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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).

Extracellular and intracellular recordings were carried out from neurons in the region of the pontine reticular formation at the transition between the nucleus reticularis pontis oralis and caudalis, and in the pontis caudalis. Responses were studied after stimulation of the mesopontine cholinergic pedunculopontine nucleus in precollicular-postmammillary transected, paralyzed preparations. Recordings of neurographic activity in hindlimb flexor and extensor nerves served to detect changes in fictive locomotion and muscle tone induced by pedunculopontine nucleus stimulation or occurring spontaneously. Short duration trains of pedunculopontine nucleus stimulation induced long lasting responses, on average over 12s in duration, in one-third of pontine reticular neurons. These prolonged responses were stimulation frequency-dependent such that the longest durations were induced by stimulation at 20-60Hz. In some cells, stimulation at lower (10Hz) or higher (100Hz) frequencies induced responses of shorter duration or were absent, while in others, higher frequencies prolonged the excitatory effects of pedunculopontine nucleus stimulation. We conclude that these stimulation frequency-dependent effects may be related to the modulation of postural muscle tone and locomotion by the pedunculopontine nucleus.

Injections into the pedunculopontine nucleus (PPN) of the cholinergic receptor agonist, carbachol (CAR), were found to reduce the amplitude of the vertex-recorded, sleep state-dependent P13 midlatency evoked potential in a dose- and time-dependent manner. This effect was blocked or reduced by pretreatment with the muscarinic receptor antagonist, scopolamine, injected into the PPN.

The vertex-recorded, sleep state-dependent P13 midlatency auditory evoked potential in the rat may be generated, in part, by pedunculopontine nucleus (PPN) projections. Injections into the PPN of the 5-HT(1A) serotonin receptor agonist, 8-hydroxy-2-di-n-propylaminotetralin hydrobromide (DPAT), were found to reduce the amplitude of the P13 potential in a dose- and time-dependent manner. The suppressive effect of DPAT was blocked or reduced by pretreatment with the 5-HT(1A) serotonin receptor antagonist, Pindobind. These results show that the P13 potential can be modulated by known inhibitory serotonergic inputs to the PPN.

The human P1/P50 midlatency auditory evoked potential and the startle response (SR) have been used as measures of sensory and sensorimotor gating, respectively. In the present study, both prepulse and paired stimulus paradigms were used in order to investigate the relationship between sensory gating mechanisms of the P13 potential, the putative rodent equivalent of the P1 potential, and those of the SR. In addition, these were compared to the properties of the N40 potential, another measure of sensory gating. Simultaneous recordings from the vertex (P13 potential and N40 potential) and neck musculature (SR) showed that (1) in a prepulse paradigm, increasing the intensity of the prepulse or decreasing the interstimulus interval resulted in increased inhibition of the P13 potential, N40 potential (to a lesser degree) and the SR (to a greater degree), (2) when using a low signal-to-noise ratio between the prepulse intensity and the background level, prepulse inhibition of the SR was reduced or absent while that of the P13 potential was present, (3) the amplitude of the 'prepulse evoked' P13 potential was significantly correlated with prepulse inhibition of the P13 potential, the N40 potential and the SR, (4) in a paired identical stimulus paradigm, decreasing the interstimulus interval resulted in increased habituation of the P13 potential, N40 potential (to a lesser degree) and the SR, and (5) increasing the intensity of the paired stimulation resulted in increased habituation of the P13 potential and the N40 potential (to a lesser degree), but not of the SR. These results demonstrate the presence of prepulse inhibition of the P13 potential, the N40 potential and the SR in a parallel manner, but show certain specific differences in their responses to parametric changes., (Copyright 1999 Elsevier Science B.V.)

Findings reported here show that there is a significant increase in the number of neurons in the pedunculopontine nucleus in most schizophrenic patients compared to age-matched controls. Nicotinamide adenine dinucleotide phosphate diaphorase histochemistry was used to label putative cholinergic neurons in the pedunculopontine nucleus and laterodorsal tegmental nucleus, while noradrenergic locus coeruleus neurons were labeled immunocytochemically using an antibody to tryosine hydroxylase. Cell counts of these neuronal groups were carried out using a Biographics image analysis system. We found significantly increased cell numbers in the pedunculopontine nucleus of schizophrenic patients compared to controls. The number of laterodorsal tegmental nucleus neurons was increased but this was not statistically significant. However, the total cell counts for pedunculopontine and laterodorsal tegmental nuclei were significantly higher in schizophrenic subjects. The number of locus coeruleus noradrenergic neurons was similar in both groups. These results implicate the brainstem reticular formation as a pathophysiological site in at least some patients with schizophrenia. In addition, these findings suggest a developmental etiology for the disease and account for some, but not all, of the symptoms of schizophrenia, including sensory gating abnormalities, sleep-wake disturbances and, perhaps, hallucinations. Overdriving of thalamic and substantia nigra function by cholinergic afferents from the midbrain may account for some of the symptoms seen in schizophrenia. These findings suggest that, at least in some schizophrenic patients, there is an increased number of neurons in the cholinergic arm of the reticular activating system. This may explain some of the symptoms of schizophrenia and points to a prenatal disturbance as one of the possible causes of the disease.

