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Visual system plasticity, the capability of visual connections to modify their structure and function in response to experience, is an essential property underlying the maturation of visual functions during development, behavioral flexibility in response to subtle environmental changes, and adaptive repair in conditions of disease or trauma [...]

An abnormal visual experience early in life, caused by strabismus, unequal refractive power of the eyes, or eye occlusion, is a major cause of amblyopia (lazy eye), a highly diffused neurodevelopmental disorder severely affecting visual acuity and stereopsis abilities. Current treatments for amblyopia, based on a penalization of the fellow eye, are only effective when applied during the juvenile critical period of primary visual cortex plasticity, resulting mostly ineffective at older ages. Here, we developed a new paradigm of operant visual perceptual learning performed under conditions of conventional (binocular) vision in adult amblyopic rats. We report that visual perceptual learning induced a marked and long-lasting recovery of visual acuity, visual depth perception abilities and binocular matching of orientation preference, and we provide a link between the last two parameters.

Retinitis pigmentosa (RP) is a family of inherited disorders caused by the progressive degeneration of retinal photoreceptors. There is no cure for RP, but recent research advances have provided promising results from many clinical trials. All these therapeutic strategies are focused on preserving existing photoreceptors or substituting light-responsive elements. Vision recovery, however, strongly relies on the anatomical and functional integrity of the visual system beyond photoreceptors. Although the retinal structure and optic pathway are substantially preserved at least in early stages of RP, studies describing the visual cortex status are missing. Using a well-established mouse model of RP, we analyzed the response of visual cortical circuits to the progressive degeneration of photoreceptors. We demonstrated that the visual cortex goes through a transient and previously undescribed alteration in the local excitation/inhibition balance, with a net shift towards increased intracortical inhibition leading to improved filtering and decoding of corrupted visual inputs. These results suggest a compensatory action of the visual cortex that increases the range of residual visual sensitivity in RP.

Retinitis Pigmentosa (RP) is a class of inherited disorders caused by the progressive death of photoreceptors in the retina. RP is still orphan of an effective treatment, with increasing optimism deriving from research aimed at arresting neurodegeneration or replacing light-responsive elements. All these therapeutic strategies rely on the functional integrity of the visual system downstream of photoreceptors. Whereas the inner retinal structure and optic radiation are known to be considerably preserved at least in early stages of RP, very little is known about the visual cortex. Remarkably, it remains completely unclear whether visual cortex plasticity is still present in RP. Using a well-established murine model of RP, the rd10 mouse, we report that visual cortical circuits retain high levels of plasticity, preserving their capability of input-dependent remodelling even at a late stage of retinal degeneration.

Amblyopia is the most common cause of visual impairment in one eye, with a prevalence of 1-5% in the world population. While amblyopia can be efficiently treated in children, it becomes irreversible in adults, due to the decline in neural plasticity past the end of the visual cortex critical period. Accordingly, no pharmacological approaches are available to rescue visual functions in adult amblyopic subjects. We report that non-invasive intranasal infusion of BDNF increased levels of this neurotrophic factor in V1 and induced a recovery of visual acuity, ocular dominance and visual depth perception in adult amblyopic rats, both in reverse-occluded animals and in those with unrestricted binocular sight. Visual recovery was long-lasting, and was prevented by pharmacological blockade of TrkB signaling in the visual cortex. These results underscore the possibility to replace invasive BDNF central administration with a safe procedure of potential interest in a number of currently still cureless central nervous system pathologies. This article is part of the Special Issue entitled "Neurobiology of Environmental Enrichment".

Several experimental procedures are currently used to investigate the impact of the environment on brain plasticity under physiological and pathological conditions. The available methodologies are aimed at obtaining global or specific reductions or intensifications of the stimuli, with initial standardization in animal models being paralleled by translational applications to humans. More procedures can be combined together or applied in series to obtain powerful experimental paradigms, and the choice of a given setting should take into account the specific genetic background, age, and phenotypic vulnerabilities of the target subjects. Sophisticated use of environmental manipulations can increase our knowledge of the mechanisms underlying experience-dependent plasticity, opening the way for new therapies for neurodevelopmental disorders, dysfunctions of plasticity, and brain aging.

