Rescue of astrocyte activity by the calcium sensor STIM1 restores long-term synaptic plasticity in female mice modelling Alzheimer's disease.

Calcium dynamics in astrocytes represent a fundamental signal that through gliotransmitter release regulates synaptic plasticity and behaviour. Here we present a longitudinal study in the PS2APP mouse model of Alzheimer's disease (AD) linking astrocyte Ca2+ hypoactivity to memory loss. At the onset of plaque deposition, somatosensory cortical astrocytes of AD female mice exhibit a drastic reduction of Ca2+ signaling, closely associated with decreased endoplasmic reticulum Ca2+ concentration and reduced expression of the Ca2+ sensor STIM1. In parallel, astrocyte-dependent long-term synaptic plasticity declines in the somatosensory circuitry, anticipating specific tactile memory loss. Notably, we show that both astrocyte Ca2+ signaling and long-term synaptic plasticity are fully recovered by selective STIM1 overexpression in astrocytes. Our data unveil astrocyte Ca2+ hypoactivity in neocortical astrocytes as a functional hallmark of early AD stages and indicate astrocytic STIM1 as a target to rescue memory deficits.

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.

Astrocytic microdomains from mouse cortex gain molecular control over long-term information storage and memory retention.

Memory consolidation requires astrocytic microdomains for protein recycling; but whether this lays a mechanistic foundation for long-term information storage remains enigmatic. Here we demonstrate that persistent synaptic strengthening invited astrocytic microdomains to convert initially internalized (pro)-brain-derived neurotrophic factor (proBDNF) into active prodomain (BDNFpro) and mature BDNF (mBDNF) for synaptic re-use. While mBDNF activates TrkB, we uncovered a previously unsuspected function for the cleaved BDNFpro, which increases TrkB/SorCS2 receptor complex at post-synaptic sites. Astrocytic BDNFpro release reinforced TrkB phosphorylation to sustain long-term synaptic potentiation and to retain memory in the novel object recognition behavioral test. Thus, the switch from one inactive state to a multi-functional one of the proBDNF provides post-synaptic changes that survive the initial activation. This molecular asset confines local information storage in astrocytic microdomains to selectively support memory circuits.

Physical Exercise Modulates Brain Physiology Through a Network of Long- and Short-Range Cellular Interactions.

In the last decades, the effects of sedentary lifestyles have emerged as a critical aspect of modern society. Interestingly, recent evidence demonstrated that physical exercise plays an important role not only in maintaining peripheral health but also in the regulation of central nervous system function. Many studies have shown that physical exercise promotes the release of molecules, involved in neuronal survival, differentiation, plasticity and neurogenesis, from several peripheral organs. Thus, aerobic exercise has emerged as an intriguing tool that, on one hand, could serve as a therapeutic protocol for diseases of the nervous system, and on the other hand, could help to unravel potential molecular targets for pharmacological approaches. In the present review, we will summarize the cellular interactions that mediate the effects of physical exercise on brain health, starting from the factors released in myocytes during muscle contraction to the cellular pathways that regulate higher cognitive functions, in both health and disease.

Intranasal delivery of BDNF rescues memory deficits in AD11 mice and reduces brain microgliosis.

A decrease in brain-derived neurotrophic factor (BDNF), a neurotrophin essential for synaptic function, plasticity and neuronal survival, is evident early in the progression of Alzheimer's disease (AD), being apparent in subjects with mild cognitive impairment or mild AD, and both proBDNF and mature BDNF levels are positively correlated with cognitive measures. BDNF delivery is, therefore, considered of great interest as a potentially useful therapeutic strategy to contrast AD. Invasive BDNF administration has indeed been recently used in animal models of AD with promising results in rescuing memory deficits, synaptic density and cell loss. Here, we tested whether non-invasive intranasal administration of different BDNF concentrations after the onset of cognitive and anatomical deficits (6 months of age) could rescue neuropathological and memory deficits in AD11 mice, a model of NGF deprivation-induced neurodegeneration. In addition to AD hallmarks, we investigated BDNF effects on microglia presence in the brain of AD11 mice, since alterations in microglia activation have been associated with ageing-related cognitive decline and with the progression of neurodegenerative diseases, including AD. We found that intranasal delivery of 42 pmol BDNF (1 µM), but not PBS, was sufficient to completely rescue performance of AD11 mice both in the object recognition test and in the object context test. No further improvement was obtained with 420 pmol (10 µM) BDNF dose. The strong improvement in memory performance in BDNF-treated mice was not accompanied by an amelioration of AD-like pathology, Aß burden, tau hyperphosphorylation and cholinergic deficit, but there was a dramatic decrease of CD11b immunoreactive brain microglia. These results reinforce the potential therapeutic uses of BDNF in AD and the non-invasive intranasal route as an effective delivery strategy of BDNF to the brain. They also strengthen the connection between neuroinflammation and neurodegenerative dementia and suggest microglia as a possible mediator of BDNF therapeutic actions in the brain.

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.

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.

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".

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.

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.

Early environmental therapy rescues brain development in a mouse model of Down syndrome.

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.

Fluoxetine in adulthood normalizes GABA release and rescues hippocampal synaptic plasticity and spatial memory in a mouse model of Down syndrome.

Down syndrome (DS) is the most common genetic disorder associated with mental retardation. It has been repeatedly shown that Ts65Dn mice, the major animal model for DS, have severe cognitive and synaptic plasticity dysfunctions caused by excessive inhibition in their temporal lobe structures. Here we employed a multidisciplinary approach spanning from the behavioral to the electrophysiological and molecular level to investigate the effects elicited by fluoxetine on cognitive abilities, hippocampal synaptic plasticity and GABA release in adult Ts65Dn mice. We report that a chronic treatment with fluoxetine administered in the drinking water normalizes GABA release and promotes recovery of spatial memory abilities, spatial working memory for alternation, and hippocampal synaptic plasticity in adult Ts65Dn mice. Our findings might encourage new experimental attempts aimed at investigating the potential of fluoxetine for application in the treatment of major functional deficits in adult people with DS.