Insulin-like growth factor I media gli effetti dell'arricchimento ambientale sul sistema visivo

E' stato recentemente dimostrato che l'arricchimento ambientale influenza profondamente lo sviluppo della corteccia visiva: in particolare, l'arricchimento ambientale dalla nascita determina un'accelerazione della maturazione dell'acuità visiva, tale che i ratti arricchiti raggiungono l'acuità visiva di un ratto adulto già a P25. I fattori, che mediano questi effetti dell'arricchimento ambientale, non sono ancora noti. L'arricchimento ambientale determina nell'adulto la produzione di fattori potenzialmente coinvolti nel controllo dello sviluppo e della plasticità della corteccia visiva; fra questi, IGF-I è un candidato particolarmente interessante. IGF-I attraversa la barriera ematoencefalica e, agendo sui recettori neuronali di IGF-I, incrementa la loro attività elettrica ed induce l'espressione di numerosi fattori importanti per la plasticità neuronale. Abbiamo esaminato se IGF-I possa essere un mediatore degli effetti dell'arricchimento ambientale sullo sviluppo della corteccia visiva. Il primo passaggio del nostro studio è stato analizzare con metodi immunoistochimici lo sviluppo dell'espressione di IGF-I nella corteccia visiva di ratti arricchiti dalla nascita ed in ratti di controllo (non arricchiti). Abbiamo scoperto che a P18 i livelli di IGF-I nei ratti arricchiti sono significativamente più alti rispetto a quelli dei ratti non arricchiti. Abbiamo poi incrementato i livelli di IGF-I nella corteccia visiva di ratti non arricchiti e valutato se questo trattamento accelera lo sviluppo dell'acuità visiva, mimando gli effetti dell'arricchimento ambientale. IGF-I è stato infuso da P18 a P25 in corteccia visiva per mezzo di minipompe osmotiche ed è stata valutata l'acuità visiva elettrofisiologicamente, tramite la misurazione dei potenziali visivi evocati (VEPs). Abbiamo anche effettuato l'esperimento inverso, bloccando l'azione di IGF-I nella corteccia visiva di ratti arricchiti da P18 a P25, infondendo un analogo di IGF-I (JB-1), ed abbiamo accertato con i VEPs se questo blocca l'azione dell'ambiente arricchito sullo sviluppo dell'acuità visiva. Abbiamo trovato che a P25 l'acuità visiva di ratti non arricchiti trattati con IGF-I è più alta di quella dei controlli trattati con salina e simile all'acuità visiva dei ratti arricchiti. Al contrario, l'acuità visiva dei ratti arricchiti trattati con JB-1 è comparabile a quella dei ratti non arricchiti. Questi risultati suggeriscono che IGF-I possa essere un fattore chiave nel mediare gli effetti dell'arricchimento ambientale sullo sviluppo della corteccia visiva

Brain Plasticity and Disease: A Matter of Inhibition

One major goal in Neuroscience is the development of strategies promoting neural plasticity in the adult central nervous system, when functional recovery from brain disease and injury is limited. New evidence has underscored a pivotal role for cortical inhibitory circuitries in regulating plasticity both during development and in adulthood. This paper summarizes recent findings showing that the inhibition-excitation balance controls adult brain plasticity and is at the core of the pathogenesis of neurodevelopmental disorders like autism, Down syndrome, and Rett syndrome

GABAergic Inhibition in Visual Cortical Plasticity

Experience is required for the shaping and refinement of developing neural circuits during well defined periods of early postnatal development called critical periods. Many studies in the visual cortex have shown that intracortical GABAergic circuitry plays a crucial role in defining the time course of the critical period for ocular dominance plasticity. With the end of the critical period, neural plasticity wanes and recovery from the effects of visual defects on visual acuity (amblyopia) or binocularity is much reduced or absent. Recent results pointed out that intracortical inhibition is a fundamental limiting factor for adult cortical plasticity and that its reduction by means of different pharmacological and environmental strategies makes it possible to greatly enhance plasticity in the adult visual cortex, promoting ocular dominance plasticity and recovery from amblyopia. Here we focus on the role of intracortical GABAergic circuitry in controlling both developmental and adult cortical plasticity. We shall also discuss the potential clinical application of these findings to neurological disorders in which synaptic plasticity is compromised because of excessive intracortical inhibition

Food restriction enhances visual cortex plasticity in adulthood

Neural circuits display a heightened sensitivity to external stimuli during well-established windows in early postnatal life. After the end of these critical periods, brain plasticity dramatically wanes. The visual system is one of the paradigmatic models for studying experience-dependent plasticity. Here we show that food restriction can be used as a strategy to restore plasticity in the adult visual cortex of rats. A short period of food restriction in adulthood is able both to reinstate ocular dominance plasticity and promote recovery from amblyopia. These effects are accompanied by a reduction of intracortical inhibition without modulation of brain-derived neurotrophic factor expression or extracellular matrix structure. Our results suggest that food restriction could be investigated as a potential way of modulating plasticity

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

Longitudinal Bottom-Up Proteomics of Serum, Serum Extracellular Vesicles, and Cerebrospinal Fluid Reveals Candidate Biomarkers for Early Detection of Glioblastoma in a Murine Model

Glioblastoma Multiforme (GBM) is a brain tumor with a poor prognosis and low survival rates. GBM is diagnosed at an advanced stage, so little information is available on the early stage of the disease and few improvements have been made for earlier diagnosis. Longitudinal murine models are a promising platform for biomarker discovery as they allow access to the early stages of the disease. Nevertheless, their use in proteomics has been limited owing to the low sample amount that can be collected at each longitudinal time point. Here we used optimized microproteomics workflows to investigate longitudinal changes in the protein profile of serum, serum small extracellular vesicles (sEVs), and cerebrospinal fluid (CSF) in a GBM murine model. Baseline, pre-symptomatic, and symptomatic tumor stages were determined using non-invasive motor tests. Forty-four proteins displayed significant differences in signal intensities during GBM progression. Dysregulated proteins are involved in cell motility, cell growth, and angiogenesis. Most of the dysregulated proteins already exhibited a difference from baseline at the pre-symptomatic stage of the disease, suggesting that early effects of GBM might be detectable before symptom onset

A mouse model for creatine transporter deficiency reveals early onset cognitive impairment and neuropathology associated with brain aging.

Mutations in the creatine (Cr) transporter (CrT) gene lead to cerebral creatine deficiency syndrome-1 (CCDS1), an X-linked metabolic disorder characterized by cerebral Cr deficiency causing intellectual disability, seizures, movement and autistic-like behavioural disturbances, language and speech impairment. Since no data are available about the neural and molecular underpinnings of this disease, we performed a longitudinal analysis of behavioural and pathological alterations associated with CrT deficiency in a CCDS1 mouse model. We found precocious cognitive and autistic-like defects, mimicking the early key features of human CCDS1. Moreover, mutant mice displayed a progressive impairment of short and long-term declarative memory denoting an early brain aging. Pathological examination showed a prominent loss of GABAergic synapses, marked activation of microglia, reduction of hippocampal neurogenesis and the accumulation of autofluorescent lipofuscin. Our data suggest that brain Cr depletion causes both early intellectual disability and late progressive cognitive decline, and identify novel targets to design intervention strategies aimed at overcoming brain CCDS1 alterations