Regular articleAging reduces the high-frequency and short-term adaptation of the vestibulo-ocular reflex in mice
Introduction
Aging can have a profound impact on vestibular system function, as can be appreciated from the prevalence of vestibular related disorders in the elderly. By the age of 70–80 years, more than half the population has vestibular dysfunction, and this is linked to increased dizziness and risk of falls (Agrawal et al., 2009). The prevalence of vestibular vertigo in this age group is 3 times that for young adults (<30 years) (Neuhauser and Lempert, 2009). Some of these symptoms are thought to be, in part at least, a consequence of senescence of the vestibular periphery (Ishiyama, 2009). For example, approximately 40% of patients referred for falls risk assessment were found to have vestibulo-ocular reflex (VOR) deficits including abnormal gain, phase lead, and asymmetries (Jacobson et al., 2008). The VOR, one of the fastest reflexes in the body, rapidly stabilizes vision to maintain one's line-of-sight by eye movements that compensate for changes in head direction. The VOR achieves this through the detection of head movements by hair cells located in the 3 semicircular canal cristae and 2 otolith organs of the inner ear. Head movement-induced hair cell activity is transmitted to the vestibular nuclei of the brainstem and vestibular cerebellum via the eighth cranial nerve and this information is converted into motor commands to the 6 extra-ocular muscles controlling eye movement. Importantly, the sensitivity or gain of the VOR is precisely tuneable, such that the extent of eye movement relative to head movement can be rapidly adjusted depending on whether the visual scene is near or far, or being viewed through magnifying or minifying lenses. The speed and precision of the VOR must be maintained over the lifespan in order to carry out daily activities and preserve quality of life. Recent studies show the human VOR performs optimally up until age 70–80, after which there is a decline in function (Li et al., 2015, Matiño-Soler et al., 2015, McGarvie et al., 2015). The reasons for this late life decline are not known, although vestibular system neurodegeneration is widely considered to be the cause.
Aging has been shown to associate with loss of vestibular hair cells, vestibular afferents, and cells in the central vestibular nuclei (Alvarez et al., 1998, Bergstrom, 1973, Johnsson, 1971, Lopez et al., 1997, Merchant et al., 2000, Rauch et al., 2001, Richter, 1980, Rosenhall, 1973, Ross et al., 1976, Velazquez-Villasenor et al., 2000, Park et al., 2001a, Park et al., 2001b). Studies report that the vestibular system gradually degrades and degenerates with age (Maes et al., 2010). For example, it has been reported that within the cristae ampullares of the semicircular canals, hair cell loss is approximately linear with age (∼0.6% per year), with type I vestibular hair cell loss proceeding at about twice the rate compared to type II hair cell loss (Merchant et al., 2000, Rauch et al., 2001). This progressive loss leads to an overall ∼45% decrease in hair cells numbers for all canals by the age of 80 (Rosenhall, 1973). Although not as dramatic, age-related decline in hair cell numbers occurs in the macular organs with a total hair cell loss ∼15% by the age of 80. There is also a large age-related reduction in otoconia volume (utricle 58%; saccule 79%) and number (utricle 30%; saccule 65%) (Merchant et al., 2000, Rauch et al., 2001). These findings suggest that static counter-tilt mediated predominantly by the otolith organs, and the higher-frequency transient VOR mediated predominantly by the canal type I vestibular hair cells, would be progressively affected by aging (e.g., Migliaccio et al., 2004, Minor et al., 1999).
Previous mouse studies examining age-related changes in the VOR were limited in scope. Stahl (2004) reported a tendency for VOR gain to decline with age, with a significant difference only at the lowest test frequency (0.1 Hz). Shiga et al. (2005) reported a significantly reduced VOR gain in 60-week old compared to 12-week old mice, for just one test frequency (0.8 Hz). A more recent study also found a significant decrease in VOR gain at a low test frequency (0.35 Hz) (Gutierrez-Castellanos, 2013). The effect of age on VOR adaptation has also been examined in mice. These studies reported that aging minimally affected short-term VOR adaptation (Stahl, 2004), but significantly affected long-term VOR adaptation (Gutierrez-Castellanos, 2013). Two limitations of these studies make it difficult to interpret the effects of aging on the VOR. The most critical limitation is the relatively young animals used to test the effects of aging. At 14–15 months old, C57BL6 mice are only at ∼50% of their median lifespan of 28–30 months (Yuan et al., 2009). If the effects of aging on the mouse vestibular system recapitulates the human time course (see introduction for human VOR decline), then significant functional decline in mice would not be anticipated until at least 25 months of age. The other main issue is the relatively low sinusoidal frequencies used to test the VOR (1.6–4 Hz), which are in the lower range of natural head movements for mice (≤20 Hz; Beraneck et al., 2008). In addition, these studies did not test the higher-frequency VOR using rapid transient head rotations, which are physiologically more relevant stimuli to the VOR. Also, the effects of aging on the static ocular counter-tilt response have not been studied in mice.
Given the prevailing evidence of a relatively late life decline in human VOR function, we sought to determine whether there was a corresponding behavioral decline in the mouse VOR, as mice would be the preferred animal model for future mechanistic studies. Our goal was to compare the baseline VOR between young mice with mice of an age that corresponds to the later human years across most of the natural VOR frequency range, that is, from static counter-tilt to rapid transient rotations. We also wanted to determine whether the short-term VOR adaptation range was different between young and aged mice. Our data revealed minimal differences in static counter-tilt response between young and aged mice, but a significant deficit in baseline VOR gain in aged mice during transient rotations. Moreover, aged mice had a significant decrease in short-term VOR adaptation range.
Section snippets
Animal groups and preparation
All surgical and experimental procedures were approved by the Animal Care and Ethics Committee of the University of New South Wales, Australia.
Data were collected exclusively for this study from 16 C57BL/6J male mice (2 mice groups, 8 young and 8 aged) from a colony bred and maintained at the University of Newcastle (NSW, Australia) Animal Facility. The young and aged groups had mice that were 3–4 and 30–32-months old, respectively. Each mouse contributed to 3 experimental sessions: no training
Counter-tilt response
Left and right eye data were fit to sinusoidal functions relating head tilt angle to eye position. There were only 4/18 conditions (2 age groups × 3 tilt planes × 3 eye components) where left and right eye data significantly differed (GLM: p < 0.05): during head tilt about the Y axis both pitch and roll components of eye position differed by 28% and 68%, respectively for aged mice; during head tilt about the Z axis the roll component of eye position differed for both aged (40%) and young (118%)
Discussion
The human VOR remains relatively stable until the 7th–8th decade and then there is a functional decline, particularly with higher head velocities (Matino-Soler et al., 2015). The present study characterized the effects of aging on the VOR using mice of an age that equates to this later period of the human lifespan. Our main finding from the baseline data was that aged mice had a numerically lower acceleration gain (GA) compared to young mice during transient head rotations that diverged with
Disclosure statement
The authors have no actual or potential conflicts of interest.
Acknowledgements
A. A. M. and this work were supported by the Garnett Passe and Rodney Williams Memorial Foundation Senior Principle Research Fellowship and a National Health and Medical Research Council of Australia (NHMRC) Project Grant APP1061752. P. P. H. was supported by a University of New South Wales (UNSW) International Research Scholarship and a Neuroscience Research Australia (NeuRA) supplementary scholarship. D. W. S. was supported by Garnett Passe and Rodney Williams Memorial Foundation Project
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