Sleep Mechanisms: Part III

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The Role Acetylcholine and Histamine in Sleep

The nucleus basalis magnocellularis, which is located in the forebrain, is a major source of cholinergic projections to neocortex, amygdala and medium septum-banda diagonalis complex. Cholinergic neurons play a critical role in the cognitive function and behavior arousal and EEG activation. AC release is greater during REM sleep than during the wakefulness and low during the Non-REM sleep. Vazquez J et al 2001.

The extensive loss of cholinergic neurons in Alzheimer's disease is responsible for decline of the cognitive functions. Anticholinergic drugs negatively affect memory and learning processes.

A recent study indicated that histaminergic neurons also play an important role in memory and learning by direct influence on memory or by modulating release of acetylcholine. (AC). Blandina P. et al 2004. Histominergic neurons are located in the tuberomammillary nucleus (TMN) of the hypothalamus. TMN send projections to different brain areas and modulates activity of cholinergic neurons. Histaminergic neurons promote wakefulness and emotional memory. Their activity is high during wakefulness and attention and low during sleep.

Histaminergic neurons directly stimulate the neocortex through the hypothalamo-cortical projections and indirectly by activation of the raphe nuclei. Histominergic descending projections activate cholinergic neurons in the mesopontine tegmentum, which activate neocortex through thalamo- and hypothalamo-cortical projections.

It is known that the baselateral amygdala (BLA) activity related to emotional memory. Histominergic neurons regulate acetylcholine release in amygdala. Microinjections of histamine in BLA impaired learning in animals conditioned to escape from the punishment box. In the neocortex, microinjections of histamine decreases cholinergic tone through H3 receptors. The systemic administration of H3 receptor agonists impairs rat performance in learned tasks.

The recent study shows that nitric oxide synapses exist on the cholinergic neurons of the laterodorsal and pedunculopontine tegmental nuclei, which send projections to the medial pontine reticular formation (mPRF). Stimulation of mPRF evokes REM sleep-like state and causes hypotonia of the upper airway muscles. mPRF microinjection of Ng-nitro-L-arginine (NLA), which inhibits nitric oxide synapses in mPRF, significantly decrease the duration of REM sleep. It is thought that nitric oxide increases the release of AC in mPRF and promotes REM sleep. Leonard T.O. et al.1997.

Dopamine

Substantia nigra is the major source of dopamine in the brain. Noradrenergic and serotonergic neurons become silent during REM sleep whereas dopaminergic neurons remain active which produce "psychotic-like mental activity of dreaming" Gottesmann C. (2002)

Reduction in the number of dopaminergic neurons in the substantia nigra causes REM sleep behavior disorder (RBD), which is characterized by a loss of skeletal muscle atonia during REM sleep. Patients with RBD have aggressive dreams in which they can injure their bed partners. The dopamine neuron loss increases activity of the globus pallidum, which inhibits midbrain structures. These structures inhibit the spinal motoneurons and their inhibition prevents development of skeletal muscle atonia during REM sleep. Eisensehr et al 2000.

Neuropeptid S

One more group of neurons was discovered recently between locus coeruleus and Barrington nucleus. These neurons release neuropeptid S (NPS) that elevates arousal and at the same time produce anxiolytic-like effect. NPS receptors were found in neocortex, thalamus, hypothalamus and amygdale. It is well known that the amygdale participate in modulation of fear and anxiety. Most likely, a unique anxiolytic effect of NPS is related to modulation of the amygdale activity by NPS. Reinscheid R.K. and Xu Y.2005

Sleep and memory

Since the important role of acetylcholine in memory consolidation is well proven, it was proposed that REM sleep during which high level of acetylcholine is observed must be involved in memory consolidation. The memory study surprisingly proved that slow-wave sleep deprivation impairs later memory consolidation after learning declarative and procedural tasks.

How slow-wave sleep with low level of acetylcholine influents memory consolidation? It is proposed that there are two stage of memory consolidation. In the first stage during the wakefulness and REM sleep the neocortex sends newly acquired information to the hippocampus, while acetylcholinergic projections release acetylcholine and suppress hippocampal feedback to neocortex. During slow-wave sleep, when the acetylcholine level is low and hippocampal feedback to the neocortex is released, memory traces temporary stored in hippocampal circuitry are transmitted back to the neocortex.

It is thought that the release of acetylcholine in the neocortex controls the flow of information from the hippocampus to the neocortex. The improvement of the declarative tasks performance after slow-wave sleep can be blocked by anticholinesterase drug. In the same experiments, the performance of procedural tasks was not impaired, which suggest that procedural memory consolidation may depend more on REM sleep.

It is proposed that REM sleep with high level of acetylcholine enhance synaptic plasticity and memory consolidation. Guis, S & Born 2004 in Power A.E. 2004.

Conclusion

In spite of the great progress in sleep research, it is still not possible to draw the whole picture of sleep mechanisms and understand the sleep purpose. Many neuroanatomic structures with different neurotransmitters at all levels of brain from the brainstem medulla to the thalamus and cerebral cortex participate in regulation of the sleep-wake cycle. Most likely, understanding sleep is almost the same as understanding the brain.

It does not mean that we cannot treat sleep disorders. The recent progress in neurochemistry and pharmacology of sleep gives us some hope.

The Insomnia and Sleep Disorders article is coming soon.

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