Restoring vision in adult amblyopia by enhancing plasticity through deletion of the transcriptional repressor REST.

Visual cortical plasticity is high during early life, but gradually decreases with development. This is due to the Otx2-driven maturation of intracortical inhibition that parallels the condensation of extracellular matrix components into perineuronal nets mainly around parvalbumin-positive GABAergic neurons. Repressor Element 1 Silencing Transcription (REST) epigenetically controls the expression of a plethora of neuron-specific genes.

The p-ERG spatial acuity in the biomedical pig under physiological conditions.

Pigs are becoming an important pre-clinical animal species for translational ophthalmology, due to similarities with humans in anatomical and physiological patterns. Different models of eye disorders have been proposed, and they are good candidates to assess biocompatibility/functionality of retinal prostheses. Electroretinography is a common tool allowing to gain information on retinal function, with several types of electroretinogram (ERG) been implemented including full field (ff-ERG), multifocal (mf-ERG) and pattern (p-ERG).

Light-induced charge generation in polymeric nanoparticles restores vision in advanced-stage retinitis pigmentosa rats.

Retinal dystrophies such as Retinitis pigmentosa are among the most prevalent causes of inherited legal blindness, for which treatments are in demand. Retinal prostheses have been developed to stimulate the inner retinal network that, initially spared by degeneration, deteriorates in the late stages of the disease. We recently reported that conjugated polymer nanoparticles persistently rescue visual activities after a single subretinal injection in the Royal College of Surgeons rat model of Retinitis pigmentosa.

Multisensory Integration: Is Medial Prefrontal Cortex Signaling Relevant for the Treatment of Higher-Order Visual Dysfunctions?

In the mammalian brain, information processing in sensory modalities and global mechanisms of multisensory integration facilitate perception. Emerging experimental evidence suggests that the contribution of multisensory integration to sensory perception is far more complex than previously expected. Here we revise how associative areas such as the prefrontal cortex, which receive and integrate inputs from diverse sensory modalities, can affect information processing in unisensory systems processes of down-stream signaling.

Biocompatibility of a Conjugated Polymer Retinal Prosthesis in the Domestic Pig.

The progressive degeneration of retinal photoreceptors is one of the most significant causes of blindness in humans. Conjugated polymers represent an attractive solution to the field of retinal prostheses, and a multi-layer fully organic prosthesis implanted subretinally in dystrophic Royal College of Surgeons (RCS) rats was able to rescue visual functions. As a step toward human translation, we report here the fabrication and testing of a similar device engineered to adapt to the human-like size of the eye of the domestic pig, an excellent animal paradigm to test therapeutic strategies for photoreceptors degeneration.

Subretinally injected semiconducting polymer nanoparticles rescue vision in a rat model of retinal dystrophy.

Inherited retinal dystrophies and late-stage age-related macular degeneration, for which treatments remain limited, are among the most prevalent causes of legal blindness. Retinal prostheses have been developed to stimulate the inner retinal network; however, lack of sensitivity and resolution, and the need for wiring or external cameras, have limited their application. Here we show that conjugated polymer nanoparticles (P3HT NPs) mediate light-evoked stimulation of retinal neurons and persistently rescue visual functions when subretinally injected in a rat model of retinitis pigmentosa.

The porcine iodoacetic acid model of retinal degeneration: Morpho-functional characterization of the visual system.

Porcine models of ophthalmological diseases are often used in pre-clinical translational studies due to pigs' similarities to humans. In particular, the iodoacetic acid (IAA) model of photoreceptor degeneration seems to mimic well the endstage phenotype of human pathologies as retinitis pigmentosa and age-related macular degeneration, with high potential for prosthesis/retinal devices testing. IAA is capable of inducing photoreceptor death by blockage of glycolysis, and its effects on the retina have been described.

Neuronal firing modulation by a membrane-targeted photoswitch.

Optical technologies allowing modulation of neuronal activity at high spatio-temporal resolution are becoming paramount in neuroscience. In this respect, azobenzene-based photoswitches are promising nanoscale tools for neuronal photostimulation. Here we engineered a light-sensitive azobenzene compound (Ziapin2) that stably partitions into the plasma membrane and causes its thinning through trans-dimerization in the dark, resulting in an increased membrane capacitance at steady state.

The function of connectomes in encoding sensory stimuli.

The enormous number of neurons and the massive sum of connecting fibers linking them make the neural processes of encoding sensory signals extraordinarily complex, and this challenge is far from being elucidated. Simply stated, for the present paper, the question is - how does the brain encode complex images? Our proposal argues that modulation of strengths of functional relationships between firing neurons in relation to an input results in the formation of stimulus-salient functional connectomes. This type of connection/coupling strength is computed by performing cross correlograms (CCG) of spike trains between simultaneously firing cells.

Behavioral Assessment of Vision in Pigs.

