Impact of age on the circadian visual system and the sleep-wake cycle in mus musculus

Abstract

Age plays a critical role in disease development and tolerance to cancer treatment, often leading to an increased risk of developing negative symptoms including sleep disturbances. Circadian rhythms and sleep become disrupted as organisms age. In this study, we explored the behavioral alterations in sleep, circadian rhythms, and masking using a novel video system and interrogate the long-term impact of age-based changes in the non-image forming visual pathway on brain anatomy. We demonstrated the feasibility and utility of the novel system and establish that older mice have disruptions in sleep, circadian rhythms, and masking behaviors that were associated with major negative volume alterations in the non-imaging forming visual system, critical for the induction and rhythmic expression of sleep. These results provide important insights into a mechanism, showing brain atrophy is linked to age in distinct non-image forming visual regions, which may predispose older individuals to developing circadian and sleep dysfunction when further challenged by disease or treatment.

Keep Your Mask On: The Benefits of Masking for Behavior and the Contributions of Aging and Disease on Dysfunctional Masking Pathways

“…Because light is a consistent, rhythmic daily stimulus and all three systems are responsive to their presentation, we hypothesize that brain regions important for regulating homeostatic sleep and extra-SCN circadian rhythms are critical for inducing masking and rely on the behavior to promote timing of sleep and activity. Our work has shown that light directly activates regions of the brain important for the regulation of homeostatic sleep and in our diurnal rodent model these regions have also shown rhythmic daily patterns of activation (Shuboni et al, 2015;Shuboni-Mulligan et al, 2021). Lesions of some of these regions have been shown to have dramatic implications for masking behavior (see Neural mechanisms of underlying masking below).…”

“…Clearly, patients experiencing hypersomnia because of radiation are unable to maintain wakefulness during the daytime, which suggests a faltering of the masking pathway’s ability to suppress sleep urges in the light. As treatment in these patients is directed to the brain, we have hypothesized that changes in the neuroanatomy of sleep circuits may be directly impacted by therapy, including the circadian visual pathway that brings light information to the circadian and masking systems ( Young et al, 2019 ; Shuboni-Mulligan et al, 2021 ).…”

“…In the SCN, in particular, plasticity has been shown to decrease between the cells of the nuclei resulting in dampened circadian rhythms of behavior in older animals ( Van Someren et al, 2002 ; Nakamura et al, 2016 ). The masking process, too, is impacted by age, as older mice have been shown to recover from masking pulses to light faster, resulting in less impactful and shorter-lasting masking effects on behavior, and exhibit structural changes within retinal ipRGCs and the circadian visual system of the brain ( Adhikari et al, 2015 ; Shuboni-Mulligan et al, 2021 ). The pupillary light reflex (PLR), which like masking is also dependent on the circadian visual system and ipRGCs, is negatively impacted by age, resulting in a decreased change in pupillary size after exposure to light in humans ( Bitsios et al, 1996 ; Lobato-Rincón et al, 2014 ).…”

Histological analysis of sleep and circadian brain circuitry in cranial radiation-induced hypersomnolence (C-RIH) mouse model

“…To determine if radiation impacted sleep during the inactive (day) or active (night) time in our mouse model, we separated the data by lighting condition. Mice are nocturnal and spend most of the time sleeping when lights are on during the day and are active during the nighttime 33 – 35 . The high dose group slept more during the inactive period, a 3% increase from the low dose (Fig 1 F), but this difference was not significant (t(30) = 0.788, p = 0.437).…”

Association of Circadian Clock Gene Expression with Glioma Tumor Microenvironment and Patient Survival

“…Disruption of these rhythms caused by chronic jetlag [ 56 , 57 ] or the genetic deletion of core clock genes [ 58 , 59 ] has a negative impact on the functionality of immune cells and can lead to premature death. Age is another factor that can disrupt clock gene expression and circadian rhythms at the organism level leading to premature death [ 60 ]. Although our analysis indicates that the PER expression level is an additional independent prognostic factor, alongside age and IDH mutation status, the untangling of any interaction between these factors deserves further examination through time series studies.…”