Glutamatergic pedunculopontine tegmental neurons control wakefulness and locomotion via distinct axonal projections

Abstract

Study Objectives The pedunculopontine tegmental nucleus (PPT) is implicated in many brain functions, ranging from sleep/wake control and locomotion, to reward mechanisms and learning. The PPT contains cholinergic, GABAergic and glutamatergic neurons with extensive ascending and descending axonal projections. Glutamatergic PPT (PPT vGlut2) neurons are thought to promote wakefulness, but the mechanisms through which this occurs are unknown. In addition, some researchers propose that PPT vGlut2 neurons promote locomotion, yet even though the PPT is a target for deep brain stimulation in Parkinson’s disease, the role of the PPT in locomotion is debated. We hypothesized that PPT vGluT2 neurons drive arousal and specific waking behaviors via certain projections and modulate locomotion via others. Methods We mapped the axonal projections of PPT vGlut2 neurons using conditional anterograde tracing and then photostimulated PPT vGlut2 soma or their axon terminal fields across sleep/wake states and analyzed sleep/wake behavior, muscle activity, and locomotion in transgenic mice. Results We found that stimulation of PPT vGlut2 soma and their axon terminals rapidly triggered arousals from NREM sleep, especially with activation of terminals in the basal forebrain (BF) and lateral hypothalamus (LH). With photoactivation of PPT vGlut2 terminals in the BF and LH, this wakefulness was accompanied by locomotion and other active behaviors, but stimulation of PPT vGlut2 soma and terminals in the substantia nigra triggered only quiet wakefulness without locomotion. Conclusions These findings demonstrate the importance of the PPT vGluT2 neurons in driving various aspects of arousal and show that heterogeneous brain nuclei, such as the PPT, can promote a variety of behaviors via distinct axonal projections.

The regulation of the pedunculopontine tegmental nucleus in sleep–wake states

“…Kroeger et al [ 13 ] found that selective activation of the PPTg glutamatergic neurons can induce longer behavioral arousal and cortical activation, while inhibition reduces arousal and increases non-REM sleep. This is consistent with a recent study by Kroeger et al, they found photoactivation of the PPTg glutamatergic neurons can wake mice from non-REM sleep, and photoactivation of distinct axonal projections can lead to differences in waking behavior [ 50 ]. Glutamatergic neurons in the PPTg neurons are composed of, in addition to neurons that are most active during waking (Wake active neurons), neurons that are active both during waking and REM sleep (Wake/REM active neurons) and those that are most active during REM sleep (REM active neurons) [ 37 ].…”

“…However, the specific pathway by which glutamatergic neurons promote arousal is not clear. Kroeger et al found that the glutamatergic neurons of the PPTg projections to the SN may promote arousal, while projections to the BF and LH may promote higher arousal levels under dynamic conditions [ 50 ]. Some evidence showed that dopaminergic neurons (SNc) received glutamatergic neurons input directly from the PPTg neurons [ 52 , 53 ].…”