Publications by authors named "Stefano Di Marco"

37 Publications

Activity of Novel Copper(II)-Based Formulations to Inhibit the Esca-Associated Fungus in Grapevine Propagation Material.

Front Plant Sci 2021 15;12:649694. Epub 2021 Mar 15.

Université de Reims Champagne-Ardenne, Unité Résistance Induite et Bioprotection des Plantes, SFR Condorcet FR CNRS 3417, Reims, France.

Grapevine trunk diseases (GTDs) are a serious and growing threat to vineyards worldwide. The need for innovative control tools persists since pesticides used against some GTDs have been banned and only methods to prevent infections or to reduce foliar symptoms have been developed so far. In this context, the application of imaging methods, already applied to study plant-microbe interactions, represents an interesting approach to understand the effect of experimental treatments applied to reduce fungal colonization, on GTD-related pathogens activity. To this aim, trials were carried out to evaluate the efficacy of copper-based treatments, formulated with hydroxyapatite (HA) as co-adjuvant with innovative delivery properties, loaded with two different copper(II) compounds (tribasic sulfate and sulfate pentahydrate), and applied to grapevine propagation material to inhibit fungal wood colonization. The treated rootstock ( × cv. K5BB) and scion cuttings ( L., cv. Chardonnay) had been inoculated with a strain of () compared to uninoculated rootstocks. Experimental treatments were applied during the water-soaking process, comparing the copper(II) compounds pure or formulated with HA, to hydrate the cuttings. After callusing, grafted vines were grown under greenhouse conditions in a nursery and inoculated with :: or with wild-type. Fifteen weeks post-inoculation, woody tissues close to the inoculation site were sampled to evaluate the efficiency of the treatments by studying the plant-microbe interaction by confocal laser scanning microscopy (CLSM). Copper and further elements were also quantified in the same tissues immediately after the treatments and on the CLSM samples. Finally, the grapevine defense responses were studied in the leaves of cuttings treated with the same formulations. The present investigation confirmed the relevant interaction of and the related transformed strain on the vascular tissues of grafted vines. Furthermore, assay revealed (i) the fungistatic effect of HA and the reduced effect of Cu fungicide when combined with HA. assays showed (ii) the reduction of infection in propagation material treated with HA-Cu formulations, (iii) the movement of HA-Cu formulations inside the plant tissues and their persistence over time, and (iv) the plant defense reaction following the treatment with pure HA or Cu, or combined.
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http://dx.doi.org/10.3389/fpls.2021.649694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005723PMC
March 2021

Retinal Neurodegeneration: Correlation between Nutraceutical Treatment and Animal Model.

Nutrients 2021 Feb 27;13(3). Epub 2021 Feb 27.

Interuniversity Consortium -Biostructures and Biosystems National Institute (INBB), Via Medaglie d'Oro 305, 00136 Roma, Italy.

Retinal diseases can be induced by a variety of factors, including gene mutations, environmental stresses and dysmetabolic processes. The result is a progressive deterioration of visual function, which sometimes leads to blindness. Many treatments are under investigation, though results are still mostly unsatisfactory and restricted to specific pathologies, particularly in the case of gene therapy. The majority of treatments have been tested in animal models, but very few have progressed to human clinical trials. A relevant approach is to study the relation between the type of treatments and the degenerative characteristics of the animal model to better understand the effectiveness of each therapy. Here we compare the results obtained from different animal models treated with natural compounds (saffron and naringenin) to anticipate the potentiality of a single treatment in different pathologies.
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http://dx.doi.org/10.3390/nu13030770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997156PMC
February 2021

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

Front Bioeng Biotechnol 2020 15;8:579141. Epub 2020 Oct 15.

Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Genova, Italy.

