A COMPARATIVE STUDY OF SLEEP, DIURNAL PATTERNS, AND EYE CLOSURE BETWEEN THE HOUSE MOUSE (MUS MUSCULUS) AND AFRICAN SPINY MOUSE (ACOMYS CAHIRINUS)

To understand the function and origins of sleep, sleep needs to be studied across many different species. Although it is well conserved throughout mammals, 95% of papers are restricted to just three species, Homo sapiens, Mus musculus, and Rattus norvegicus. We aimed to characterize sleep and wake in a Murid rodent Acomys cahirinus in greater detail alongside the well-studied laboratory house mouse (Mus musculus) and wild M. musculus using a well validated, non-invasive, piezoelectric system for sleep and activity monitoring. We confirmed A. cahirinus, M. musculus, and wild M. musculus to be primarily nocturnal, but with clearly distinct behavioral patterns. Specifically, the activity of A. cahirinus sharply increases right at dark onset, which is common in nocturnal species, but surprisingly, decreases sharply just one hour later. Using infra-red camera recordings in single and group cage conditions, we found that A. cahirinus is more active early in the night period than late night period in single and group cages, and this decreased activity in the latter half of the night is much greater compared to M. musculus. In order to better understand these differences in activity, we investigated the sleep architecture of A. cahirinus using electroencephalogram (EEG) recordings. Our data show that A. cahirinus have a few key differences in sleep from M. musculus. A. cahirinus have significantly longer daily sleep periods and exhibit a much higher amount of REM sleep. A. cahirinus are awake at dark onset, but sleep more than M. musculus after the middle of the night. Most strikingly, A. cahirinus do not close their eyes virtually at all while sleeping, day or night. In order to test whether the sleep patterns of A. cahirinus are affected by or responsive to different light input, we set up a light flashing experiment during the daytime. While sleep amount did not change significantly during light flashing, A. cahirinus spent significantly less time in REM compared to baseline. In contrast, M. musculus had no difference in REM sleep percentage. Histological studies showed A. cahirinus have thinner retinal layers, but much thicker corneas than M. musculus. Electroretinography (ERG) results, specifically b-wave amplitudes, are significantly different between these two species. While eye closure and sleep have not been systematically studied across mammals, our observation is clearly a rare behavior. This raises further questions about A. cahirinus sleep architecture, the adaptive value of eyes open sleep to A. cahirius and whether they may have limited visual processing even during normal sleep

Longitudinal Data Methods for Evaluating Genome-by-Epigenome Interactions in Families

Background: Longitudinal measurement is commonly employed in health research and provides numerous benefits for understanding disease and trait progression over time. More broadly, it allows for proper treatment of correlated responses within clusters. We evaluated 3 methods for analyzing genome-by-epigenome interactions with longitudinal outcomes from family data. Results: Linear mixed-effect models, generalized estimating equations, and quadratic inference functions were used to test a pharmacoepigenetic effect in 200 simulated posttreatment replicates. Adjustment for baseline outcome provided greater power and more accurate control of Type I error rates than computation of a pre-to-post change score. Conclusions: Comparison of all modeling approaches indicated a need for bias correction in marginal models and similar power for each method, with quadratic inference functions providing a minor decrement in power compared to generalized estimating equations and linear mixed-effects models

The effects of aging on sleep parameters in a healthy, melatonin-competent mouse model

Background: Sleep disturbances are common maladies associated with human age. Sleep duration is decreased, sleep fragmentation is increased, and the timing of sleep onset and sleep offset is earlier. These disturbances have been associated with several neurodegenerative diseases. Mouse models for human sleep disturbances can be powerful due to the accessibility to neuroscientific and genetic approaches, but these are hampered by the fact that most mouse models employed in sleep research have spontaneous mutations in the biosynthetic pathway(s) regulating the rhythmic production of the pineal hormone melatonin, which has been implicated in human sleep. Purpose and method: The present study employed a non-invasive piezoelectric measure of sleep wake cycles in young, middle-aged and old CBA mice, a strain capable of melatonin biosynthesis, to investigate naturally-occurring changes in sleep and circadian parameters as the result of aging. Results: The results indicate that young mice sleep less than do middle-aged or aged mice, especially during the night, while the timing of activity onset and acrophase is delayed in aged mice compared to younger mice. Conclusion: These data point to an effect of aging on the quality and timing of sleep in these mice but also that there are fundamental differences between control of sleep in humans and in laboratory mice

