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


Gareth Banks, Ines Heise, Becky Starbuck, Tamzin Osborne, Laura Wisby, Paul Potter, Ian J. Jackson, Russell G. Foster, Stuart N. Peirson, Patrick M. Nolan
Clinical Neurology / Neuroscience (all) / Ageing / Developmental Biology / Geriatrics and Gerontology


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The Genetics of Circadian Rhythms in Neurospora

Patricia L. Lakin-Thomas, Deborah Bell-Pedersen, Stuart Brody


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MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire, UK a r t i c l e i n f o

Article history:

Received 9 May 2014

Received in revised form 23 July 2014

Accepted 28 July 2014

Available online 2 August 2014 rhythm exerting control over a wide range of physiological and behavioral processes. The circadian clock is defined by its ability to ce of external timing t be synchronized to ent. In mammals, the nd circadian rhythms as well as its familiar ain circadian rhythms g sleep or alertness are well maintained in healthy individuals, aging is known to have a negative impact on all these processes, leading ultimately to disrupted circadian rhythms and sleep/wake cycles in older individuals. In humans, the reported effects of aging include an increased occurrence of cataracts (Klein and Klein, 2013), loss of retinal photoreceptors (Gao and Hollyfield, 1992), reduced circadian regulation of melatonin and temperature (Pandi-Perumal et al., 2005; Weinert, 2010), a reduction in sleep duration and q This is an open access article under the CC BY license (http:// * Corresponding author at: MRC Harwell, Harwell Science and Innovation

Campus, Oxfordshire, OX11 0RD, UK. Tel./fax: ?44 (0)1235 841091.

Contents lists availab

Neurobiolog lse

Neurobiology of Aging 36 (2015) 380e393E-mail address: (P.M. Nolan).1982). The timing of the sleep/wake cycle is also regulated by the internal circadian clock, which provides an innate biological (Hubbard et al., 2013). Although the interactions between retinal light input pathways, the circadian clock, and the sleep homeostat1. Introduction

In healthy individuals, a rhythmic sleep/wake cycle is maintained through the interaction of homeostatic and circadian mechanisms, as well as being modulated by external cues. The homeostatic process refers to an increase of sleep pressure that accumulates during wakefulness and is relieved by sleep (Borbely, maintain free running rhythms in the absen cues. However, to be of use, this clock mus external cuesda process known as entrainm most influential external cue for both sleep a is light. Light is detected by the retina and, role in image-forming vision, also acts to entr and directly modulate sleep by promotin 2015 The Authors. Published by Elsevier Inc. All rights reserved.Keywords:




Light input

Mouse strain0197-4580/$ e see front matter  2015 The Authors. b s t r a c t

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.Nuffield Laboratory of Ophthalmology (Nuffiel ment of Clinical Neurosciences), University of Oxford, John Radcliffe Hospital, Oxford, UKbMRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Western General Hospital, Edinburgh, UK c d DepartGenetic background influences age-relat nonvisual retinal responses, circadian rh

Gareth Banks a, Ines Heise a, Becky Starbuck a, Tamz

Paul Potter a, Ian J. Jackson b, Russell G. Foster c, Stu a journal homepage: www.ePublished by Elsevier Inc. All righd decline in visual and thms, and sleepq

Osborne a, Laura Wisby a, t N. Peirson c, Patrick M. Nolan a,* le at ScienceDirect y of Aging vier .com/locate/neuagingts reserved. gy oconsolidation, and an increased susceptibility to misalignments in circadian phase (Dijk et al., 1999) and increased fragmentation of sleep and time spent asleep during the day (Huang et al., 2002).

Animal models have been used widely to understand the mechanisms underlying not only rhythmic behavior but also aging.

Prominent among these models are inbred mouse strains. Inbred mice are commonly used in a range of biological research areas as their genetic homogeneity allows researchers in different laboratories to independently replicate results without the genetic background of the model being a confounding factor. They are also used extensively in genetic studies in which specific genes can be selectively knocked out or mutated to study their effects on the whole organism. A large number of different inbred mouse strains currently exist and through a combination of spontaneous mutation and genetic drift each inbred strain carries its own combination of mutations within its genome (Stevens et al., 2007). Two of the most commonly used mouse strains are C57BL/6J and C3H-HeH.