The pontine brain stem hypothesis of desynchronized sleep generation has been tested with cellular methods confirming its three principal tenets: Ascending activation is apparent in the increased discharge of almost every forebrain neuronal population that has been studied. The precise synaptic mechanisms mediating this net excitation have not been elucidated but tonic postsynaptic facilitation is likely to underlie EEG desynchronization while presynaptic inhibition and phasic postsynaptic facilitation are probably involved in PGO wave generation. Descending inhibition of spinal reflex activity has been documented and analyzed in detail. Indirect, but strong evidence favors the operation of tonic postsynaptic inhibition, phasic postsynaptic excitation and presynaptic inhibition in the genesis of atonia, muscle twitches, and phasic sensory changes respectively. Pontine control of some of these events has been strengthened by the satisfaction of criteria for executive neurones by the giant cells of the pontine reticular formation (FTG). These neurones may be directly responsible for phasic events including the REMs, muscle twitches, and PGO waves. They may be indirectly responsible for EEG desynchronization through recruitment of more rostral reticular elements. They are probably not responsible for the atonia which is more likely mediated by their more caudal medullary reticular congeners. The mechanism of periodic activation of the executive neurones in the FTG may be that of reciprocal interaction with other pontine level-setting elements for which the best candidates are those neurones in the locus coeruleus and dorsal raphe nucleus having activity curves reciprocal to those of the FTG. A precise neurophysiological and mathematical model of reciprocal interaction is described. The reciprocal interaction hypothesis of desynchronized sleep control finds independent confirmation in a vast array of pharmacological data on sleep. In particular, the following tenets of the hypothesis are supported: The executive elements of the pontine brain stem control system include the giant cells of the reticular formation (FTG). These cells are cholinoceptive and cholinergic. They excite postsynaptic follower elements including each other. When cholinergically activated, the FTG neurones cholinergically generated desynchronized sleep events including EEG desynchronization, eye movements, PGO and other phasic events. Drugs which enchance cholinergic synaptic transmission, especially when injected into the giant cell fields, enchance descynchronized sleep. By contrast, anticholinergic compounds suppress desynchronized sleep. Cholinergic agents may also show suppress desynchronized sleep when injected into the presumed level setting neuronal pools of the dorsal raphe nucleus (DRN) and locus coeruleus (LC). The level-setting elements for the FTG include cells in the DRN and LC. These cells may be aminergic and aminoceptive, inhibiting their postsynaptic followers including each other. When activated, they suppress desynchronized sleep events especially atonia and PGO activity. Drugs which enchance aminergic synaptic transmission tend to suppress desynchronized sleep. Antiaminergic agents tend to enhance desynchronized sleep. Aminergic drugs should suppress desynchronized sleep when injected into the pool of generator neurones in the FTG. The reciprocal interaction hypothesis thus orders an otherwise confusing pharmacological literature and gives rise to new and testable hypotheses of sleep-cycle regulation. The combination of chronic microelectrode recording and microinjection techniques may thus result in a precise cellular neuropharmacology of those reticular systems long thought to regulate sleep and other vegetative phenomena.

Neuronal Activity During the Sleep-Waking Cycle

The medullary and spinal efferents of the pedunculopontine tegmental nucleus and adjacent mesopontine tegmentum were investigated by employing (1) the anterograde autoradiographic methodology and (2) the retrograde transport of HRP and/or WGA-HRP in combination with choline acetyltransferase immunohistochemistry.

The anterograde experiments identified five descending pathways from the mesopontine tegmentum: (1) Probst's tract, which descends in the dorsolateral reticular formation in close relation to the nucleus of the solitary tract; (2) a ventrolateral branch of Probst's tract that extends ventrolaterally alongside the spinal trigeminal nucleus; (3) a ventromedial branch of Probst's tract that extends ventromedially through the gigantocellular field of the medulla; (4) the medial reticulospinal tract, which descends in parallel with the medial longitudinal fasciculus and turns ventrolaterally along the dorsal surface of the inferior olive to enter the ventrolateral funiculus of the spinal cord; and (5) a crossed ventromedial pathway, which descends in a ventral paramedian position through the magnocellular field of the medulla.

The origins of these pathways reflected a rough lateral-to-medial topography of mesopontine tegmental cell groups. The parabrachial nucleus, situated furthest laterally, for example, projected primarily through Probst's tract and its ventrolateral branch. The pedunculopontine tegmental nucleus, midbrain extrapyramidal area, and the subceruleal region, situated more medially, projected descending axons largely through the ventromedial branch of Probst's tract. The pontine tegmental field, situated furthest medially and ventromedially, was the largest contributor to the medial reticulospinal tract.

The retrograde transport experiments confirmed these general organizational features. The combination of retrograde transport with choline acetyltransferase immunohistochemistry established that the cholinergic pedunculopontine tegmental nucleus contributes a large portion to the mesopontine tegmental innervation of the medullary reticular formation. A much smaller number of cholinergic pedunculopontine neurons project as far as the spinal cord. Spinal projections from the mesopontine tegmentum originate largely from non-cholinergic neurons of the midbrain extrapyramidal area, subceruleal region, Kolliker-Fuse division of the parabrachial nucleus, and pontine tegmental field.

Medullary and spinal efferents of the pedunculopontine tegmental nucleus and adjacent mesopontine tegmentum in the rat.

1. Extracellular recordings were made from caudate nucleus neurones in decerebrate cats using five-barrel micropipette electrodes.2. Electrical stimulation of the substantia nigra caused spike rate depressions in 121 of 260 caudate neurones as evidenced by changes in the post-stimulus histograms of their firing patterns. Spike rate facilitation occurred with forty-two caudate units.3. Neurones depressed by nigral stimuli were consistently depressed by micro-iontophoretic dopamine.4. Alpha-methyldopamine, administered iontophoretically, antagonized the depressant responses induced by both nigral stimulation and iontophoretic dopamine.5. The data are compatible with the concept that the caudate neuronal depressant responses produced by nigral stimulation are mediated by a direct dopaminergic nigro-neostriatal pathway. The possibility of mediation via polysynaptic pathways cannot, however, be completely excluded.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1970.sp009143

Caudate nucleus neurones: correlation of the effects of substantia nigra stimulation with iontophoretic dopamine

Electrical properties of Purkinje cells were recorded by intracellular microelectrode during extracellular electrophoretic application of gamma aminobutyrate, norepinephrine, cyclic adenosine monophosphate, and dibutyryl cyclic adenosine monophosphate. All these substances hyperpolarized Purkinje cells. Transmembrane resistance decreased during gamma aminobutyrate hyperpolarization. In contrast, norepinephrine and the cyclic nucleotides generally elevated resistance. These results show that cyclic nucleotides mimic the unique effects of norepinephrine on the bioelectric properties of neuronal membranes.

http://science.sciencemag.org/content/sci/171/3967/192.full.pdf

F. A. Steiner

Papers

Acetylcholine sensitivity of cat's medullary neurons.