Hypothetical neurochemical mechanisms of paradoxical sleep deficiency in Alzheimer’s disease

Abstract

Based on the known experimental data on the specific morphological and neurochemical changes in the neural circuits involved in the occurrence of paradoxical sleep (REM sleep) that are observed in Alzheimer’s disease (AD) and our analysis of the effects of neuromodulators on the functioning of these circuits we propose that REM sleep deficiency in AD is caused by the following mechanisms: (1) the activity of the lateral geniculate body and occipital cortex is not sufficient to generate the ponto-geniculo-occipital (PGO) waves that are specific for REM sleep due to lower activity of cholinergic cells of the pedunculopontine and laterodorsal tegmental nuclei (PPN and LDTN) and lower density of cholinergic receptors; (2) because of reduced activity of cholinergic neurons of the PPN and LDN on GABAergic interneurons projecting to noradrenergic and serotonergic cells, the activity of the latter cannot be completely inhibited, as should occur during REM sleep; (3) the concentration of melanin-concentrating hormone is not sufficient for sleep due to the decreased activity of cholinergic cells of the basal forebrain nucleus, which excite neurons that produce this hormone; and (4) the activity of histaminergic cells increases and the activity of neurons that release melanin-concentrating hormone decreases due to the increased orexin level. Our analysis shows that common use of drugs that increase the acetylcholine concentration in patients with AD may result in increased activity of orexinergic cells and this must prevent the occurrence of REM sleep. We hypothesize that microstimulation of PPN may improve the occurrence of REM sleep because it should decrease the activity of serotoninergic, noradrenergic, and histaminergic cells and promote the generation of PGO waves and hippocampal theta activity. This treatment may improve the conditions for memory consolidation in patients with AD. Such microstimulation should be applied at night according to a special protocol.