A comparative study of sleep and diurnal patterns in house mouse (Mus musculus) and spiny mouse (Acomys cahirinus)

Most published sleep studies use three species: human, house mouse, or Norway rat. The degree to which data from these species captures variability in mammalian sleep remains unclear. To gain insight into mammalian sleep diversity, we examined sleep architecture in the spiny basal murid rodent Acomys cahirinus. First, we used a piezoelectric system validated for Mus musculus to monitor sleep in both species. We also included wild M. musculus to control for alterations generated by laboratory-reared conditions for M. musculus. Using this comparative framework, we found that A. cahirinus, lab M. musculus, and wild M. musculus were primarily nocturnal, but exhibited distinct behavioral patterns. Although the activity of A. cahirinus increased sharply at dark onset, it decreased sharply just two hours later under group and individual housing conditions. To further characterize sleep patterns and sleep-related variables, we set up EEG/EMG and video recordings and found that A. cahirinus sleep significantly more than M. musculus, exhibit nearly three times more REM, and sleep almost exclusively with their eyes open. The observed differences in A. cahirinus sleep architecture raise questions about the evolutionary drivers of sleep behavior

APOE-ε4 synergizes with sleep disruption to accelerate Aβ deposition and Aβ-associated tau seeding and spreading

Alzheimer\u27s disease (AD) is the most common cause of dementia. The APOE-ε4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset AD. The APOE genotype modulates the effect of sleep disruption on AD risk, suggesting a possible link between apoE and sleep in AD pathogenesis, which is relatively unexplored. We hypothesized that apoE modifies Aβ deposition and Aβ plaque-associated tau seeding and spreading in the form of neuritic plaque-tau (NP-tau) pathology in response to chronic sleep deprivation (SD) in an apoE isoform-dependent fashion. To test this hypothesis, we used APPPS1 mice expressing human APOE-ε3 or -ε4 with or without AD-tau injection. We found that SD in APPPS1 mice significantly increased Aβ deposition and peri-plaque NP-tau pathology in the presence of APOE4 but not APOE3. SD in APPPS1 mice significantly decreased microglial clustering around plaques and aquaporin-4 (AQP4) polarization around blood vessels in the presence of APOE4 but not APOE3. We also found that sleep-deprived APPPS1:E4 mice injected with AD-tau had significantly altered sleep behaviors compared with APPPS1:E3 mice. These findings suggest that the APOE-ε4 genotype is a critical modifier in the development of AD pathology in response to SD

A Comparative Study of Sleep and Diurnal Patterns in House Mouse (\u3cem\u3eMus musculus\u3c/em\u3e) and Spiny Mouse (\u3cem\u3eAcomys cahirinus\u3c/em\u3e)

Most published sleep studies use three species: human, house mouse, or Norway rat. The degree to which data from these species captures variability in mammalian sleep remains unclear. To gain insight into mammalian sleep diversity, we examined sleep architecture in the spiny basal murid rodent Acomys cahirinus. First, we used a piezoelectric system validated for Mus musculus to monitor sleep in both species. We also included wild M. musculus to control for alterations generated by laboratory-reared conditions for M. musculus. Using this comparative framework, we found that A. cahirinus, lab M. musculus, and wild M. musculus were primarily nocturnal, but exhibited distinct behavioral patterns. Although the activity of A. cahirinus increased sharply at dark onset, it decreased sharply just two hours later under group and individual housing conditions. To further characterize sleep patterns and sleep-related variables, we set up EEG/EMG and video recordings and found that A. cahirinus sleep significantly more than M. musculus, exhibit nearly three times more REM, and sleep almost exclusively with their eyes open. The observed differences in A. cahirinus sleep architecture raise questions about the evolutionary drivers of sleep behavior