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. The active conjugated polymers were layered onto two distinct passive substrates, namely electro-spun silk fibroin (ESF) and polyethylene terephthalate (PET). Naive pigs were implanted subretinally with the active device in one eye, while the contralateral eye was sham implanted with substrate only. Retinal morphology and functionality were assessed before and after surgery by means of optical coherence tomography and full-field electroretinogram (ff-ERG) analysis. After the sacrifice, the retina morphology and inflammatory markers were analyzed by immunohistochemistry of the excised retinas. Surprisingly, ESF-based prostheses caused a proliferative vitreoretinopathy with disappearance of the ff-ERG b-wave in the implanted eyes. In contrast, PET-based active devices did not evoke significant inflammatory responses. As expected, the subretinal implantation of both PET only and the PET-based prosthesis locally decreased the thickness of the outer nuclear layer due to local photoreceptor loss. However, while the implantation of the PET only substrate decreased the ff-ERG b-wave amplitude with respect to the pre-implant ERG, the eyes implanted with the active device fully preserved the ERG responses, indicating an active compensation of the surgery-induced photoreceptor loss. Our findings highlight the possibility of developing a new generation of conjugated polymer/PET-based prosthetic devices that are highly biocompatible and potentially suitable for subretinal implantation in patients suffering from degenerative blindness.
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http://dx.doi.org/10.3389/fbioe.2020.579141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605258PMC
October 2020

Modulation of neuronal firing: what role can nanotechnology play?

Nanomedicine (Lond) 2020 12 16;15(30):2895-2900. Epub 2020 Nov 16.

Center for Synaptic Neuroscience & Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132 Genova, Italy.

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http://dx.doi.org/10.2217/nnm-2020-0398DOI Listing
December 2020

Modeling a population of retinal ganglion cells with restricted Boltzmann machines.

Sci Rep 2020 10 6;10(1):16549. Epub 2020 Oct 6.

Istituto Italiano di Tecnologia, Genoa, Italy.

The retina is a complex circuit of the central nervous system whose aim is to encode visual stimuli prior the higher order processing performed in the visual cortex. Due to the importance of its role, modeling the retina to advance in interpreting its spiking activity output is a well studied problem. In particular, it has been shown that latent variable models can be used to model the joint distribution of Retinal Ganglion Cells (RGCs). In this work, we validate the applicability of Restricted Boltzmann Machines to model the spiking activity responses of a large a population of RGCs recorded with high-resolution electrode arrays. In particular, we show that latent variables can encode modes in the RGC activity distribution that are closely related to the visual stimuli. In contrast to previous work, we further validate our findings by comparing results associated with recordings from retinas under normal and altered encoding conditions obtained by pharmacological manipulation. In these conditions, we observe that the model reflects well-known physiological behaviors of the retina. Finally, we show that we can also discover temporal patterns, associated with distinct dynamics of the stimuli.
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http://dx.doi.org/10.1038/s41598-020-73691-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538558PMC
October 2020

Saffron Crudes and Compounds Restrict MACC1-Dependent Cell Proliferation and Migration of Colorectal Cancer Cells.

Cells 2020 08 3;9(8). Epub 2020 Aug 3.

Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin, and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany.

The high mortality rate of colorectal cancer (CRC) patients is directly associated with metastatic dissemination. However, therapeutic options specifically for metastasis are still limited. We previously identified Metastasis-Associated in Colon Cancer 1 (MACC1) as a major causal metastasis-inducing gene. Numerous studies confirmed its value as a biomarker for metastasis risk. We investigated the inhibitory impact of saffron on MACC1-induced cancer cell growth and motility. Saffron crudes restricted the proliferation and migration of MACC1-expressing CRC cells in a concentration- and MACC1-dependent manner. Saffron delays cell cycle progression at G2/M-phase and does not induce apoptosis. Rescue experiments showed that these effects are reversible. Analysis of active saffron compounds elucidated that crocin was the main compound that reproduced total saffron crudes effects. We showed the interaction of MACC1 with the cancer stem cell (CSC) marker DCLK1, which contributes to metastasis formation in different tumor entities. Saffron extracts reduced DCLK1 with crocin being responsible for this reduction. Saffron's anti-proliferative and anti-migratory effects in MACC1-expressing cells are mediated by crocin through DCLK1 down-regulation. This research is the first identification of saffron-based compounds restricting cancer cell proliferation and motility progression via the novel target MACC1.
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http://dx.doi.org/10.3390/cells9081829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463853PMC
August 2020

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

Nat Nanotechnol 2020 08 29;15(8):698-708. Epub 2020 Jun 29.

