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.

Environment and brain plasticity: towards an endogenous pharmacotherapy.

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.

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.

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.

Leukemia inhibitory factor impairs structural and neurochemical development of rat visual cortex in vivo.

Minipump infusions into visual cortex in vivo at the onset of the critical period have revealed that the proinflammatory cytokine leukemia inhibitory factor (LIF) delays the maturation of thalamocortical projection neurons of the lateral geniculate nucleus, and tecto-thalamic projection neurons of the superior colliculus, and cortical layer IV spiny stellates and layer VI pyramidal neurons. Here, we report that P12-20 LIF infusion inhibits somatic maturation of pyramidal neurons and of all interneuron types in vivo. Likewise, DIV 12-20 LIF treatment in organotypic cultures prevents somatic growth GABA-ergic neurons. Further, while NPY expression is increased in the LIF-infused hemispheres, the expression of parvalbumin mRNA and protein, Kv3.1 mRNA, calbindin D-28k protein, and GAD-65 mRNA, but not of GAD-67 mRNA or calretinin protein is substantially reduced. Also, LIF treatment decreases parvalbumin, Kv3.1, Kv3.2 and GAD-65, but not GAD-67 mRNA expression in OTC. Developing cortical neurons are known to depend on neurotrophins. Indeed, LIF alters neurotrophin mRNA expression, and prevents the growth promoting action of neurotophin-4 in GABA-ergic neurons. The results imply that LIF, by altering neurotrophin expression and/or signaling, could counteract neurotrophin-dependent growth and neurochemical differentiation of cortical neurons.

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.

Olfactory evaluation in Mild Cognitive Impairment: correlation with neurocognitive performance and endothelial function.

Mild Cognitive Impairment (MCI) is an intermediate condition between normal aging and dementia, associated with an increased risk of progression into the latter within months or years. Olfactory impairment, a well-known biomarker for neurodegeneration, might be present in the condition early, possibly representing a signal for future pathological onset. Our study aimed at evaluating olfactory function in MCI and healthy controls in relation to neurocognitive performance and endothelial function. A total of 85 individuals with MCI and 41 healthy controls, matched for age and gender, were recruited. Olfactory function was assessed by Sniffin' Sticks Extended Test (Burghart, Medizintechnik, GmbH, Wedel, Germany). A comprehensive neurocognitive assessment was performed. Endothelial function was assessed by flow-mediated dilation (FMD) of the brachial artery by ultrasound. MCI individuals showed an impaired olfactory function compared to controls. The overall olfactory score is able to predict MCI with a good sensitivity and specificity (70.3 and 77.4% respectively). In MCI, olfactory identification score is correlated with a number of neurocognitive abilities, including overall cognitive status, dementia rating, immediate and delayed memory, visuospatial ability and verbal fluency. FMD was reduced in MCI (2.90 ± 2.15 vs. 3.66 ± 1.96%, P = 0.016) and was positively associated with olfactory identification score (ρs =0.219, P = 0.025). The association remained significant after controlling for age, gender, and smoking. In conclusion, olfactory evaluation is able to discriminate between MCI and healthy individuals. Systemic vascular dysfunction might be involved, at least indirectly, in olfactory dysfunction in MCI.

Brain structural and functional development: genetics and experience.

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.

Enriched early life experiences reduce adult anxiety-like behavior in rats: a role for insulin-like growth factor 1.

Early life experiences can affect brain development, contributing to shape interindividual differences in stress vulnerability and anxiety-like behavior. In rodents, high levels of maternal care have long-lasting positive effects on the behavior of the offspring and stress response; post-weaning rearing in an enriched environment (EE) or massage counteract the negative effects of maternal separation or prenatal stressors. We recently found that insulin-like growth factor 1 (IGF-1) is a key mediator of early EE or massage on brain development. Whether early enrichment of experience can induce long-lasting effects on anxiety-like behavior and whether IGF-1 is involved in these effects is not known. We assessed anxiety-like behavior by means of the elevated plus maze in control adult rats and in adult rats subjected to early EE or to massage. We found that both EE and massage reduced adult anxiety-like behavior. Early IGF-1 systemic injections in rat pups reared in standard condition mimic the effects of EE and massage, reducing anxiety-like behavior in the adult; blocking early IGF-1 action in massaged and EE animals prevents massage and EE effects. In EE and IGF-1-treated animals, we assessed the hippocampal expression of glucocorticoid receptors (GRs) at postnatal day 12 (P12) and P60, finding a significantly higher GR expression at P60 for both treatments. These results suggest that IGF-1 could be involved in mediating the long-lasting effects of early life experiences on vulnerability/resilience to stress in adults.

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.

Evidence for metaplasticity in the human visual cortex.

