Sleep promoting higher centres
1 The ventrolateral preoptic nucleus (VLPO) in the anterior hypothalamus inhibits the aminergic nuclei through GABA-ergic neurones. It also has separate projections to the LDT/PPT.
The VLPO and TMN have mutually inhibitory actions so that as the VLPO activity builds up during wakefulness its inhibition of the TMN progressively increases and eventually reaches the point at which the TMN becomes inactive. The VLPO at this time also inhibits the other aminergic nuclei and initiates NREM sleep, and subsequently allows REM sleep. As the homeostatic drive to sleep gradually wanes, the VLPO inhibition of the TMN decreases, allowing it to become active again and to inhibit VLPO activity.
This releases the other aminergic nuclei from inhibition and enables wakefulness to appear.
This reciprocal inhibition functions as a bistable oscillator or flip-flop mechanism which leads to rapid changes between sleep and wakefulness, minimizing the duration for which a mixed sleep–wake state persists .
2 Adenosine accumulation in the extracellular spaces in the basal forebrain inhibits the cholinergic neurones in this region, which would otherwise promote wakefulness and REM sleep. Adenosine may have more widespread actions within the brainstem and influence the VLPO, and may form a component of the homeostatic sleep drive mechanism.
Pathways to cerebral cortex
1 Thalamus. This is the main gate for sensory information, other than olfaction, and for the ascending reticular activating system, comprising mainly the aminergic nuclei reaching the cerebral cortex.
Thalamic synchronization protects the cerebral cortex from these influences and effectively deafferentates it during NREM sleep.
2 Basal forebrain and hypothalamus. These closely linked areas integrate sleep/wake drives, circadian influences and neural activity related to external stimuli.
The complexity of these centres has been described above and they also interact with the thalamus, particularly the reticular nucleus which is an extension of the ascending reticular activating system. The output of the basal forebrain and hypothalamus is widespread within the cerebral cortex including the limbic cortex.
The cerebral cortex does not initiate sleep, but its impact on the adaptive drive allows sleep to occur or it may delay its onset. Its activity is determined by the combined input from the thalamus, basal forebrain and hypothalamus. Histaminergic and dopaminergic mechanisms are particularly important in maintaining wakefulness and both these and REM sleep are supported by cholinergic activity.