Optogenetic identification of a rapid eye movement sleep modulatory circuit in the hypothalamus

Nat Neurosci. 2013 Nov;16(11):1637-43. doi: 10.1038/nn.3522. Epub 2013 Sep 22.

Abstract

Rapid-eye movement (REM) sleep correlates with neuronal activity in the brainstem, basal forebrain and lateral hypothalamus. Lateral hypothalamus melanin-concentrating hormone (MCH)-expressing neurons are active during sleep, but their effects on REM sleep remain unclear. Using optogenetic tools in newly generated Tg(Pmch-cre) mice, we found that acute activation of MCH neurons (ChETA, SSFO) at the onset of REM sleep extended the duration of REM, but not non-REM, sleep episodes. In contrast, their acute silencing (eNpHR3.0, archaerhodopsin) reduced the frequency and amplitude of hippocampal theta rhythm without affecting REM sleep duration. In vitro activation of MCH neuron terminals induced GABAA-mediated inhibitory postsynaptic currents in wake-promoting histaminergic neurons of the tuberomammillary nucleus (TMN), and in vivo activation of MCH neuron terminals in TMN or medial septum also prolonged REM sleep episodes. Collectively, these results suggest that activation of MCH neurons maintains REM sleep, possibly through inhibition of arousal circuits in the mammalian brain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 6-Cyano-7-nitroquinoxaline-2,3-dione / pharmacology
  • Animals
  • Animals, Newborn
  • Bicuculline / pharmacology
  • Channelrhodopsins
  • Excitatory Amino Acid Antagonists / pharmacology
  • GABA-A Receptor Antagonists / pharmacology
  • Gene Expression Regulation
  • Hypothalamic Hormones / genetics
  • Hypothalamus / cytology
  • Hypothalamus / drug effects
  • Hypothalamus / physiology*
  • Melanins / genetics
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nerve Net / drug effects
  • Nerve Net / physiology*
  • Neural Pathways / drug effects
  • Neural Pathways / physiology*
  • Neurons / drug effects
  • Neurons / physiology
  • Optogenetics*
  • Pituitary Hormones / genetics
  • Sleep, REM / physiology*
  • Theta Rhythm / drug effects
  • Theta Rhythm / genetics
  • Transduction, Genetic
  • Valine / analogs & derivatives
  • Valine / pharmacology

Substances

  • Channelrhodopsins
  • Excitatory Amino Acid Antagonists
  • GABA-A Receptor Antagonists
  • Hypothalamic Hormones
  • Melanins
  • Pituitary Hormones
  • melanin-concentrating hormone
  • 6-Cyano-7-nitroquinoxaline-2,3-dione
  • 2-amino-5-phosphopentanoic acid
  • Valine
  • Bicuculline