The pedunculopontine nucleus (PPN) has been implicated in sleep-wake control, arousal responses, and motor functions. The PPN also has been implicated in the generation of the P1 middle-latency auditory-evoked potential. The present study was undertaken to determine the topographical distribution, threshold, and response properties of depth-recorded potentials following auditory click stimulation. Experiments were conducted in both decerebrate cat and rat, with a view towards determining the presence of P1-like middle-latency auditory-evoked potentials in the midbrain of both species. These results demonstrate a) the presence in and around the PPN of a P1-like potential in the decerebrate rat similar to that described in the accompanying article as the P13 in the intact rat; b) the presence in and around the PPN of a P1-like potential in the decerebrate cat similar to that previously described by others as wave A in the intact cat; c) although thresholds for these potentials were similar to those of intact preparations, following frequencies were higher in the decerebrate preparations, i.e., responsiveness to repetitive stimulation was higher; and d) depth-recorded somatosensory-evoked potentials also were studied in the cat and found to show an evoked potential at a similar latency as middle-latency auditory depth-recorded potentials. These findings suggest that click stimulus-evoked, depth-recorded potentials are present in and around the PPN in the decerebrate rat and cat, i.e., in the absence of cortex, at a similar latency as in intact preparations.

The pedunculopontine nucleus (PPN) has been implicated in sleep-wake control, arousal responses, and motor functions. The PPN also has been implicated in the generation of the P1 middle-latency auditory-evoked potential. The present study was undertaken to determine the nature of the responsiveness of single neurons in and around the PPN following auditory stimulation. Somatosensory responsiveness also was tested in some cells. These results demonstrate a) the presence of a significant proportion of PPN neurons that respond to auditory click stimuli; b) two populations of neurons showing either low threshold/short latency/low habituation or high threshold/longer latency/high habituation; c) the responses of longer latency neurons precede the onset and peak of depth- and vertex-recorded middle-latency auditory-evoked potentials; d) thresholds of longer latency neurons similar to the threshold for wave A in the intact cat, the P13 potential in the intact rat, or the startle reflex; and e) convergent somatosensory and auditory responses at a similar latency in a number of PPN neurons. These findings suggest that neurons in and around the PPN may participate in auditory and somatosensory information processing related to arousal, and may contribute to the manifestation of the P1 auditory middle-latency evoked potential.

Basic fibroblast growth factor (bFGF) was found to increase the survival of immunocytochemically-identified cholinergic mesopontine neurons in dissociated cell cultures of embryonic rat midbrain. In contrast, cultures exposed to, (a) bFGF and an antibody to bFGF, (b) antibody to bFGF alone, or (c) untreated, contained approximately half the number of cholinergic neurons compared to bFGF-treated cultures.

Following injections of retrograde tracers into the spinal cord enlargements, the mesencephalic locomotor region (MLR) was electrically stimulated to induce locomotion in decerebrate rats. MLR sites coincided with cholinergic pedunculopontine nucleus (PPN) neurons, which were selectively labelled using NADPH diaphorase histochemistry. Retrogradely labelled (spinal-projecting) PPN neurons were scattered among cholinergic PPN neurons. The absence of retrogradely labelled, NADPH diaphorase positive PPN neurons indicates that spinal enlargement projections are non-cholinergic.

Retrograde tracers were injected into the rat medioventral medulla (MED) and the injection site was identified as a locomotion- inducing area by electrical stimulation in the decerebrate preparation. Histological reconstructions showed that about 10% of cholinergic pedunculopontine (PPN) and laterodorsal tegmental (LDT) neurons project to the MED. Also, large numbers of non-cholinergic cells in and around the PPN and LDT were found to project to the MED.

The mesencephalic locomotor region (MLR) was identified physiologically by inducing controlled locomotion on a treadmill in the precollicular rat following application of low amplitude current pulses to areas of the pontomesencephalic tegmentum. The same brains were processed using either of two techniques known to label neurons of the pedunculopontine nucleus (PPN)-choline acetyltransferase (ChAT) immunocytochemistry or nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase histochemistry. Histological reconstruction of locomotion-inducing sites were localized within or adjacent to ChAT or NADPH-diaphorase labeled cell groups. Three dimensional reconstructions of the PPN were used to visualize the colocalization of low threshold locomotion-inducing stimulation sites within PPN neuronal aggregates. These findings lend further support to the suggestion that the PPN is part of the MLR. A theoretical framework is proposed to account for results derived from various lines of research on this area.

Nicotinamide adenine dinucleotide phosphate (NAD-PH) diaphorase histochemistry was used to localize cholinergic neurons in the pedunculopontine nucleus of neonatal and adult rats. Measurements of cell body areas revealed an average area around 200 microns2 at birth, followed by a significant increase to approximately 500 microns2 by 2 weeks of age. Thereafter, there was a decrease in cell area such that by 5 weeks of age the neurons had attained their adult size of around 300 microns2. The marked increase in cell size at the end of 2 weeks of age is discussed in relation to significant events in the development of locomotor and other rhythmic function control systems.

The medial longitudinal fasciculus (MLF) and immediately adjacent reticular formation were stimulated electrically just caudal to the trochlear nucleus in the cat. In the pontomedullary reticular formation within 1.5 mm of the midline, antidromically excited neurons were detected in (1) the contralateral abducens nucleus, (2) the contralateral reticular formation just caudal and caudoventral to the abducens nucleus, and (3) the ipsilateral nucleus reticularis pontis caudalis beneath and rostral to the abducens nucleus. The possible involvement of these neurons in eye or body movements is discussed.