The threshold and direction of excitability changes induced by low- and high-frequency repetitive transcranial magnetic stimulation (rTMS) in the primary motor cortex can be effectively reverted by a preceding session of transcranial direct current stimulation (tDCS), a phenomenon referred to as "metaplasticity". Here, we used a combined tDCS-rTMS protocol and visual evoked potentials (VEPs) in healthy subjects to provide direct electrophysiological evidence for metaplasticity in the human visual cortex. Specifically, we evaluated changes in VEPs at two different contrasts (90 and 20 %) before and at different time points after the application of anodal or cathodal tDCS to occipital cortex (i.e., priming), followed by an additional conditioning with low- or high-frequency rTMS. Anodal tDCS increased the amplitude of VEPs and this effect was paradoxically reverted by applying high-frequency (5 Hz), conventionally excitatory rTMS (p < 0.0001). Similarly, cathodal tDCS led to a decrease in VEPs amplitude, which was reverted by a subsequent application of conventionally inhibitory, 1 Hz rTMS (p < 0.0001). Similar changes were observed for both the N1 and P1 component of the VEP. There were no significant changes in resting motor threshold values (p > 0.5), confirming the spatial selectivity of our conditioning protocol. Our findings show that preconditioning primary visual area excitability with tDCS can modulate the direction and strength of plasticity induced by subsequent application of 1 or 5 Hz rTMS. These data indicate the presence of mechanisms of metaplasticity that keep synaptic strengths within a functional dynamic range in the human visual cortex.

Treatment of neurodevelopmental disorders in adulthood.

Brain development in neurodevelopmental disorders has been considered to comprise a sequence of critical periods, and abnormalities occurring during early development have been considered irreversible in adulthood. However, findings in mouse models of neurodevelopmental disorders, including fragile X, Rett syndrome, Down syndrome, and neurofibromatosis type I suggest that it is possible to reverse certain molecular, electrophysiological, and behavioral deficits associated with these disorders in adults by genetic or pharmacological manipulations. Furthermore, recent studies have suggested that critical period-like plasticity can be reactivated in the adult brain by environmental manipulations or by pharmacotherapy. These studies open up a tantalizing possibility that targeted pharmacological treatments in combination with regimes of training or rehabilitation might alleviate or reverse the symptoms of neurodevelopmental disorders even after the end of critical developmental periods. Even though translation from animal experimentation to clinical practice is challenging, these results suggest a rational basis for treatment of neurodevelopmental disorders in adulthood.

A sensitive period for environmental regulation of eating behavior and leptin sensitivity.

Western lifestyle contributes to body weight dysregulation. Leptin down-regulates food intake by modulating the activity of neural circuits in the hypothalamic arcuate nucleus (ARC), and resistance to this hormone constitutes a permissive condition for obesity. Physical exercise modulates leptin sensitivity in diet-induced obese rats. The role of other lifestyle components in modulating leptin sensitivity remains elusive. Environmentally enriched mice were used to explore the effects of lifestyle change on leptin production/action and other metabolic parameters. We analyzed adult mice exposed to environmental enrichment (EE), which showed decreased leptin, reduced adipose mass, and increased food intake. We also analyzed 50-d-old mice exposed to either EE (YEE) or physical exercise (YW) since birth, both of which showed decreased leptin. YEE mice showed no change in food intake, increased response to leptin administration, increased activation of STAT3 in the ARC. The YW leptin-induced food intake response was intermediate between young mice kept in standard conditions and YEE. YEE exhibited increased and decreased ratios of excitatory/inhibitory synapses onto α-melanocyte-stimulating hormone and agouti-related peptide neurons of the ARC, respectively. We also analyzed animals as described for YEE and then placed in standard cages for 1 mo. They showed no altered leptin production/action but demonstrated changes in excitatory/inhibitory synaptic contacts in the ARC similar to YEE. EE and physical activity resulted in improved insulin sensitivity. In conclusion, EE and physical activity had an impact on feeding behavior, leptin production/action, and insulin sensitivity, and EE affected ARC circuitry. The leptin-hypothalamic axis is maximally enhanced if environmental stimulation is applied during development.

Gene expression patterns underlying the reinstatement of plasticity in the adult visual system.

The nervous system is highly sensitive to experience during early postnatal life, but this phase of heightened plasticity decreases with age. Recent studies have demonstrated that developmental-like plasticity can be reactivated in the visual cortex of adult animals through environmental or pharmacological manipulations. These findings provide a unique opportunity to study the cellular and molecular mechanisms of adult plasticity. Here we used the monocular deprivation paradigm to investigate large-scale gene expression patterns underlying the reinstatement of plasticity produced by fluoxetine in the adult rat visual cortex. We found changes, confirmed with RT-PCRs, in gene expression in different biological themes, such as chromatin structure remodelling, transcription factors, molecules involved in synaptic plasticity, extracellular matrix, and excitatory and inhibitory neurotransmission. Our findings reveal a key role for several molecules such as the metalloproteases Mmp2 and Mmp9 or the glycoprotein Reelin and open up new insights into the mechanisms underlying the reopening of the critical periods in the adult brain.

Activation of Rho GTPases triggers structural remodeling and functional plasticity in the adult rat visual cortex.