Centre for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Genoa, Italy.

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. P3HT NPs spread out over the entire subretinal space and promote light-dependent activation of spared inner retinal neurons, recovering subcortical, cortical and behavioural visual responses in the absence of trophic effects or retinal inflammation. By conferring sustained light sensitivity to degenerate retinas after a single injection, and with the potential for high spatial resolution, P3HT NPs provide a new avenue in retinal prosthetics with potential applications not only in retinitis pigmentosa, but also in age-related macular degeneration.
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http://dx.doi.org/10.1038/s41565-020-0696-3DOI Listing
August 2020

Effects of Cord Blood Serum (CBS) on viability of retinal Müller glial cells under in vitro injury.

PLoS One 2020 4;15(6):e0234145. Epub 2020 Jun 4.

Ophthalmology Unit, DIMES, Alma Mater Studiorum University of Bologna, S.Orsola-Malpighi Teaching Hospital, Bologna, Italy.

Oxidative stress and inflammation determine retinal ganglion cell degeneration, leading to retinal impairment and vision loss. Müller glial cells regulate retinal repair under injury, through gliosis. Meanwhile, reactive gliosis can turn in pathological effects, contributing to neurodegeneration. In the present study, we tested whether Cord Blood Serum (CBS), rich of growth factors, might improve the viability of Müller cells under in vitro damage. BDNF, NGF, TGF-α, GDNF and EGF levels were measured in CBS samples by Human Magnetic Luminex Assay. CBS effects were evaluated on rat (rMC-1) and human (MIO-M1) Müller cells, under H2O2 and IL-1β damage. Cells grown with FBS or CBS both at 5% were exposed to stress and analyzed in terms of cell viability, GFAP, IL-6 and TNF-α expression. CBS was also administrated after treatment with K252a, inhibitor of the neurotrophin receptor Trk. Cell viability of rMC-1 and MIO-M1 resulted significantly improved when pretreated with CBS and exposed to H2O2 and IL-1β, in comparison to the standard culture with FBS. Accordingly, the gliosis marker GFAP resulted down-regulated following CBS priming. In parallel, we observed a lower expression of the inflammatory mediators in rMC-1 (TNF-α) and MIO-M1 (IL-6, TNF- α), especially in presence of inflammatory damage. Trk inhibition through K252a administration impaired the effects of CBS under stress conditions on MIO-M1 and rMC-1 viability, not significantly different from FBS condition. CBS is enriched with neurotrophins and its administration to rMC-1 and MIO-M1 attenuates the cytotoxic effects of H2O2 and IL-1β. Moreover, the decrease of the main markers of gliosis and inflammation suggests a promising use of CBS for neuroprotection aims. This study is a preliminary basis that prompts future investigations to deeply explore and confirm the CBS potential.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234145PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272066PMC
August 2020

Cord Blood Serum (CBS)-Based Eye Drops Modulate Light-Induced Neurodegeneration in Albino Rat Retinas.

Biomolecules 2020 04 28;10(5). Epub 2020 Apr 28.

Ophthalmology Unit, University of Bologna and S. Orsola-Malpighi Teaching Hospital, 40138 Bologna, Italy.

Age-related macular degeneration (AMD) is one of the leading causes of visual loss in western countries, it has no cure, and its incidence will grow in the future, for the overall population aging. Albino rats with retinal degeneration induced by exposure to high-intensity light (light-damage, LD) have been extensively used as a model of AMD to test neuroprotective agents. Among them, trophic factors (NGF and BDNF) have been shown to play a significant role in photoreceptors' survival. Interestingly, cord blood serum (CBS) is an extract full of chemokines and trophic factors; we, therefore, hypothesized that CBS could be an excellent candidate for neuroprotection. Here, we investigate whether CBS-based eye drops might mitigate the effects of light-induced retinal degeneration in albino rats. CBS treatment significantly preserved flash-electroretinogram (f-ERG) response after LD and reduced the "hot-spot" extension. Besides, CBS-treated animals better preserved the morphology of the outer nuclear layer, together with a reduction in microglia migration and activation. Interestingly, the treatment did not modulate reactive gliosis and activation of the self-protective mechanism (FGF2). In conclusion, our results suggest that CBS-based eye drops might be successfully used to mitigate retinal neurodegenerative processes such as AMD.
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http://dx.doi.org/10.3390/biom10050678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277721PMC
April 2020

Antioxidant Saffron and Central Retinal Function in ABCA4-Related Stargardt Macular Dystrophy.

