Genetic background influences age-related decline in visual and nonvisual retinal responses, circadian rhythms, and sleep

Abstract

The circadian system is entrained to the environmental light/dark cycle via retinal photoreceptors and regulates numerous aspects of physiology and behavior, including sleep. These processes are all key factors in healthy aging showing a gradual decline with age. Despite their importance, the exact mechanisms underlying this decline are yet to be fully understood. One of the most effective tools we have to understand the genetic factors underlying these processes are genetically inbred mouse strains. The most commonly used reference mouse strain is C57BL/6J, but recently, resources such as the International Knockout Mouse Consortium have started producing large numbers of mouse mutant lines on a pure genetic background, C57BL/6N. Considering the substantial genetic diversity between mouse strains we expect there to be phenotypic differences, including differential effects of aging, in these and other strains. Such differences need to be characterized not only to establish how different mouse strains may model the aging process but also to understand how genetic background might modify age-related phenotypes. To ascertain the effects of aging on sleep/wake behavior, circadian rhythms, and light input and whether these effects are mouse strain-dependent, we have screened C57BL/6J, C57BL/6N, C3H-HeH, and C3H-Pde6b+ mouse strains at 5 ages throughout their life span. Our data show that sleep, circadian, and light input parameters are all disrupted by the aging process. Moreover, we have cataloged a number of strain-specific aging effects, including the rate of cataract development, decline in the pupillary light response, and changes in sleep fragmentation and the proportion of time spent asleep.

The origins and evolution of sleep

“…Large differences in sleep duration and timing among humans suggests that existing genetic variation among individuals potently affects sleep (Hartmann, 1973;Kronholm et al, 2006;He et al, 2009). While many laboratory studies investigating the molecular mechanisms of sleep regulation have relied on highly inbred model systems including mice, zebrafish and fruit flies, the study of sleep in outbred populations has revealed that geographical location, evolutionary history and naturally occurring genetic variation contribute to robust sleep differences within animals of the same species (Duboué et al, 2011;Zimmerman et al, 2012;Banks et al, 2015;Svetec et al, 2015). Even though sleep has been characterized in surprisingly few evolutionary systems, small, non-mammalian model organisms with a well-defined evolutionary history provide opportunities to identify novel mechanisms underlying sleep regulation (Fig.…”

Effect of chronic corticosterone application on depression‐like behavior in C57BL/6N and C57BL/6J mice

“…A recent sequence comparison of B6J and B6N from Taconic Farms showed that these sub-strains differ only in 34 single nucleotide polymorphisms, 2 indels in coding regions and 15 structural gene variants. Despite their genetic similarity, both sub-strains differ in a number of phenotypes including behaviors (Bechard et al 2012;Blum et al 1982;Bothe et al 2004;Bryant et al 2008;Crusio et al 1991;Hager et al 2014;Kumar et al 2013;Matsuo et al 2010;Mogil & Wilson 1997;Mouri et al 2012;Mulligan et al 2008;Ramachandra et al 2007;Siegmund et al 2005;Simon et al 2013;Stiedl et al 1999), circadian rhythms (Banks et al 2014), metabolic functions and responses to high-fat diet (Andersson et al 2010;Heiker et al 2014;Podrini et al 2013;Simon et al 2013;Walker et al 2014), as well as the physiology and pathology of the cardiovascular (Cardin et al 2014;Kararigas et al 2014;Moreth et al 2014), visual (Mattapallil et al 2012;Simon et al 2013) and auditory systems (Kendall & Schacht 2014;Schnabolk et al 2014). These phenotype differences are important, because many studies use genetic mouse models on these two C57BL/6 genetic backgrounds.…”

The natural DISC1-deletion present in several inbred mouse strains does not affect sleep

“…Despite their genetic similarity e.g. refs 32 and 33 B6N and B6J substrains show differences in a number of behavioral tests, although video-based analysis shows their rest/activity behavior to be indistinguishable at the relevant age 34 . Second, our study used a different EEG electrode configuration, which affects the frequency contributions of the recorded signal.…”