Laura Baroncelli

The antidepressant fluoxetine restores plasticity in the adult visual cortex.

We investigated whether fluoxetine, a widely prescribed medication for treatment of depression, restores neuronal plasticity in the adult visual system of the rat. We found that chronic administration of fluoxetine reinstates ocular dominance plasticity in adulthood and promotes the recovery of visual functions in adult amblyopic animals, as tested electrophysiologically and behaviorally. These effects were accompanied by reduced intracortical inhibition and increased expression of brain-derived neurotrophic factor in the visual cortex. Cortical administration of diazepam prevented the effects induced by fluoxetine, indicating that the reduction of intracortical inhibition promotes visual cortical plasticity in the adult. Our results suggest a potential clinical application for fluoxetine in amblyopia as well as new mechanisms for the therapeutic effects of antidepressants and for the pathophysiology of mood disorders.

Environmental enrichment in adulthood promotes amblyopia recovery through a reduction of intracortical inhibition

Loss of visual acuity caused by abnormal visual experience during development (amblyopia) is an untreatable pathology in adults. We report that environmental enrichment in adult amblyopic rats restored normal visual acuity and ocular dominance. These effects were due to reduced GABAergic inhibition in the visual cortex, accompanied by increased expression of BDNF and reduced density of extracellular-matrix perineuronal nets, and were prevented by enhancement of inhibition through benzodiazepine cortical infusion.

Massage Accelerates Brain Development and the Maturation of Visual Function

Environmental enrichment (EE) was shown recently to accelerate brain development in rodents. Increased levels of maternal care, and particularly tactile stimulation through licking and grooming, may represent a key component in the early phases of EE. We hypothesized that enriching the environment in terms of body massage may thus accelerate brain development in infants. We explored the effects of body massage in preterm infants and found that massage accelerates the maturation of electroencephalographic activity and of visual function, in particular visual acuity. In massaged infants, we found higher levels of blood IGF-1. Massage accelerated the maturation of visual function also in rat pups and increased the level of IGF-1 in the cortex. Antagonizing IGF-1 action by means of systemic injections of the IGF-1 antagonist JB1 blocked the effects of massage in rat pups. These results demonstrate that massage has an influence on brain development and in particular on visual development and suggest that its effects are mediated by specific endogenous factors such as IGF-1.

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.

Experience-dependent reactivation of ocular dominance plasticity in the adult visual cortex

A crucial issue in neurobiology is to understand the main mechanisms restricting neural plasticity to brief windows of early postnatal life. The visual system is one of the paradigmatic models for studying experience-dependent plasticity. The closure of one eye (monocular deprivation, MD) causes a marked ocular dominance (OD) shift of neurons in the primary visual cortex only during the critical period. Here, we report that environmental enrichment (EE), a condition of increased sensory-motor stimulation, reactivates OD plasticity in the adult visual cortex, as assessed with both visual evoked potentials and single-unit recordings. This effect is accompanied by a marked increase in cerebral serotonin (5-HT) levels. Blocking 5-HT enhancement in the visual cortex of EE rats completely prevents the OD shift induced by MD. We also found that EE leads to a reduced intracortical GABAergic inhibition and an increased BDNF expression and that the modulation of these molecular factors is neutralized by cortical infusion of the 5-HT synthesis inhibitor pCPA. Our results show that EE rejuvenates the adult visual cortex and that 5-HT is a crucial factor in this process, triggering a cascade of molecular events that allow the reinstatement of neural plasticity. The non-invasive nature of EE makes this paradigm particularly eligible for clinical application.

Insulin-Like Growth Factor 1 (IGF-1) Mediates the Effects of Enriched Environment (EE) on Visual Cortical Development

Enriched environment (EE) has been recently shown to affect visual cortex development and plasticity, and to prevent dark rearing effects. The factors mediating EE effects on visual cortical development and plasticity are still unclear. We have investigated whether IGF-1 is involved in mediating EE effects on the developing visual cortex. We show that EE increases the number of IGF-1 positive neurons in the visual cortex at P18. Increasing IGF-1 in the visual cortex of non-EE rats by means of osmotic minipumps implanted at P18 mimics EE effects, accelerating visual acuity development, assessed with Visual Evoked Potentials (VEPs). Blocking IGF-1 action in the visual cortex of EE rats by means of the IGF-1 receptor antagonist JB1 from P18 completely blocks EE action on visual acuity development. These results show that IGF-1 is a key factor mediating EE effects on visual cortical development. We then show that IGF-1 affects GAD65 immunoreactivity in perisomatic innervation and the condensation of Chondroitin Sulphate Proteoglycans (CSPGs) in perineuronal nets (PNNs) in the visual cortex. This suggests that IGF-1 action in mediating EE effects could be exerted through the modulation of intracortical inhibitory circuitry and PNN development.

Extracellular matrix inhibits structural and functional plasticity of dendritic spines in the adult visual cortex

Brain cells are immersed in a complex structure forming the extracellular matrix. The composition of the matrix gradually matures during postnatal development, as the brain circuitry reaches its adult form. The fully developed extracellular environment stabilizes neuronal connectivity and decreases cortical plasticity as highlighted by the demonstration that treatments degrading the matrix are able to restore synaptic plasticity in the adult brain. The mechanisms through which the matrix inhibits cortical plasticity are not fully clarified. Here we show that a prominent component of the matrix, chondroitin sulfate proteoglycans (CSPGs), restrains morphological changes of dendritic spines in the visual cortex of adult mice. By means of in vivo and in vitro two-photon imaging and electrophysiology, we find that after enzymatic digestion of CSPGs, cortical spines become more motile and express a larger degree of structural and functional plasticity.

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.

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.