Amblyopia is a neurodevelopmental disorder of the visual cortex arising from abnormal visual experience early in life which is a major cause of impaired vision in infants and young children (prevalence around 3.5%). Current treatments such as eye patching are ineffective in a large number of patients, especially when applied after the juvenile critical period. Physical exercise has been recently shown to enhance adult visual cortical plasticity and to promote visual acuity recovery. With the aim to understand the potentialities for translational applications, we investigated the effects of voluntary physical activity on recovery of depth perception in adult amblyopic rats with unrestricted binocular vision; visual acuity recovery was also assessed. We report that three weeks of voluntary physical activity (free running) induced a marked and long-lasting recovery of both depth perception and visual acuity. In the primary visual cortex, ocular dominance recovered both for excitatory and inhibitory cells and was linked to activation of a specific intracortical GABAergic circuit.

Genes and environmental stimuli cooperate in the regulation of brain development and formation of the adult neuronal architecture. Genetic alterations or exposure to perturbing environmental conditions, therefore, can lead to altered neural processes associated with neurodevelopmental disorders and brain disabilities. In this context, environmental enrichment emerged as a promising and noninvasive experimental treatment for favoring recovery of cognitive and sensory functions in different neurodevelopmental disorders. The aim of this review is to depict, mainly through the much explicative examples of amblyopia, Down syndrome, and Rett syndrome, the increasing interest in the potentialities and applications of enriched environment-like protocols in the field of neurodevelopmental disorders and the understanding of the molecular mechanisms underlying the beneficial effects of these protocols, which might lead to development of pharmacological interventions.

International audience; Objectives: The aim of this study was to investigate whether short-term inverse occlusion, combined with moderate physical exercise, could promote the recovery of visual acuity and stereopsis in a group of adult anisometropic amblyopes. Methods: Ten adult anisometropic patients underwent six brief (2 h) training sessions over a period of 4 weeks. Each training session consisted in the occlu-sion of the amblyopic eye combined with physical exercise (intermittent cycling on a stationary bike). Visual acuity (measured with ETDRS charts), stereoacuity (measured with the TNO test), and sensory eye dominance (measured with binocular rivalry) were tested before and after each training session, as well as in follow-up visits performed 1 month, 3 months, and 1 year after the end of the training. Results: After six brief (2 h) training sessions, visual acuity improved in all 10 patients (0.15 AE 0.02 LogMar), and six of them also recovered stereopsis. The improvement was preserved for up to 1 year after training. A pilot experiment suggested that physical activity might play an important role for the recovery of visual acuity and stereopsis. Conclusions: Our results suggest a noninvasive training strategy for adult human amblyopia based on an inverse-occlusion procedure combined with physical exercise.

Visual cortex plasticity is high during a critical period of early postnatal development, but rapidly diminishes with the transition to adulthood. Accordingly, visual disorders such as amblyopia (lazy eye), can be treated early in life by long-term occlusion of the non-amblyopic eye, but may become irreversible in adults, because of the decline in brain plasticity. Here we show that a novel counter-intuitive approach can promote the recovery of visual function in adult amblyopic patients: short-term occlusion of the amblyopic (not the fellow) eye, combined with physical exercise (cycling). After six brief (2h) training sessions, visual acuity improved in all ten patients (0.15±0.02 LogMar), and six of them also recovered stereopsis. The improvement was preserved for up to one year after training. A control experiment revealed that physical activity was crucial for the recovery of visual acuity and stereopsis. Thus, we propose a non-invasive therapeutic strategy for adult human amblyopia based an inverse-occlusion and physical exercise procedure.

