title: Noradrenaline from Locus Coeruleus Neurons Acts on Pedunculo-Pontine Neurons to Prevent REM Sleep and Induces Its Loss-Associated Effects in Rats.
abstract: Normally, rapid eye movement sleep (REMS) does not appear during waking or non-REMS. Isolated, independent studies showed that elevated noradrenaline (NA) levels inhibit REMS and induce REMS loss-associated cytomolecular, cytomorphological, psychosomatic changes and associated symptoms. However, the source of NA and its target in the brain for REMS regulation and function in health and diseases remained to be confirmedin vivo. Using tyrosine hydroxylase (TH)-siRNA and virus-coated TH-shRNA in normal freely moving rats, we downregulated NA synthesis in locus coeruleus (LC) REM-OFF neuronsin vivo. These TH-downregulated rats showed increased REMS, which was prevented by infusing NA into the pedunculo-pontine tegmentum (PPT), the site of REM-ON neurons, normal REMS returned after recovery. Moreover, unlike normal or control-siRNA- or shRNA-injected rats, upon REMS deprivation (REMSD) TH-downregulated rat brains did not show elevated Na-K ATPase (molecular changes) expression and activity. To the best of our knowledge, these are the firstin vivofindings in an animal model confirming that NA from the LC REM-OFF neurons (1) acts on the PPT REM-ON neurons to prevent appearance of REMS, and (2) are responsible for inducing REMSD-associated molecular changes and symptoms. These observations clearly show neuro-physio-chemical mechanism of why normally REMS does not appear during waking. Also, that LC neurons are the primary source of NA, which in turn causes some, if not many, REMSD-associated symptoms and behavioral changes. The findings are proof-of-principle for the first time and hold potential to be exploited for confirmation toward treating REMS disorder and amelioration of REMS loss-associated symptoms in patients.
authors.affiliation: School of Life Sciences, Jawaharlal Nehru University , New Delhi 110607, India.
authors.forename: Mudasir Ahmad
authors.initials: MA
authors.lastname: Khanday
authors.affiliation: School of Life Sciences, Jawaharlal Nehru University , New Delhi 110607, India.
authors.forename: Bindu I
authors.initials: BI
authors.lastname: Somarajan
authors.affiliation: School of Life Sciences, Jawaharlal Nehru University , New Delhi 110607, India.
authors.forename: Rachna
authors.initials: R
authors.lastname: Mehta
authors.affiliation: School of Life Sciences, Jawaharlal Nehru University , New Delhi 110607, India.
authors.forename: Birendra Nath
authors.initials: BN
authors.lastname: Mallick
mesh_terms: D000818:Animals; D008125:Locus Coeruleus / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009638:Norepinephrine / Q000378:metabolism*; D045042:Pedunculopontine Tegmental Nucleus / Q000378:metabolism* / Q000473:pathology; D065821:Pontine Tegmentum / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D017208:Rats, Wistar; D012892:Sleep Deprivation / Q000378:metabolism / Q000473:pathology; D012895:Sleep, REM / Q000502:physiology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014446:Tyrosine 3-Monooxygenase; D000254:Sodium-Potassium-Exchanging ATPase; D009638:Norepinephrine
keywords: REM-OFF/REM-ON neurons; REMS deprivation; REMS generation; RNAi; inhibition; tyrosine hydroxylase 