Long-term beneficial impact of the randomised trial 'Train the Brain', a motor/cognitive intervention in mild cognitive impairment people: effects at the 14-month follow-up.

No treatment options are currently available to counteract cognitive deficits and/or delay progression towards dementia in older people with mild cognitive impairment (MCI). The 'Train the Brain' programme is a combined motor and cognitive intervention previously shown to markedly improve cognitive functions in MCI individuals compared to non-trained MCI controls, as assessed at the end of the 7-month intervention. Here, we extended the previous analyses to include the long-term effects of the intervention and performed a data disaggregation by gender, education and age of the enrolled participants. We report that the beneficial impact on cognitive functions was preserved at the 14-month follow-up, with greater effects in low-educated compared to high-educated individuals, and in women than in men.

Molecular Mechanisms of Neural Plasticity: From Basic Research to Implications for Visual Functional Rescue.

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 [...].

Visual Perceptual Learning Induces Long-Lasting Recovery of Visual Acuity, Visual Depth Perception Abilities and Binocular Matching in Adult Amblyopic Rats.

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.

Antioxidants Prevent the Effects of Physical Exercise on Visual Cortical Plasticity.

BACKGROUND: Physical activity has been recently shown to enhance adult visual cortical plasticity, both in human subjects and animal models. While physical activity activates mitochondrial oxidative metabolism leading to a transient production of reactive oxygen species, it remains unknown whether this process is involved in the plasticizing effects elicited at the visual cortical level. RESULTS: Here, we investigated whether counteracting oxidative stress through a dietary intervention with antioxidants (vitamins E and C) interferes with the impact of physical exercise on visual cortex plasticity in adult rats. Antioxidant supplementation beyond the closure of the critical period blocked ocular dominance plasticity in response to eye deprivation induced by physical activity in adult rats. CONCLUSIONS: Antioxidants exerted their action through a mithormetic effect that involved dampening of oxidative stress and insulin-like growth factor 1 (IGF-1) signaling in the brain.

Visual Cortex Engagement in Retinitis Pigmentosa.

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.

Reduced ccl11/eotaxin mediates the beneficial effects of environmental stimulation on the aged hippocampus.

A deterioration in cognitive performance accompanies brain aging, even in the absence of neurodegenerative pathologies. However, the rate of cognitive decline can be slowed down by enhanced cognitive and sensorimotor stimulation protocols, such as environmental enrichment (EE). Understanding how EE exerts its beneficial effects on the aged brain pathophysiology can help in identifying new therapeutic targets. In this regard, the inflammatory chemokine ccl11/eotaxin-1 is a marker of aging with a strong relevance for neurodegenerative processes. Here, we demonstrate that EE in both elderly humans and aged mice decreases circulating levels of ccl11. Interfering, in mice, with the ccl11 decrease induced by EE ablated the beneficial effects on long-term memory retention, hippocampal neurogenesis, activation of local microglia and of ribosomal protein S6. On the other hand, treatment of standard-reared aged mice with an anti-ccl11 antibody resulted in EE-like improvements in spatial memory, hippocampal neurogenesis, and microglial activation. Taken together, our findings point to a decrease in circulating ccl11 concentration as a key mediator of the enhanced hippocampal function resulting from exposure to EE.

Effects of combined training on neuropsychiatric symptoms and quality of life in patients with cognitive decline.

BACKGROUND AND AIMS: Cognitive impairments associated with aging and dementia are major sources of neuropsychiatric symptoms (NPs) and deterioration in quality of life (QoL). Preventive measures to both reduce disease and improve QoL in those affected are increasingly targeting individuals with mild cognitive impairment (MCI) at early disease stage. However, NPs and QoL outcomes are too commonly overlooked in intervention trials. The purpose of this study was to test the effects of physical and cognitive training on NPs and QoL in MCI. METHODS: Baseline data from an MCI court (N = 93, mean age 74.9 ± 4.7) enrolled in the Train the Brain (TtB) study were collected. Subjects were randomized in two groups: a group participated to a cognitive and physical training program, while the other sticked to usual standard care. Both groups underwent a follow-up re-evaluation after 7 months from baseline. NPs were assessed using the Neuropsychiatric Inventory (NPI) and QoL was assessed using Quality of Life-Alzheimer's Disease (QOL-AD) scale. RESULTS: After 7 months of training, training group exhibited a significant reduction of NPs and a significant increase in QOL-AD with respect to no-training group (p = 0.0155, p = 0.0013, respectively). Our preliminary results suggest that a combined training can reduce NPs and improve QoL. CONCLUSIONS: Measuring QoL outcomes is a potentially important factor in ensuring that a person with cognitive deficits can 'live well' with pathology. Future data from non-pharmacological interventions, with a larger sample and a longer follow-up period, could confirm the results and the possible implications for such prevention strategies for early cognitive decline.

Running towards amblyopia recovery.

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.

Preservation of Visual Cortex Plasticity in Retinitis Pigmentosa.

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.

From Basic Visual Science to Neurodevelopmental Disorders: The Voyage of Environmental Enrichment-Like Stimulation.

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.

Pterostilbene Improves Cognitive Performance in Aged Rats: An in Vivo Study.