The influence of exposure to impoverished environments on brain development is unexplored since most studies investigated how environmental impoverishment affects adult brain. To shed light on the impact of early impoverishment on developmental trajectories of the nervous system, we developed a protocol of environmental impoverishment in which dams and pups lived from birth in a condition of reduced sensory-motor stimulation. Focusing on visual system, we measured two indexes of functional development, that is visual acuity, assessed by using Visual Evoked Potentials (VEPs), and VEP latency. In addition, we assessed in the visual cortex levels of Insulin-Like Growth Factor 1 (IGF-1) and myelin maturation, together with the expression of the GABA biosynthetic enzyme GAD67. We found that early impoverishment strongly delays visual acuity and VEP latency development. These functional changes were accompanied by a significant reduction of IGF-1 protein and GAD67 expression, as well as by delayed myelination of nerve fibers, in the visual cortex of impoverished pups. Thus, exposure to impoverished living conditions causes a significant alteration of developmental trajectories leading to a prominent delay of brain maturation. These results underscore the significance of adequate levels of environmental stimulation for the maturation of central nervous system.

Cognitive decline with age shows strong interindividual variance. Several epidemiological studies have shown that some of the factors associated with maintaining a good cognitive performance with age are lifestyle factors, such as practising physical activity and being engaged in cognively stimulating activities, which are potentially modifiable even in old age. In parallel, studies in animal models have shown that physical exercise and environmental stimulation result in better cognitive performance, potentiation of neural plasticity, neuroprotection. More recently, intervention studies in humans begin to show that training based on cognitive or physical activity enhance cognitive performance in older adults. At the core of lifestyle effects on cognitive ageing is neural plasticity and the action of multiple molecular factors which translate physical and cognitive activity into adaptive and protective changes in the brain, allowing elders to better face ageing-related cognitive changes.

Age-related cognitive impairment and dementia are an increasing societal burden. Epidemiological studies indicate that lifestyle factors, e.g. physical, cognitive and social activities, correlate with reduced dementia risk; moreover, positive effects on cognition of physical/cognitive training have been found in cognitively unimpaired elders. Less is known about effectiveness and action mechanisms of physical/cognitive training in elders already suffering from Mild Cognitive Impairment (MCI), a population at high risk for dementia. We assessed in 113 MCI subjects aged 65–89 years, the efficacy of combined physical-cognitive training on cognitive decline, Gray Matter (GM) volume loss and Cerebral Blood Flow (CBF) in hippocampus and parahippocampal areas, and on brain-blood-oxygenation-level-dependent (BOLD) activity elicited by a cognitive task, measured by ADAS-Cog scale, Magnetic Resonance Imaging (MRI), Arterial Spin Labeling (ASL) and fMRI, respectively, before and after 7 months of training vs. usual life. Cognitive status significantly decreased in MCI-no training and significantly increased in MCI-training subjects; training increased parahippocampal CBF, but no effect on GM volume loss was evident; BOLD activity increase, indicative of neural efficiency decline, was found only in MCI-no training subjects. These results show that a non pharmacological, multicomponent intervention improves cognitive status and indicators of brain health in MCI subjects.

Brain aging is characterized by functional deterioration across multiple systems, associated to a progressive decay of neural plasticity. Here, we explored environmental enrichment (EE), a condition of enhanced sensory-motor and cognitive stimulation, as a strategy to restore plasticity processes in the old brain. Visual system is one of the paradigmatic models for studying experience-dependent plasticity. While reducing input from one eye through monocular deprivation induces a marked ocular dominance (OD) shift of neurons in the primary visual cortex during development, the same manipulation is totally ineffective after the closure of the critical period. We show that EE is able to reactivate OD plasticity in the visual cortex of aging rats, as assessed with both visual-evoked potentials and single-unit recordings. A marked reduction in intracortical GABAergic inhibition and a remodeling of extracellular matrix accompany this effect. The non-invasive nature of EE makes this paradigm eligible for human application.