Nutrients 2019 Oct 15;11(10). Epub 2019 Oct 15.

Dipartimento di Scienze dell'Invecchiamento, Neurologiche, Ortopediche e della Testa-Collo, Fondazione Policlinico Universitario A. Gemelli- IRCCS, 00168 Rome, Italy.

Retinal oxidative damage, associated with an ATP-binding cassette, sub-family A, member 4, also known as ABCA4 gene mutation, has been implicated as a major underlying mechanism for Stargardt disease/fundus flavimaculatus (STG/FF). Recent findings indicate that saffron carotenoid constituents crocins and crocetin may counteract retinal oxidative damage, inflammation and protect retinal cells from apoptosis. This pilot study aimed to evaluate central retinal function following saffron supplementation in STG/FF patients carrying ABCA4 mutations.

Methods: in a randomized, double-blind, placebo-controlled study (clinicaltrials.gov: NCT01278277), 31 patients with ABCA4-related STG/FF and a visual acuity >0.25 were randomly assigned to assume oral saffron (20 mg) or placebo over a six month period and then reverted to P or S for a further six month period. Full ophthalmic examinations, as well as central 18° focal electroretinogram (fERG) recordings, were performed at baseline and after six months of either saffron or placebo. The fERG fundamental harmonic component was isolated by Fourier analysis. Main outcome measures were fERG amplitude (in µV) and phase (in degrees). The secondary outcome measure was visual acuity.

Results: supplement was well tolerated by all patients throughout follow-up. After saffron, fERG amplitude was unchanged; after placebo, amplitude tended to decrease from baseline (mean change: -0.18 log µV, < 0.05). Reverting the treatments, amplitude did not change significantly. fERG phase and visual acuity were unchanged throughout follow-up.

Conclusions: short-term saffron supplementation was well tolerated and had no detrimental effects on the electroretinographic responses of the central retina and visual acuity. The current findings warrant further long-term clinical trials to assess the efficacy of saffron supplementation in slowing down the progression of central retinal dysfunction in ABCA4-related STG/FF.
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http://dx.doi.org/10.3390/nu11102461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6835540PMC
October 2019

Saffron: A Multitask Neuroprotective Agent for Retinal Degenerative Diseases.

Antioxidants (Basel) 2019 Jul 17;8(7). Epub 2019 Jul 17.

Facolta' di Medicina e Chirurgia, Fondazione Policlinico A. Gemelli, Universita' Cattolica del S. Cuore, 00136 Roma, Italy.

Both age related macular degeneration (AMD) and light induced retinal damage share the common major role played by oxidative stress in the induction/progression of degenerative events. Light damaged (LD) rats have been widely used as a convenient model to gain insight into the mechanisms of degenerative disease, to enucleate relevant steps and to test neuroprotectants. Among them, saffron has been shown to ameliorate degenerative processes and to regulate many genes and protective pathways. Saffron has been also tested in AMD patients. We extended our analysis to a possible additional effect regulated by saffron and compared in AMD patients a pure antioxidant treatment (Lutein/zeaxanthin) with saffron treatment. Animal model. Sprague-Dawley (SD) adult rats, raised at 5 lux, were exposed to 1000 lux for 24 h and then either immediately sacrificed or placed back at 5 lux for 7 days recovery period. A group of animals was treated with saffron. We performed in the animal model: (1) SDS-PAGE analysis; (2) Western Blotting (3) Enzyme activity assay (4) Immunolabelling; in AMD patients: a longitudinal open-label study 29 (±5) months in two groups of patients: lutein/zeaxanthin (19) and saffron (23) treated. Visual function was tested every 8 months by ERG recordings in addition to clinical examination. Enzymatic activity of MMP-3 is reduced in LD saffron treated retinas and is comparable to control as it is MMP-3 expression. LD treated retinas do not present "rosettes" and microglia activation and migration is highly reduced. Visual function remains stable in saffron treated AMD patients while deteriorates in the lutein/zeaxanthin group. Our results provide evidence of an additional way of action of saffron treatment confirming the complex nature of neuroprotective activities of its chemical components. Accordingly, long term follow-up in AMD patients reveals an added value of saffron supplementation treatment compared to classical antioxidant protocol.
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http://dx.doi.org/10.3390/antiox8070224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681062PMC
July 2019

