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. Electrophysiological and behavioural analyses reveal a prosthesis-dependent recovery of light sensitivity and visual acuity that persists up to 6–10 months after surgery. The rescue of the visual function is accompanied by an increase in the basal metabolic activity of the primary visual cortex, as demonstrated by positron emission tomography imaging. Our results highlight the possibility of developing a new generation of fully organic, highly biocompatible and functionally autonomous photovoltaic prostheses for subretinal implants to treat degenerative blindness.

To test whether the saffron extract (Crocus sativus L.) given as a dietary supplement counteracts the effects of continuous light exposure in the albino rat retina. Three experimental groups of Sprague-Dawley rats were used. Experimental animals were prefed either saffron or beta-carotene (1 mg extract/kg/d) before they were exposed to bright continuous light (BCL) for 24 hours. Flash electroretinograms (fERGs) were recorded in control and treated rats the day before and 1 week after light exposure. At the end of the second recording session, the animals were killed and the retinas were quickly removed, fixed, cryosectioned, and labeled so that the thickness of the outer nuclear layer (ONL) could be analyzed. Changes in protein level and cellular localization of fibroblast growth factor (FGF)2 were determined by Western blot analysis and retinal immunohistochemistry, respectively. In a second series of experiments, rats were killed at the end of light exposure, and the amount of apoptotic figures in the ONL was assessed by terminal transferase-mediated deoxyuridine triphosphate (d-UTP)-biotin nick-end labeling (TUNEL). BCL induced DNA fragmentation, characteristic of dying cells, almost exclusively in the photoreceptor layer. The rate of photoreceptor death induced by BCL is expressed as the frequency of TUNEL-positive profiles per millimeter. The photoreceptor layer was largely preserved in saffron-treated animals because it was the fERG response. In addition, the rate of photoreceptor death induced by BCL appeared drastically reduced in treated animals. In beta-carotene prefeeding experiments, morphologic analysis showed preservation of the ONL similar to that obtained with saffron prefeeding, whereas the fERG response was unrecordable. Western blot analysis showed that exposure to light induced a strong upregulation of FGF2 in control and beta-carotene-treated rats, but s no change was noted in saffron-treated rats. These results show that saffron may protect photoreceptors from retinal stress, maintaining both morphology and function and probably acting as a regulator of programmed cell death.

The first target of any therapy for retinal neurodegeneration is to slow down the progression of the disease and to maintain visual function. Cerium oxide or ceria nanoparticles reduce oxidative stress, which is known to play a pivotal role in neurodegeneration. Our aim was to investigate whether cerium oxide nanoparticles were able to mitigate neurodegeneration including microglial activation and related inflammatory processes induced by exposure to high intensity light. Cerium oxide nanoparticles were injected intravitreally or intraveinously in albino Sprague-Dawley rats three weeks before exposing them to light damage of 1000 lux for 24 h. Electroretinographic recordings were performed a week after light damage. The progression of retinal degeneration was evaluated by measuring outer nuclear layer thickness and TUNEL staining to quantify photoreceptors death. Immunohistochemical analysis was used to evaluate retinal stress, neuroinflammatory cytokines and microglial activation. Only intravitreally injected ceria nanoparticles were detected at the level of photoreceptor outer segments 3 weeks after the light damage and electoretinographic recordings showed that ceria nanoparticles maintained visual response. Moreover, this treatment reduced neuronal death and “hot spot” extension preserving the outer nuclear layer morphology. It is noteworthy that in this work we demonstrated, for the first time, the ability of ceria nanoparticles to reduce microglial activation and their migration toward outer nuclear layer. All these evidences support ceria nanoparticles as a powerful therapeutic agent in retinal neurodegenerative processes.

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. Here we demonstrate that conjugated polymer nanoparticles can reinstate physiological signals at the cortical level and visually driven activities when microinjected in 10-months-old Royal College of Surgeons rats bearing fully light-insensitive retinas. The extent of visual restoration positively correlates with the nanoparticle density and hybrid contacts with second-order retinal neurons. The results establish the functional role of organic photovoltaic nanoparticles in restoring visual activities in fully degenerate retinas with intense inner retina rewiring, a stage of the disease in which patients are subjected to prosthetic interventions.

Developing neuronal systems intrinsically generate coordinated spontaneous activity that propagates by involving a large number of synchronously firing neurons. In vivo, waves of spikes transiently characterize the activity of developing brain circuits and are fundamental for activity-dependent circuit formation. In vitro, coordinated spontaneous spiking activity, or network bursts (NBs), interleaved within periods of asynchronous spikes emerge during the development of 2D and 3D neuronal cultures. Several studies have investigated this type of activity and its dynamics, but how a neuronal system generates these coordinated events remains unclear. Here, we investigate at a cellular level the generation of network bursts in spontaneously active neuronal cultures by exploiting high-resolution multielectrode array recordings and computational network modelling. Our analysis reveals that NBs are generated in specialized regions of the network (functional neuronal communities) that feature neuronal links with high cross-correlation peak values, sub-millisecond lags and that share very similar structural connectivity motifs providing recurrent interactions. We show that the particular properties of these local structures enable locally amplifying spontaneous asynchronous spikes and that this mechanism can lead to the initiation of NBs. Through the analysis of simulated and experimental data, we also show that AMPA currents drive the coordinated activity, while NMDA and GABA currents are only involved in shaping the dynamics of NBs. Overall, our results suggest that the presence of functional neuronal communities with recurrent local connections allows a neuronal system to generate spontaneous coordinated spiking activity events. As suggested by the rules used for implementing our computational model, such functional communities might naturally emerge during network development by following simple constraints on distance-based connectivity. Coordinated spontaneous spiking activity is fundamental for the normal formation of brain circuits during development. However, how ensembles of neurons generate these events remains unclear. To address this question, in the present study, we investigated the network properties that might be required to a neuronal system for the generation of these spontaneous waves of spikes. We performed our study on spontaneously active neuronal cell cultures using high-resolution electrical recordings and a computational network model developed to reproduce our experimental data both quantitatively and qualitatively. Through the analysis of both experimental and simulated data, we found that network bursts are initiated in regions of the network, or “functional communities”, characterized by particular local connectivity properties. We also found that these regions can amplify the background asynchronous spiking activity preceding a network burst and, in this way, can give rise to coordinated spiking events. As a whole, our results suggest the presence of functional communities of neurons in a developing neuronal system that might naturally emerge by following simple constraints on distance-based connectivity. These regions are most likely required for the generation of the spontaneous coordinated activity that can drive activity-dependent circuit formation.