EXCITATION OF THE BRAIN-STEM PEDUNCULOPONTINE TEGMENTUM CHOLINERGIC CELLS INDUCES WAKEFULNESS AND REM-SLEEP

Considerable evidence suggests that brain stem pedunculopontine tegmen tum (PPT) cholinergic cells are critically involved in the normal regu lation of wakefulness and rapid eye movement (REM) sleep. However, muc h of this evidence comes from indirect studies. Thus, although involve ment of PPT cholinergic neurons has been suggested by numerous investi gations, the excitation of PPT cholinergic neurons causal to the behav ioral state of wakefulness and REM sleep has never been directly demon strated. In the present study we examined the effects of three differe nt levels of activation of PPT cholinergic cells in wakefulness and sl eep behavior. The effects of glutamate on the activity of PPT choliner gic cells were studied by microinjection of one of the three different doses of L-glutamate (0.3, 1.0, and 3.0 mu g) or saline (vehicle cont rol) into the PPT cholinergic cell compartment while quantifying the e ffects on wakefulness and sleep in free moving chronically instrumente d cats. All microinjections were made during wakefulness and were foll owed by 4 h of recording. Polygraphic records were scored for wakefuln ess, slow-wave sleep states 1 and 2, slow wave sleep with pontogenicul ooccipital waves, and REM sleep. Dependent variables quantified after each microinjection included the percentage of recording time spent in each state, the latency to onset of REM sleep, the number of episodes per hour for REM sleep, and the duration of each REM sleep episode. A total of 48 microinjections was made into 12 PPT sites in six cats. M icroinjection of 0.3- and 1.0-mu g doses of L-glutamate into the choli nergic cell compartment of the PPT increased the total amount of REM s leep in a dose-dependent manner. Both doses of L-glutamate increased R EM sleep at the expense of slow-wave sleep but not wakefulness. Microi njection of 3.0 mu g L-glutamate kept animals awake for 2-3 h by elimi nating slow-wave and REM sleep. The results show that the microinjecti on of the excitatory amino acid L-glutamate into the PPT cholinergic c ell compartments can increase wakefulness and/or REM sleep depending o n the L-glutamate dosage. These findings unambiguously confirm the hyp othesis that the excitation of the PPT cholinergic cells is causal to the generation of wakefulness and REM sleep.