A classical example of age-dependent plasticity is ocular dominance (OD) plasticity, triggered by monocular deprivation (MD). Sensitivity of cortical circuits to a brief period of MD is maximal in juvenile animals and downregulated in adult age. It remains unclear whether a reduced potential for morphological remodeling underlies this downregulation of physiological plasticity in adulthood. Here we have tested whether stimulation of structural rearrangements is effective in promoting experience-dependent plasticity in adult age. We have exploited a bacterial protein toxin, cytotoxic necrotizing factor 1 (CNF1), that regulates actin dynamics and structure of neuronal processes via a persistent activation of Rho GTPases. Injection of CNF1 into the adult rat visual cortex triggered a long-lasting activation of the Rho GTPase Rac1, with a consequent increase in spine density and length in pyramidal neurons. Adult rats treated with CNF1, but not controls, showed an OD shift toward the open eye after MD. CNF1-mediated OD plasticity was selectively attributable to the enhancement of open-eye responses, whereas closed-eye inputs were unaffected. This effect correlated with an increased density of geniculocortical terminals in layer IV of monocularly deprived, CNF1-treated rats. Thus, Rho GTPase activation reinstates OD plasticity in the adult cortex via the potentiation of more active inputs from the open eye. These data establish a direct link between structural remodeling and functional plasticity and demonstrate a role for Rho GTPases in brain plasticity in vivo. The plasticizing effects of Rho GTPase activation may be exploited to promote brain repair.

Experience-dependent expression of NPAS4 regulates plasticity in adult visual cortex.

There is evidence that developmental-like plasticity can be reactivated in the adult visual cortex. Although activity-dependent transcription factors underlying the process of plasticity reactivation are currently unknown, recent studies point towards NPAS4 as a candidate gene for the occurrence of plasticity in the adult visual system. Here, we addressed whether NPAS4 is involved in the reinstatement of plasticity by using the monocular deprivation protocol and long-term fluoxetine treatment as a pharmacological strategy that restores plasticity in adulthood. A combination of molecular assays for gene expression and epigenetic analysis, gene delivery by lentiviral infection, shRNA interference and electrophysiology as a functional read-out, revealed a previously unknown role for the transcription factor NPAS4 in the regulation of adult visual cortical plasticity. We found that NPAS4 overexpression restores ocular dominance plasticity in adult naive animals whereas NPAS4 down-regulation prevents the plastic outcome caused by fluoxetine in adulthood.Our findings lead the way to the identification of novel therapeutic targets for pathological conditions where reorganization of neuronal networks would be beneficial in adult life.

IGF-1 restores visual cortex plasticity in adult life by reducing local GABA levels.

The central nervous system architecture is markedly modified by sensory experience during early life, but a decline of plasticity occurs with age. Recent studies have challenged this dogma providing evidence that both pharmacological treatments and paradigms based on the manipulation of environmental stimulation levels can be successfully employed as strategies for enhancing plasticity in the adult nervous system. Insulin-like growth factor 1 (IGF-1) is a peptide implicated in prenatal and postnatal phases of brain development such as neurogenesis, neuronal differentiation, synaptogenesis, and experience-dependent plasticity. Here, using the visual system as a paradigmatic model, we report that IGF-1 reactivates neural plasticity in the adult brain. Exogenous administration of IGF-1 in the adult visual cortex, indeed, restores the susceptibility of cortical neurons to monocular deprivation and promotes the recovery of normal visual functions in adult amblyopic animals. These effects were accompanied by a marked reduction of intracortical GABA levels. Moreover, we show that a transitory increase of IGF-1 expression is associated to the plasticity reinstatement induced by environmental enrichment (EE) and that blocking IGF-1 action by means of the IGF-1 receptor antagonist JB1 prevents EE effects on plasticity processes.

A richness that cures.

A study in Nature by Fischer et al. shows that environmental enrichment or increasing histone acetylation rescue the ability to form new memories and re-establish access to remote memories even in the presence of brain degeneration. Chromatin remodeling may be the final gate environmental enrichment opens to enhance plasticity and represents a promising target for therapeutical intervention in neurodegenerative diseases.

Developmental downregulation of histone posttranslational modifications regulates visual cortical plasticity.

The action of visual experience on visual cortical circuits is maximal during a critical period of postnatal development. The long-term effects of this experience are likely mediated by signaling cascades regulating experience-dependent gene transcription. Developmental modifications of these pathways could explain the difference in plasticity between the young and adult cortex. We studied the pathways linking experience-dependent activation of ERK to CREB-mediated gene expression in vivo. In juvenile mice, visual stimulation that activates CREB-mediated gene transcription also induced ERK-dependent MSK and histone H3 phosphorylation and H3-H4 acetylation, an epigenetic mechanism of gene transcription activation. In adult animals, ERK and MSK were still inducible; however, visual stimulation induced weak CREB-mediated gene expression and H3-H4 posttranslational modifications. Stimulation of histone acetylation in adult animals by means of trichostatin promoted ocular dominance plasticity. Thus, differing, experience-dependent activations of signaling molecules might be at the basis of the differences in experience-dependent plasticity between juvenile and adult cortex.