Arousal mechanisms related to posture and locomotion: 1. Descending modulation.

Much of the controversy surrounding the induction of locomotion following stimulation of mesopontine sites, including the pedunculopontine nucleus (PPN), appears based on procedural differences, including stimulus onset, delay preceding stepping, and frequency of stimuli. The results reviewed in this chapter address these issues and provide novel information suggesting that descending projections from the PPN may exert a frequency-dependent effect. Stimulation at approximately 60 Hz (which induces prolonged tonic firing) may exercise a "push" towards locomotion (activation of pontine interneurons) as well as a "pull" away from decreased muscle tone (inhibiting giant pontine reticulospinal cells). Higher frequencies of stimulation (> 100 Hz, which induces phasic burst-like activity) may "push" towards decreases in muscle tone, including the atonia of rapid eye movement sleep (activating giant pontine reticulospinal cells).

Arousal mechanisms related to posture and locomotion: 2. Ascending modulation.

An intrinsic function of the reticular activating system (RAS) is its participation in fight vs. flight responses such that alerting stimuli simultaneously activate thalamocortical systems, as well as postural and locomotor systems, in order to enable an appropriate response. The P50 midlatency auditory-evoked potential appears to be an ascending manifestation of the cholinergic arm of the RAS in eliciting changes in arousal state. Abnormalities in the manifestation of the P50 potential are present in disorders which include: (1) dysregulation of sleep-wake cycles; (2) abnormalities in reflex/postural, especially, startle, responses; and (3) malfunctions in flight vs. flight responses. In general, the P50 potential appears to be upregulated (increased amplitude and/or decreased sensory gating) in disorders which are marked by upregulation of RAS outputs (hypervigilance), and downregulated in disorders characterized by decreased RAS outputs (hypovigilance). Many of the disorders discussed have a developmental etiology and a postpubertal age of onset.

Developmental changes in the effects of serotonin on neurons in the region of the pedunculopontine nucleus.

The percent of rapid eye movement (REM) sleep decreases dramatically between 10 and 30 days postnatally in the rat. The pedunculopontine nucleus (PPN) is known to modulate waking and REM sleep. We recorded intracellularly from 127 neurons in the PPN in 12-21-day rat brainstem slices maintained in warmed, oxygenated artificial cerebrospinal fluid. We identified three types of PPN neurons based on intrinsic membrane properties, type I (LTS), type II (A) and type III (A+LTS), as previously described. The percent of type I neurons increased from 6% at 12 days to 17% by 21 days, while the percent of type III neurons decreased from 21% at 12-17 days, to 4% after 17 days. Thus, PPN neurons may differentiate into type I bursting neurons and type II slow-firing neurons across this critical stage in development. The 5-HT1 receptor agonist 5-carboxyamido-tryptamine (5-CT) was found to hyperpolarize 58% of 12-16-day PPN neurons, did not affect 25% and depolarized 17%. However, a higher percentage of 17-21-day PPN neurons were hyperpolarized (85%), and a lower percentage unaffected (10%) or depolarized (5%), suggesting that serotonergic responses switched from both excitatory and inhibitory before, to almost purely inhibitory after, 17 days. These findings indicate a reorganization of PPN intrinsic membrane properties and serotonergic responses occur across this stage, in keeping with the proposed presence of a REM sleep inhibitory process during development. We suggest that disturbances in this developmental process may lead to disorders marked by increased REM sleep drive.

Effects of rotation on the P13 mid-latency auditory evoked potential in rat.

The P13 mid-latency auditory evoked potential in Rat is a sleep state-dependent response thought to be equivalent to the human P50 potential, a measure of the output of the reticular activating system. The amplitude of these potentials can be considered a measure of level of arousal, while, using a paired stimulus paradigm, the degree of habituation of the responses also can be assessed. Different durations of rotation were found to reduce the amplitude of the P13 potential, which recovered in a duration-dependent manner. Different durations of rotation led to decreases in habituation of the P13 potential again in a duration-dependent manner. These results suggest that rotation may affect the level of arousal as well as habituation to repetitive sensory inputs. Such effects could be interpreted to imply the presence, following rotation of sufficient duration, of a deficit in sensory gating, or distractibility, and are relevant for the study of the effects of space motion sickness.

Effects of pedunculopontine nucleus (PPN) stimulation on caudal pontine reticular formation (PnC) neurons in vitro.

Stimulation of the pedunculopontine nucleus (PPN) is known to induce changes in arousal and postural/locomotor states. Previously, PPN stimulation was reported to induce prolonged responses (PRs) in extracellularly recorded PnC neurons in the decerebrate cat. The present study used intracellular recordings in semihorizontal slices from rat brain stem (postnatal days 12-21) to determine responses in PnC neurons following PPN stimulation. Two-thirds (65%) of PnC neurons showed PRs after PPN stimulation. PnC neurons with PRs had higher amplitude afterhyperpolarizations (AHP) than non-PR (NPR) neurons. Both PR and NPR neurons were of mixed cell types characterized by "A" and/or "LTS," or neither of these types of currents. PnC cells showed decreased AHP duration with age, due mostly to decreased AHP duration in NPR cells. The longest mean duration PRs were induced by stimulation at 60 and 90 Hz compared with 10 or 30 Hz. Maximal firing rates in PnC cells during PRs were induced by PPN stimulation at 60 Hz compared with 10, 30, or 90 Hz. BaCl2 superfusion blocked PPN stimulation-induced PRs, suggesting that PRs may be mediated by blockade of potassium channels, in keeping with increased input resistance observed during PRs. Depolarizing pulses failed to elicit, and hyperpolarizing pulses failed to reset, PPN stimulation-induced PRs, suggesting that PRs may not be plateau potentials. Pharmacological testing revealed that nifedipine superfusion failed to block PPN stimulation-induced PRs; i.e., PRs may not be calcium channel-dependent. The muscarinic cholinergic agonist carbachol induced depolarization in most PR neurons tested, and the muscarinic cholinergic antagonist scopolamine reduced or blocked PPN stimulation-induced PRs in some PnC neurons, suggesting that some PRs may be due to muscarinic receptor activation. The nonspecific ionotropic glutamate receptor antagonist kynurenic acid failed to block PPN stimulation-induced PRs, as did the metabotropic glutamate receptor antagonist (R, S)-alphamethyl-4-carboxyphenylglycine, suggesting that PRs may not be mediated by glutamate receptors. These findings suggest that PPN stimulation-induced PRs may be due to increased excitability following closing of muscarinic receptor-sensitive potassium channels, allowing PnC neurons to respond to a transient, frequency-dependent depolarization with long-lasting stable states. PPN stimulation appears to induce PRs using parameters known best to induce locomotion. This mechanism may be related to switching from one state to another (e.g., locomotion vs. standing or sitting, waking vs. non-REM sleep or REM sleep).