BACKGROUND/AIMS: Pterostilbene (Pt; trans-3,5-dimethoxy-4'-hydroxystilbene) is a natural phenol found in blueberries and grapevines. It shows remarkable biomedical activities similar to those of resveratrol. Its high bioavailability is a major advantage for possible biomedical applications. The goal of the study was to evaluate the effects of chronic pterostilbene administration on cognitive performance in aged rats with mild cognitive impairment. METHODS: 18-month-old animals were subjected to behavioral tests to establish the "baseline", then divided into treatment and control groups. The former were chronically fed Pt (22.5 mg/kg-day) for 20 consecutive days. At the end of this period all animals were tested again and sacrificed. The dentate gyrus, the hippocampus and the prefrontal and perirhinal cortices were then collected, and RT-qPCR and/or Western blot analyses were performed on a few transcripts/proteins involved in synaptic remodeling. Mitochondrial content was also assessed. RESULTS: Pt administration improved performance in behavioral tests and positively affected memory consolidation. We found increased levels of REST, PSD-95 and mitochondrial porin1 in the dentate gyrus and a positive correlation between T-maze test score and levels of cAMP responsive element binding protein (CREB) phosphorylation. CONCLUSION: These results underscore the therapeutic potential of Pt supplementation for age-related cognitive decline.

A new counterintuitive training for adult amblyopia.

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 occlusion 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 ± 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.

Intranasal BDNF administration promotes visual function recovery in adult amblyopic rats.

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".

Environmental Enrichment Induces Changes in Long-Term Memory for Social Transmission of Food Preference in Aged Mice through a Mechanism Associated with Epigenetic Processes.

Decline in declarative learning and memory performance is a typical feature of normal aging processes. Exposure of aged animals to an enriched environment (EE) counteracts this decline, an effect correlated with reduction of age-related changes in hippocampal dendritic branching, spine density, neurogenesis, gliogenesis, and neural plasticity, including its epigenetic underpinnings. Declarative memories depend on the medial temporal lobe system, including the hippocampus, for their formation, but, over days to weeks, they become increasingly dependent on other brain regions such as the neocortex and in particular the prefrontal cortex (PFC), a process known as system consolidation. Recently, it has been shown that early tagging of cortical networks is a crucial neurobiological process for remote memory formation and that this tagging involves epigenetic mechanisms in the recipient orbitofrontal (OFC) areas. Whether EE can enhance system consolidation in aged animals has not been tested; in particular, whether the early tagging mechanisms in OFC areas are deficient in aged animals and whether EE can ameliorate them is not known. This study aimed at testing whether EE could affect system consolidation in aged mice using the social transmission of food preference paradigm, which involves an ethologically based form of associative olfactory memory. We found that only EE mice successfully performed the remote memory recall task, showed neuronal activation in OFC, assessed with c-fos immunohistochemistry and early tagging of OFC, assessed with histone H3 acetylation, suggesting a defective system consolidation and early OFC tagging in aged mice which are ameliorated by EE.

Early impoverished environment delays the maturation of cerebral cortex.

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.

A Systematic Look at Environmental Modulation and Its Impact in Brain Development.

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.

Experience-dependent reduction of soluble ß-amyloid oligomers and rescue of cognitive abilities in middle-age Ts65Dn mice, a model of Down syndrome.

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 Aß 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 Aß 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.

Experience Affects Critical Period Plasticity in the Visual Cortex through an Epigenetic Regulation of Histone Post-Translational Modifications.

During an early phase of enhanced sensitivity called the critical period (CP), monocular deprivation causes a shift in the response of visual cortex binocular neurons in favor of the nondeprived eye, a process named ocular dominance (OD) plasticity. While the time course of the CP for OD plasticity can be modulated by genetic/pharmacological interventions targeting GABAergic inhibition, whether an increased sensory-motor experience can affect this major plastic phenomenon is not known. We report that exposure to environmental enrichment (EE) accelerated the closure of the CP for OD plasticity in the rat visual cortex. Histone H3 acetylation was developmentally regulated in primary visual cortex, with enhanced levels being detectable early in enriched pups, and chromatin immunoprecipitation revealed an increase at the level of the BDNF P3 promoter. Administration of the histone deacetylase inhibitor SAHA (suberoylanilide hydroxamic acid) to animals reared in a standard cage mimicked the increase in H3 acetylation observed in the visual cortex and resulted in an accelerated decay of OD plasticity. Finally, exposure to EE in adulthood upregulated H3 acetylation and was paralleled by a reopening of the CP. These findings demonstrate a critical involvement of the epigenetic machinery as a mediator of visual cortex developmental plasticity and of the impact of EE on OD plasticity. SIGNIFICANCE STATEMENT: While it is known that an epigenetic remodeling of chromatin structure controls developmental plasticity in the visual cortex, three main questions have remained open. Which is the physiological time course of histone modifications? Is it possible, by manipulating the chromatin epigenetic state, to modulate plasticity levels during the critical period? How can we regulate histone acetylation in the adult brain in a noninvasive manner? We show that the early exposure of rat pups to enriching environmental conditions accelerates the critical period for plasticity in the primary visual cortex, linking this effect to increased histone acetylation, specifically at the BDNF gene level. Moreover, we report that the exposure of adult animals to environmental enrichment enhances histone acetylation and reopens juvenile-like plasticity.