Environmental enrichment (EE) is known to profoundly affect the central nervous system (CNS) at the functional, anatomical and molecular level, both during the critical period and during adulthood. Recent studies focusing on the visual system have shown that these effects are associated with the recruitment of previously unsuspected neural plasticity processes. At early stages of brain development, EE triggers a marked acceleration in the maturation of the visual system, with maternal behaviour acting as a fundamental mediator of the enriched experience in both the foetus and the newborn. In adult brain, EE enhances plasticity in the cerebral cortex, allowing the recovery of visual functions in amblyopic animals. The molecular substrate of the effects of EE on brain plasticity is multi-factorial, with reduced intracerebral inhibition, enhanced neurotrophin expression and epigenetic changes at the level of chromatin structure. These findings shed new light on the potential of EE as a non-invasive strategy to ameliorate deficits in the development of the CNS and to treat neurological disorders.

The routes of five satellite-tracked loggerhead turtles (Caretta caretta), subjected to an experimental translocation away from their usual migratory routes, have been analysed in relation to the concurrent oceanographic conditions. Remote sensing data on sea surface temperature and height anomalies, as well as trajectories of surface drifters were used, to get simultaneous information on the currents encountered by the turtles during their long-range oceanic movements. Turtles mostly turned out to move in the same direction as the main currents, and their routes were often influenced by circulation features they encountered. A comparison between turtle ground speeds with that of drifters shows that in several instances, the turtles did not drift passively with the currents but contributed actively to the overall movement. Two turtles embarked on an oceanic crossing, probably induced by seasonal changes in surface temperatures, a crossing that was largely determined by the main currents existing in the area.

The open-sea movements of marine animals are affected by the drifting action of currents that, if not compensated for, can produce non-negligible deviations from the correct route towards a given target. Marine turtles are paradigmatic skilful oceanic navigators that are able to reach remote goals at the end of long-distance migrations, apparently overcoming current drift effects. Particularly relevant is the case of leatherback turtles (Dermochelys coriacea), which spend entire years in the ocean, wandering in search of planktonic prey. Recent analyses have revealed how the movements of satellite-tracked leatherbacks in the Indian, Atlantic and Pacific Oceans are strongly dependent on the oceanic currents, up to the point that turtles are often passively transported over long distances. However, leatherbacks are known to return to specific areas to breed every 2–3 years, thus finding their way back home after long periods in the oceanic environment. Here we examine the navigational consequences of the leatherbacks' close association with currents and discuss how the combined reliance on mechanisms of map-based navigation and local orientation cues close to the target may allow leatherbacks to accomplish the difficult task of returning to specific sites after years spent wandering in a moving medium.

Environmental enrichment (EE) has long been exploited to investigate the influence of the environment on brain structure and function. Robust morphological and functional effects elicited by EE at the neuronal level have been reported to be accompanied by improvements in cognitive performance. Recently, EE has been shown to accelerate the development of the visual system and to enhance visual-cortex plasticity in adulthood. These new findings highlight the potential of EE as a promising non-invasive strategy to ameliorate deficits in the maturation of the nervous system and to promote recovery of normal sensory functions in pathological conditions affecting the adult brain.

Down syndrome (DS) is the most diffused genetic cause of intellectual disability and, after the age of forty, is invariantly associated with Alzheimer's disease (AD). In the last years, the prolongation of life expectancy in people with DS renders the need for intervention paradigms aimed at improving mental disability and counteracting AD pathology particularly urgent. At present, however, there are no effective therapeutic strategies for DS and concomitant AD in mid-life people. The most intensively studied mouse model of DS is the Ts65Dn line, which summarizes the main hallmarks of the DS phenotype, included severe learning and memory deficits and age-dependent AD-like pathology. Here we report for the first time that middle-age Ts65Dn mice display a marked increase in soluble Aβ oligomer levels in their hippocampus. Moreover, we found that long-term exposure to environmental enrichment (EE), a widely used paradigm that increases sensory-motor stimulation, reduces Aβ oligomers and rescues spatial memory abilities in trisomic mice. Our findings underscore the potential of EE procedures as a non-invasive paradigm for counteracting brain aging processes in DS subjects.

