Excitation of the brain stem pedunculopontine tegmentum cholinergic cells induces wakefulness and REM sleep.

Considerable evidence suggests that brain stem pedunculopontine tegmentum (PPT) cholinergic cells are critically involved in the normal regulation of wakefulness and rapid eye movement (REM) sleep. However, much of this evidence comes from indirect studies. Thus, although involvement of PPT cholinergic neurons has been suggested by numerous investigations, the excitation of PPT cholinergic neurons causal to the behavioral state of wakefulness and REM sleep has never been directly demonstrated. In the present study we examined the effects of three different levels of activation of PPT cholinergic cells in wakefulness and sleep behavior. The effects of glutamate on the activity of PPT cholinergic cells were studied by microinjection of one of the three different doses of L-glutamate (0.3, 1.0, and 3.0 microg) or saline (vehicle control) into the PPT cholinergic cell compartment while quantifying the effects on wakefulness and sleep in free moving chronically instrumented cats. All microinjections were made during wakefulness and were followed by 4 h of recording. Polygraphic records were scored for wakefulness, slow-wave sleep states 1 and 2, slow-wave sleep with pontogeniculooccipital 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. Microinjection of 0.3- and 1.0-microg doses of L-glutamate into the cholinergic cell compartment of the PPT increased the total amount of REM sleep in a dose-dependent manner. Both doses of L-glutamate increased REM sleep at the expense of slow-wave sleep but not wakefulness. Microinjection of 3.0 microg L-glutamate kept animals awake for 2-3 h by eliminating slow-wave and REM sleep. The results show that the microinjection of the excitatory amino acid L-glutamate into the PPT cholinergic cell compartments can increase wakefulness and/or REM sleep depending on the L-glutamate dosage. These findings unambiguously confirm the hypothesis that the excitation of the PPT cholinergic cells is causal to the generation of wakefulness and REM sleep.