Swine (Sus scrofa) are often the 'gold standard' laboratory animal for ophthalmology research due to the anatomic and physiologic similarities between the porcine and human eye and retina. Despite the importance of this model, few tools for behavioral vision assessment in pigs are available. The aim of this study was to identify and validate a feasible and reproducible behavioral test to assess vision in a pig model of photoreceptor degeneration.

Interfacing Graphene-Based Materials With Neural Cells.

The scientific community has witnessed an exponential increase in the applications of graphene and graphene-based materials in a wide range of fields, from engineering to electronics to biotechnologies and biomedical applications. For what concerns neuroscience, the interest raised by these materials is two-fold. On one side, nanosheets made of graphene or graphene derivatives (graphene oxide, or its reduced form) can be used as carriers for drug delivery.

Optogenetic Modulation of Intracellular Signalling and Transcription: Focus on Neuronal Plasticity.

Several fields in neuroscience have been revolutionized by the advent of optogenetics, a technique that offers the possibility to modulate neuronal physiology in response to light stimulation. This innovative and far-reaching tool provided unprecedented spatial and temporal resolution to explore the activity of neural circuits underlying cognition and behaviour. With an exponential growth in the discovery and synthesis of new photosensitive actuators capable of modulating neuronal networks function, other fields in biology are experiencing a similar re-evolution.

A fully organic retinal prosthesis restores vision in a rat model of degenerative blindness.

The degeneration of photoreceptors in the retina is one of the major causes of adult blindness in humans. Unfortunately, no effective clinical treatments exist for the majority of retinal degenerative disorders. Here we report on the fabrication and functional validation of a fully organic prosthesis for long-term in vivo subretinal implantation in the eye of Royal College of Surgeons rats, a widely recognized model of retinitis pigmentosa.

Characterization of a Polymer-Based, Fully Organic Prosthesis for Implantation into the Subretinal Space of the Rat.

Replacement strategies arise as promising approaches in case of inherited retinal dystrophies leading to blindness. A fully organic retinal prosthesis made of conjugated polymers layered onto a silk fibroin substrate is engineered. First, the biophysical and surface properties are characterized; then, the long-term biocompatibility is assessed after implantation of the organic device in the subretinal space of 3-months-old rats for a period of five months.

Amyloid plaque-independent deficit of early postnatal visual cortical plasticity in the 5XFAD transgenic model of Alzheimer's disease.

Autosomal dominant forms of familial Alzheimer's disease are linked to an aberrant processing of the amyloid-β protein precursor, which results in an increased production of amyloid-β (Aβ) peptides that first form oligomers and eventually aggregate in the form of extracellular amyloid plaques in the brain. The accumulation of Aβ peptides oligomers seems to correlate with alterations of synaptic transmission in experimental models of Alzheimer's disease. Whether Aβ aggregation disrupts synaptic function independently of amyloid plaques deposition still needs further research.

Activity-dependent NPAS4 expression and the regulation of gene programs underlying plasticity in the central nervous system.

The capability of the brain to change functionally in response to sensory experience is most active during early stages of development but it decreases later in life when major alterations of neuronal network structures no longer take place in response to experience. This view has been recently challenged by experimental strategies based on the enhancement of environmental stimulation levels, genetic manipulations, and pharmacological treatments, which all have demonstrated that the adult brain retains a degree of plasticity that allows for a rewiring of neuronal circuitries over the entire life course. A hot spot in the field of neuronal plasticity centres on gene programs that underlie plastic phenomena in adulthood.

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.

Molecular mechanisms at the basis of plasticity in the developing visual cortex: epigenetic processes and gene programs.

Neuronal circuitries in the mammalian visual system change as a function of experience. Sensory experience modifies neuronal networks connectivity via the activation of different physiological processes such as excitatory/inhibitory synaptic transmission, neurotrophins, and signaling of extracellular matrix molecules. Long-lasting phenomena of plasticity occur when intracellular signal transduction pathways promote epigenetic alterations of chromatin structure that regulate the induction of transcription factors that in turn drive the expression of downstream targets, the products of which then work via the activation of structural and functional mechanisms that modify synaptic connectivity.

Visual cortex plasticity: a complex interplay of genetic and environmental influences.

The central nervous system architecture is highly dynamic and continuously modified by sensory experience through processes of neuronal plasticity. Plasticity is achieved by a complex interplay of environmental influences and physiological mechanisms that ultimately activate intracellular signal transduction pathways regulating gene expression. In addition to the remarkable variety of transcription factors and their combinatorial interaction at specific gene promoters, epigenetic mechanisms that regulate transcription have emerged as conserved processes by which the nervous system accomplishes the induction of 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.

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.

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.

Serotonin triggers a transient epigenetic mechanism that reinstates adult visual cortex plasticity in rats.

Cortical circuitries are highly sensitive to experience during early life but this phase of heightened plasticity decreases with development. We recently demonstrated that fluoxetine reinstates a juvenile-like form of plasticity in the adult visual system. Here we explored cellular and molecular mechanisms that underlie the occurrence of these plastic phenomena.