Summary Brain plasticity, defined as the capability of cerebral neurons to change in response to experience, is fundamental for behavioral adaptability, learning, memory, functional development, and neural repair. The visual cortex is a widely used model for studying neuroplasticity and the underlying mechanisms. Plasticity is maximal in early development, within the so-called critical period, while its levels abruptly decline in adulthood [1]. Recent studies, however, have revealed a significant residual plastic potential of the adult visual cortex by showing that, in adult humans, short-term monocular deprivation alters ocular dominance by homeostatically boosting responses to the deprived eye [2–4]. In animal models, a reopening of critical period plasticity in the adult primary visual cortex has been obtained by a variety of environmental manipulations, such as dark exposure, or environmental enrichment, together with its critical component of enhanced physical exercise [5–8]. Among these non-invasive procedures, physical exercise emerges as particularly interesting for its potential of application to clinics, though there has been a lack of experimental evidence available that physical exercise actually promotes visual plasticity in humans. Here we report that short-term homeostatic plasticity of the adult human visual cortex induced by transient monocular deprivation is potently boosted by moderate levels of voluntary physical activity. These findings could have a bearing in orienting future research in the field of physical activity application to clinical research.

Amblyopia is the most diffused form of visual function impairment affecting one eye, with a prevalence of 1–5% in the total world population. Amblyopia is usually caused by an early functional imbalance between the two eyes, deriving from anisometropia, strabismus, or congenital cataract, leading to severe deficits in visual acuity, contrast sensitivity and stereopsis. While amblyopia can be efficiently treated in children, it becomes irreversible in adults, as a result of a dramatic decline in visual cortex plasticity which occurs at the end of the critical period (CP) in the primary visual cortex. Notwithstanding this widely accepted dogma, recent evidence in animal models and in human patients have started to challenge this view, revealing a previously unsuspected possibility to enhance plasticity in the adult visual system and to achieve substantial visual function recovery. Among the new proposed intervention strategies, non invasive procedures based on environmental enrichment, physical exercise or visual perceptual learning (vPL) appear particularly promising in terms of future applicability in the clinical setting. In this survey, we will review recent literature concerning the application of these behavioral intervention strategies to the treatment of amblyopia, with a focus on possible underlying molecular and cellular mechanisms.

The diving behaviour of four leatherback turtles (Dermochelys coriacea) was recorded for periods of 0.5–8.1 months during their postnesting movements in the Indian and Atlantic Oceans, when they covered 1569–18,994 km. Dive data were obtained using satellite-linked transmitters which also provided information on the dive depths and profiles of the turtles. Turtles mainly dove to depths b200 m, with maximum dive durations under 30–40 min and exhibited diel variations in their diving activity for most part of the routes, with dives being usually longer at night. Diurnal dives were in general quite short, but cases of very deep (N900 m) and prolonged (N70 min) dives were however recorded only during daytime. The three turtles that were tracked for the longest time showed a marked change in behaviour during the tracking, decreasing their dive durations and ceasing to dive deeply. Moreover, diel variations disappeared, with nocturnal dives becoming short and numerous. This change in turtle diving activity appeared to be related to water temperature, suggesting an influence of seasonal prey availability on their diving behaviour. The turtle diving activity was independent on the shape of their routes, with no changes between linear movements in the core of main currents or looping segments in presence of oceanic eddies. D 2005 Elsevier B.V. All rights reserved.

Loggerhead turtles (Caretta caretta) are known to migrate towards fixed, individually-specific residential feeding grounds. To study their spatial behaviour and their navigational ability, five loggerheads nesting in South Africa were captured when about to start their postnesting migration and tracked by satellite after having been displaced from their usual migratory route. The first turtle, released south of Madagascar about 1,148 km from the capture site, moved west up to mainland Africa and then reached her feeding grounds by following the coast. A second turtle, released farther away (2,140 km) close to La Reunion Island, stopped for some time on the Madagascar east coast, then turned southwards to round the island and regain the African mainland in the northwest, without however allowing us to establish the location of her residential grounds. Three other turtles were released off the Tanzanian coast, 2,193 km north of their nesting area, at the northern edge of the distribution of the feeding grounds along the African coast. All of them headed north, and one turtle found her residential grounds located north of the release site. The other two females started long-distance oceanic wanderings in which they crossed nearly the entire Indian Ocean, apparently being transported by the sea currents of the region. We conclude that adult loggerhead turtles are apparently unable to compensate for the displacement and can return to a pelagic life style characteristic of juvenile turtles. These findings suggest that South African loggerheads rely on simple orientation mechanisms, such as the use of the coastline, as a guide, and compass orientation, possibly integrated by spatiotemporal programmes and/or acquired maps of familiar sites.

