IMPORTANCE OF CHOLINERGIC, GABAERGIC, SEROTONERGIC AND OTHER NEURONS IN THE MEDIAL MEDULLARY RETICULAR-FORMATION FOR SLEEP-WAKE STATES STUDIED BY CYTOTOXIC LESIONS IN THE CAT

Previous evidence has suggested that neurons in the medial medullary reticular formation play a critical role in the modulation of forebrain and spinal cord activity that occurs during the sleep-waking cycle and particularly in association with the state of paradoxical sleep. The importance of these neurons, including cholinergic, serotonergic and GABAergic cells [Holmes C. J. et al. (1994) Neuroscience 62, 1155-1178] for sleep-wake states was investigated after their destruction with the neurotoxin quisqualic acid injected into the medullary gigantocellular and magnocellular tegmental fields in cats. To assess the effects of the neuronal loss, polygraphic recording and behavioural observations were performed in baseline and for three weeks after the lesion, and the changes in these measures were correlated with the volume of destruction of medullary regions and the numbers of chemically identified cells within those regions. Following the cytotoxic lesions, which affected similar to 60% of the medullary gigantocellular and magnocellular tegmental fields, there was a significant reduction in the amount of paradoxical sleep (to a mean of 64% of baseline) during the first postlesion week, that recovered variably across cats in the second and third weeks. There was little to no change in the amount or organization of waking and slow wave sleep. The individually variable amounts of postlesion paradoxical sleep were correlated positively with the number of surviving cholinergic cells, negatively with the number of surviving serotonergic cells and positively with the ratio of surviving cholinergic or GABAergic cells to serotonergic cells. The most marked effect of the lesion was a substantial increase in the amplitude of the nuchal electromyogram during slow wave sleep (to 198%) and paradoxical sleep (to 378% of baseline in the first postlesion week). The increase in muscle tone was associated with movements of the head, neck or limbs during paradoxical sleep. Although, in some cats, the abnormal neck muscle tone decreased with time, limb movements continued to occur during paradoxical sleep for the duration of the experiment. The ratio of the total number of remaining cholinergic or GABAergic cells to serotonergic cells correlated negatively with the increased muscle tone and/or movements. It was concluded that the neurons of the medial medullary reticular formation contribute to, but are not necessary for, the generation of paradoxical sleep, and have particular importance for the regulation of muscle tone and inhibition of movement during this state. From correlative evidence, it appears that medullary cholinergic neurons may play a facilitatory role, whereas serotonergic cells would play an inhibitory role in the generation of paradoxical sleep and associated motor inhibition. The relative numbers and presumed activities of these putative paradoxical sleep-ON versus paradoxical sleep-OFF cell populations appears to be most important for the appearance of the state and muscle atonia. Intrinsic GABAergic neurons may play an intermediary role, with their local projections being potentially important for inhibiting paradoxical sleep-OFF cells but also for disinhibiting paradoxical sleep-ON cells within the medial medullary reticular formation and raphe.