Enriched experience and recovery from amblyopia in adult rats: Impact of motor, social and sensory components
Highlights
► Visual or motor enrichment induced recovery from amblyopia in adult amblyopic rats. ► Visual perceptual learning induced recovery from amblyopia in adult amblyopic rats. ► Visual function recovery was accompanied by a reduced inhibitory tone in V1. ► Active use of the amblyopic eye was necessary for the recovery process.
Introduction
Amblyopia is the most common impairment of visual function affecting one eye in adults, with a prevalence of about 1–5% of the total world population (Holmes and Clarke, 2002). This pathology is caused by early abnormal visual experience with a functional imbalance between the two eyes owing to anisometropia, strabismus or congenital cataract, resulting in a dramatic loss of visual acuity in an apparently healthy eye and a broad range of other perceptual abnormalities, including deficits in contrast sensitivity and in stereopsis (Lewis and Maurer, 2005; Levi, 2006). In animal models, amblyopia can be artificially caused by imposing a long-term reduction of inputs from one eye by lid suture (monocular deprivation, MD) (Smith, 1981; Harwerth et al., 1983; Prusky et al., 2000a, Prusky et al., 2000b), or by inducing experimental anisometropia or strabismus (Singer et al., 1980; Mitchell et al., 1984; Kiorpes et al., 1998). The classic hallmarks of amblyopia in animal models are a permanent loss of visual acuity (VA) in the affected eye and a pronounced ocular dominance (OD) shift of visual cortical neurons in favor of the normal eye (Singer et al., 1980; Timney, 1983; Mitchell et al., 1984; Kiorpes et al., 1998; Maurer et al., 1999; Prusky et al., 2000a).
It is currently accepted that, due to a lack of sufficient residual plasticity within the brain, amblyopia is untreatable in adulthood. However, recent experimental results obtained both in animal models and in clinical trials have challenged this traditional view, unmasking a previously unsuspected potential for promoting recovery after the end of the critical period for visual cortex plasticity (Levi and Li, 2009; Bavelier et al., 2010; Baroncelli et al., 2011). A large body of evidence converged in indicating the inhibitory tone as a central hub for the restoration of plasticity in the adult visual cortex showing that a decrease of GABAergic transmission levels is required for the rescue of neural plasticity and recovery from amblyopic condition (Harauzov et al., 2010; Sale et al., 2010). In particular, environmental enrichment (EE), a widely used paradigm whereby the animals are given the opportunity for voluntary physical activity, enhanced social interactions, and multi-sensory stimulation (van Praag et al., 2000; Sale et al., 2009), turned out to be very effective in restoring visual abilities in adult animals (Sale et al., 2007).
The possibility to reinstate plasticity in the adult visual cortex by using a non-invasive procedure such as EE is appealing for its potential clinical application. Recent results in humans, indeed, have shown that experimental paradigms which could be considered akin to EE, such as playing videogames or practicing visual perceptual learning (PL), are able to promote recovery from amblyopia in adulthood (Levi and Li, 2009; Li et al., 2011). However, an exhaustive characterization of the relative contribution given by each of the EE components to recovery from amblyopia, as well as the mechanisms of action of EE-like protocols such as visual PL, is still lacking. This information could be useful in order to elaborate new protocols of environmental stimulation suitable for amblyopic human subjects.
Here, we assessed separately the efficacy of physical exercise, increased levels of social interaction, enhanced visual stimulation, or visual PL for their potential in promoting recovery from amblyopia in adult rats and investigated the molecular mechanisms underlying their efficacy, focusing on the intracortical inhibition/excitation balance.
Section snippets
Animal treatment and surgical procedures
A total of 101 Long-Evans hooded rats were used in this study, which has been approved by the Italian Ministry of Public Health and was carried out in accordance with the European Communities Council Directive of 24 November 1986 (86/609/EEC). All efforts were made to minimize animal suffering, to reduce the number of animals used, and to utilize alternatives to in vivo techniques, if available.
The animals were housed in a room with a temperature of 21 °C and a 12/12 h light–dark cycle. We
Physical activity induces amblyopia recovery in adult rats
We first investigated whether enhanced levels of physical exercise are able to promote recovery from amblyopia. A group of rats rendered amblyopic by monocular deprivation (MD) carried out at the peak of the critical period (postnatal day 21, P21) were subjected to reverse suture (RS) in adulthood (>P60) and then either transferred, for three weeks, in standard cages endowed with a running wheel connected to an automatic wheel turn recording device (n = 5), or left in standard cages for control
Effects elicited by motor, social and visual stimulation on amblyopia recovery
It is widely held that the positive effects elicited by EE are due to the combination of the various stimulating factors (motor, social, sensory) included in this protocol. However, very few studies have specifically examined the contribution given by each EE component in inducing plasticity in the adult brain. This analysis could be very helpful not only in a basic research perspective, but also for the elaboration of novel protocols of environmental stimulations suitable to be applied to
Conclusions
Environmental enrichment is a complex paradigm, since an increased stimulation is provided at multiple sensory, motor, and social levels. Although most humans do experience a high degree of environmental complexity, levels of physical, social and sensory stimulation vary greatly among individuals and in different periods of life. Our results obtained using motor enrichment and protocols of visual stimulation show that these components are crucially involved in amblyopia recovery elicited by EE
Conflict of interest
The authors declare that they have no conflicts of interest.
Acknowledgments
Work supported by the grant “Progetto di Ateneo 2008” to AS and a Scuola Normale Superiore grant to LM and LB.
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2021, Experimental NeurologyCitation Excerpt :Importantly, the combination of physical exercise and short-term deprivation of the amblyopic eye effectively promoted the long-term recovery of both visual acuity and stereopsis in adult amblyopic subjects (Lunghi et al., 2019c). It is also compelling to note that the adult visual cortex retains learning competences and this is reflected into the success of perceptual learning protocols to promote recovery from amblyopia in rodents (Baroncelli et al., 2012; Bonaccorsi et al., 2014). Some perceptual improvement has been demonstrated in human patients as well, with the essential ingredients of visual training protocols being incorporated into video game formats for home-based interventions (Astle et al., 2011; Green and Bavelier, 2012; Levi and Li, 2009; Tsirlin et al., 2015).
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These authors equally contributed to this work.