Background

Sleep disturbances are often linked to Alzheimer’s disease (AD). However, their exact relationship remains elusive. Since sleep is essential for memory consolidation, abnormalities in sleep-related brain activities may affect memory.

During rapid eye movement (REM) sleep, hippocampal theta oscillations become dominant whereas sharp wave-ripples (SWRs) appear during NREM sleep. These sleep-related hippocampal oscillations play a causal role in memory consolidation. Recently, we discovered that these oscillations are functionally coupled with ponto-geniculo-occipital (PGO) waves across sleep stages in wild-type mice.

Although PGO waves have long been known as a prominent electrophysiological marker of REM sleep since 1959, the function of PGO waves remains unclear. We recently found that PGO waves can be seen not just during REM sleep, but also during NREM sleep. Crucially, they appear at a certain phase of hippocampal theta oscillations during REM sleep whereas the coupling with PGO waves shortens hippocampal SWRs during NREM sleep. Thus, for the first time, we reported that the ponto-hippocampal coupling is sleep-stage-dependent.

Interestingly, a similar ponto-hippocampal coupling was subsequently reported in non-human primates, implying the clinical relevance of the ponto-hippocampal coupling. However, no previous studies have examined the ponto-hippocampal coupling in AD even though the pons and hippocampus are vulnerable regions in AD.

Hypothesis

In this PhD project, combining in vivo electrophysiological, optogenetic and behavioural approaches in an AD mouse model, APP^NL-G-F, we will test the hypothesis that the ponto-hippocampal coupling is disrupted in AD and that the manipulation of the ponto-hippocampal coupling enhances sleep-dependent memory consolidation. To this end, we propose two work packages (WPs).

Research outline

In WP1, by combining in vivo electrophysiological and behavioural approaches, we will examine if and how the ponto-hippocampal coupling is disrupted in APP^NL-G-F mice of both sexes at two age points. In addition, we will also correlate hippocampus-dependent memory with the degree of ponto-hippocampal coupling. 

In WP2, by combining closed-loop optogenetic stimulation, we will facilitate the coupling between PGO waves and hippocampal theta oscillations during REM sleep and examine if artificial manipulation of the ponto-hippocampal coupling can enhance memory consolidation during REM sleep. To this end, we will optogenetically activate pontine cholinergic neurons, which have been implicated in PGO wave generation. This optogenetic-based neuromodulation will be done by detecting REM sleep and estimating the phase of ongoing hippocampal theta oscillations. Then we will examine if this closed-loop optogenetic-based neuromodulation enhances sleep-dependent memory consolidation.

The outcomes of this study will provide the first evidence that the ponto-hippocampal coupling is disrupted in the AD brain and open avenues for novel neuromodulation-based interventions for people with dementia.