Down syndrome (DS), the most common genetic disorder associated with intellectual disabilities, is an untreatable condition characterized by a number of developmental defects and permanent deficits in the adulthood. Ts65Dn mice, the major animal model for DS, display severe cognitive and synaptic plasticity defects closely resembling the human phenotype. Here, we employed a multidisciplinary approach to investigate, for the first time in developing Ts65Dn mice, the effects elicited by early environmental enrichment (EE) on brain maturation and function. We report that exposure to EE resulted in a robust increase in maternal care levels displayed by Ts65Dn mothers and led to a normalization of declarative memory abilities and hippocampal plasticity in trisomic offspring. The positive effects of EE on Ts65Dn phenotype were not limited to the cognitive domain, but also included a rescue of visual system maturation. The beneficial EE effects were accompanied by increased BDNF and correction of over-expression of the GABA vesicular transporter vGAT. These findings highlight the beneficial impact of early environmental stimuli and their potential for application in the treatment of major functional deficits in children with DS.

Brain development is the result of the combined work of genes and environment. In this paper we first briefly discuss how, in terms of cellular and molecular plasticity mechanisms, the richness of early environment can control developmental trajectories and can induce long-term changes in neural circuits that underlie enduring changes in brain structure and function. We then see that experience most effectively moulds neural circuit development during specific time windows called critical periods. After the closure of these privileged windows for plasticity, it is very difficult to promote repair from 'errors' in brain development. As an example, congenital cataracts, refractive defects, or strabismus, if not precociously corrected during development, cause permanent deficit in visual acuity of the affected eye, a condition known as amblyopia. Little or no recovery from amblyopia is possible in the adult. However, recent results show that by using protocols of enriched environment it is possible to design interventions, which, by acting on specific plasticity factors, enhance adult cortical plasticity and allow recovery from amblyopia. This suggests that a better knowledge of how experience and environment engage endogenous plasticity factors could help to design interventions aimed at promoting recovery from neurodevelopmental defects, even after the end of critical periods.

Brain plasticity refers to the remarkable property of cerebral neurons to change their structure and function in response to experience, a fundamental theoretical theme in the field of basic research and a major focus for neural rehabilitation following brain disease. While much of the early work on this topic was based on deprivation approaches relying on sensory experience reduction procedures, major advances have been recently obtained using the conceptually opposite paradigm of environmental enrichment, whereby an enhanced stimulation is provided at multiple cognitive, sensory, social, and motor levels. In this survey, we aim to review past and recent work concerning the influence exerted by the environment on brain plasticity processes, with special emphasis on the underlying cellular and molecular mechanisms and starting from experimental work on animal models to move to highly relevant work performed in humans. We will initiate introducing the concept of brain plasticity and describing classic paradigmatic examples to illustrate how changes at the level of neuronal properties can ultimately affect and direct key perceptual and behavioral outputs. Then, we describe the remarkable effects elicited by early stressful conditions, maternal care, and preweaning enrichment on central nervous system development, with a separate section focusing on neurodevelopmental disorders. A specific section is dedicated to the striking ability of environmental enrichment and physical exercise to empower adult brain plasticity. Finally, we analyze in the last section the ever-increasing available knowledge on the effects elicited by enriched living conditions on physiological and pathological aging brain processes.

Brain plasticity can be defined as the capacity of cerebral neurons and neural circuits to change, structurally and functionally, in response to experience. This fundamental property is essential for maturation of sensory functions during development, for the adaptability of our behaviour to the environment through learning and memory processes and for brain repair in response to disease and trauma.