Effects of the Dual Orexin Receptor Antagonist DORA-22 on Sleep in 5XFAD Mice

Introduction: Sleep disruption is a characteristic of Alzheimer\u27s disease (AD) that may exacerbate disease progression. This study tested whether a dual orexin receptor antagonist (DORA) would enhance sleep and attenuate neuropathology, neuroinflammation, and cognitive deficits in an AD-relevant mouse model, 5XFAD. Methods: Wild-type (C57Bl6/SJL) and 5XFAD mice received chronic treatment with vehicle or DORA-22. Piezoelectric recordings monitored sleep and spatial memory was assessed via spontaneous Y-maze alternations. Aβ plaques, Aβ levels, and neuroinflammatory markers were measured by immunohistochemistry, enzyme-linked immunosorbent assay, and real-time polymerase chain reaction, respectively. Results: In 5XFAD mice, DORA-22 significantly increased light-phase sleep without reducing Aβ levels, plaque density, or neuroinflammation. Effects of DORA-22 on cognitive deficits could not be determined because the 5XFAD mice did not exhibit deficits. Discussion: These findings suggest that DORAs may improve sleep in AD patients. Further investigations should optimize the dose and duration of DORA-22 treatment and explore additional AD-relevant animal models and cognitive tests

Corpora amylacea are associated with tau burden and cognitive status in Alzheimer\u27s disease

Corpora amylacea (CA) and their murine analogs, periodic acid Schiff (PAS) granules, are age-related, carbohydrate-rich structures that serve as waste repositories for aggregated proteins, damaged cellular organelles, and other cellular debris. The structure, morphology, and suspected functions of CA in the brain imply disease relevance. Despite this, the link between CA and age-related neurodegenerative diseases, particularly Alzheimer\u27s disease (AD), remains poorly defined. We performed a neuropathological analysis of mouse PAS granules and human CA and correlated these findings with AD progression. Increased PAS granule density was observed in symptomatic tau transgenic mice and APOE knock-in mice. Using a cohort of postmortem AD brain samples, we examined CA in cognitively normal and dementia patients across Braak stages with varying APOE status. We identified a Braak-stage dependent bimodal distribution of CA in the dentate gyrus, with CA accumulating and peaking by Braak stages II-III, then steadily declining with increasing tau burden. Refined analysis revealed an association of CA levels with both cognition and APOE status. Finally, tau was detected in whole CA present in human patient cerebrospinal fluid, highlighting CA-tau as a plausible prodromal AD biomarker. Our study connects hallmarks of the aging brain with the emergence of AD pathology and suggests that CA may act as a compensatory factor that becomes depleted with advancing tau burden

Progressive sleep disturbance in various transgenic mouse models of Alzheimer’s disease

Alzheimer’s disease (AD) is the leading cause of dementia. The relationship between AD and sleep dysfunction has received increased attention over the past decade. The use of genetically engineered mouse models with enhanced production of amyloid beta (Aβ) or hyperphosphorylated tau has played a critical role in the understanding of the pathophysiology of AD. However, their revelations regarding the progression of sleep impairment in AD have been highly dependent on the mouse model used and the specific techniques employed to examine sleep. Here, we discuss the sleep disturbances and general pathology of 15 mouse models of AD. Sleep disturbances covered in this review include changes to NREM and REM sleep duration, bout lengths, bout counts and power spectra. Our aim is to describe in detail the severity and chronology of sleep disturbances within individual mouse models of AD, as well as reveal broader trends of sleep deterioration that are shared among most models. This review also explores a variety of potential mechanisms relating Aβ accumulation and tau neurofibrillary tangles to the progressive deterioration of sleep observed in AD. Lastly, this review offers perspective on how study design might impact our current understanding of sleep disturbances in AD and provides strategies for future research

Longitudinal data methods for evaluating genome-by-epigenome interactions in families

Abstract Background Longitudinal measurement is commonly employed in health research and provides numerous benefits for understanding disease and trait progression over time. More broadly, it allows for proper treatment of correlated responses within clusters. We evaluated 3 methods for analyzing genome-by-epigenome interactions with longitudinal outcomes from family data. Results Linear mixed-effect models, generalized estimating equations, and quadratic inference functions were used to test a pharmacoepigenetic effect in 200 simulated posttreatment replicates. Adjustment for baseline outcome provided greater power and more accurate control of Type I error rates than computation of a pre-to-post change score. Conclusions Comparison of all modeling approaches indicated a need for bias correction in marginal models and similar power for each method, with quadratic inference functions providing a minor decrement in power compared to generalized estimating equations and linear mixed-effects models