Nature 441, 589-594 (1 June 2006) | doi:10.1038/nature04767; Received 20 November 2005; Accepted 20 March 2006; Published online 10 May 2006

A putative flip–flop switch for control of REM sleep

Jun Lu1, David Sherman1, Marshall Devor1,2 & Clifford B. Saper1

  1. Department of Neurology and Program in Neuroscience, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA
  2. Department of Cell and Animal Biology, Hebrew University, Jerusalem 91904, Israel

Correspondence to: Jun Lu1Clifford B. Saper1 Correspondence and requests for materials should be addressed to J.L. (Email: or C.B.S. (Email:


Rapid eye movement (REM) sleep consists of a dreaming state in which there is activation of the cortical and hippocampal electroencephalogram (EEG), rapid eye movements, and loss of muscle tone. Although REM sleep was discovered more than 50 years ago, the neuronal circuits responsible for switching between REM and non-REM (NREM) sleep remain poorly understood. Here we propose a brainstem flip–flop switch, consisting of mutually inhibitory REM-off and REM-on areas in the mesopontine tegmentum. Each side contains GABA (gamma-aminobutyric acid)-ergic neurons that heavily innervate the other. The REM-on area also contains two populations of glutamatergic neurons. One set projects to the basal forebrain and regulates EEG components of REM sleep, whereas the other projects to the medulla and spinal cord and regulates atonia during REM sleep. The mutually inhibitory interactions of the REM-on and REM-off areas may form a flip–flop switch that sharpens state transitions and makes them vulnerable to sudden, unwanted transitions—for example, in narcolepsy.


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