Male; D045042:Pedunculopontine Tegmental Nucleus / Q000187:drug effects / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D020813:Receptor, trkB / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D012895:Sleep, REM / Q000187:drug effects / Q000502:physiology*; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D002227:Carbazoles; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; C049985:staurosporine aglycone; D020813:Receptor, trkB
keywords: 
  REM sleep; brain-derived neurotrophic factor; homeostatic regulation; pedunculopontine tegmental nucleus; sleep-wake activity; tropomyosin receptor kinase B