In recent years, emerging studies have observed gut microbiota (GM) alterations in Alzheimer's disease (AD), even in individuals with mild cognitive impairment (MCI). Further, impaired sleep and circadian patterns are common symptoms of AD, while sleep and circadian rhythm disruption (SCRD) is associated with greater β-amyloid (Aβ) burden and AD risk, sometimes years before the clinical onset of AD. Moreover, reports have demonstrated that GM and its metabolites exhibit diurnal rhythmicity and the role of SCRD in dampening the GM rhythmicity and eubiosis. This review will provide an evaluation of clinical and animal studies describing GM alterations in distinct conditions, including AD, sleep and circadian disruption. It aims to identify the overlapping and distinctive GM alterations in these conditions and their contributions to pathophysiology. Although most studies are observational and use different methodologies, data indicate partial commonalities in GM alterations and unanimity at functional level. Finally, we discuss the possible interactions between SCRD and GM in AD pathogenesis, as well as several methodological improvements that are necessary for future research.

Sleep is highly conserved across animal species. Both wake- and sleep-promoting neurons are implicated in the regulation of wake-sleep transition at dusk in However, little is known about how they cooperate and whether they act via different mechanisms. Here, we demonstrated that in female, sleep onset was specifically delayed by blocking the Shaker cognate L channels [Shal; also known as voltage-gated K channel 4 (K4)] in wake-promoting cells, including large ventral lateral neurons (l-LNvs) and pars intercerebralis (PI), but not in sleep-promoting dorsal neurons (DN1s). Delayed sleep onset was also observed in males by blocking K4 activity in wake-promoting neurons. Electrophysiological recordings show that K4 channels contribute A-type currents in LNvs and PI cells, but are much less conspicuous in DN1s. Interestingly, blocking K4 in wake-promoting neurons preferentially increased firing rates at dusk ∼ZT13, when the resting membrane potentials and firing rates were at lower levels. Furthermore, pigment-dispersing factor (PDF) is essential for the regulation of sleep onset by K4 in l-LNvs, and downregulation of PDF receptor (PDFR) in PI neurons advanced sleep onset, indicating K4 controls sleep onset via regulating PDF/PDFR signaling in wake-promoting neurons. We propose that K4 acts as a sleep onset controller by suppressing membrane excitability in a clock-dependent manner to balance the wake-sleep transition at dusk. Our results have important implications for the understanding and treatment of sleep disorders such as insomnia. The mechanisms by which our brains reversibly switch from waking to sleep state remain an unanswered and intriguing question in biological research. In this study, we identified that Shal/K4, a well known voltage-gated K channel, acts as a controller of wake-sleep transition at dusk in circadian neurons. We find that interference of K4 function with a dominant-negative form (DNK4) in subsets of circadian neurons specifically disrupts sleep onset at dusk, although K4 itself does not exhibit circadian oscillation. K4 preferentially downregulates neuronal firings at ZT9-ZT17, supporting that it plays an essential role in wake-sleep transition at dusk. Our findings may help understand and eventually treat sleep disorders such as insomnia.

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Circadian patterns of locomotor activity are influenced by social interactions. Studies on insects highlight the importance of volatile odors and the olfactory system. Wild-type Drosophila exhibit immediate re-entrainment to new light:dark (LD) cycles, whereas cry b and jet c mutants show deficits in re-entrainability. We found that both male mutants re-entrained faster to phase-shifted LD cycles when social interactions with WT female flies were promoted than the isolated males. In addition, we found that accelerated re-entrainment mediated by social interactions depended on both visual and olfactory cues, and the effect of both cues presented jointly was nearly identical to the sum of the effects of the two cues presented separately. Moreover, we found that re-entrainment deficits in period (per) expression-oscillation in jet c mutants were partially restored by promoting social interactions. Our results demonstrated that, in addition to olfaction, social interactions through the visual system also play important roles in clock entrainment.