Innovative Delivery of Cu(II) Ions by a Nanostructured Hydroxyapatite: Potential Application in Planta to Enhance the Sustainable Control of .

Phytopathology 2019 May 11;109(5):748-759. Epub 2019 Apr 11.

1 Dipartimento di Scienze e Tecnologie Agrarie, Alimentari, Ambientali e Forestali, Sezione Patologia Vegetale ed Entomologia, Università degli Studi di Firenze, Firenze I-50144, Italy.

Downy mildew caused by is probably the most serious disease affecting grapevine (), and it is capable of causing consistent yield losses. In organic viticulture, the only acceptable and effective means to control the disease is by applications of copper-based fungicides. However, the use of copper in agriculture is expected to be further restricted by European countries because of its critical ecotoxicological and phytotoxicological profile. Research on ways to reduce the effective amounts of copper by developing innovative formulations as well as optimization of the distribution and persistence of copper-based pesticides for downy mildew control seems to be a promising approach. This research investigated the delivery properties of biomimetic synthetic hydroxyapatite (HA) to enhance the biological activity of Cu(II) ions. To this aim, four Cu(II) compounds were formulated with the innovative HA component and applied in an in vitro antifungal assay against , a common grapevine pathogen suitable for in vitro activity tests, and finally, in in planta efficacy assays against under greenhouse conditions. The in vitro results highlighted a different inhibition activity for each Cu(II) compound and indicated a different interaction between the cupric compounds and HA, potentially related to different delivery mechanisms of Cu(II) from HA. Under greenhouse conditions, additional findings on the biological activity of the applied formulations were gained, especially on the efficacy of various concentrations of HA in the formulations, the influence of dose variation of the formulation and the treatment efficiency, and the persistence under rain-washing effect. This study revealed promising findings on the formulation based on the HA particles and the soluble Cu(II) compound, which resulted in reduced disease severity and incidence in all of the experimental conditions, including the lower Cu(II) dosage and the rain-washing effect. This suggests that coformulation of the three insoluble Cu(II) compounds with HA might significantly enhance the adsorption and release of Cu(II) ions by HA particles.
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http://dx.doi.org/10.1094/PHYTO-02-18-0033-RDOI Listing
May 2019

Topical Treatment with Cord Blood Serum in Glaucoma Patients: A Preliminary Report.

Case Rep Ophthalmol Med 2018 25;2018:2381296. Epub 2018 Jul 25.

Emilia Romagna Cord Blood Bank-Transfusion Service, S.Orsola-Malpighi Teaching Hospital, Bologna, Italy.

Purpose: To report data which happened to be observed in two glaucoma patients treated with Cord Blood Serum (CBS) eye drops.

Design: A case report and retrospective data analysis.

Methods: CBS topical eye drops, characterized in advance for growth factors (GFs) content, were administered for two months with the aim to relieve their subjective symptoms, in two patients who had referred ocular surface discomfort, although in absence of any sign of keratopathy. As patients were also affected by advanced glaucoma at risk of vision loss and under treatment with hypotensive drugs, they had been also monitored over the same period with IOP controls and visual field tests in our unit.

Results: During subsequent visits, data from Mean Deviation and Pattern Standard Deviation in the visual fields were retrospectively collected and compared with before and after treatment with CBS, and an amelioration was observed.

Conclusions: CBS contains a combination of GFs, which potentially exert a neuroprotective action and elect CBS as an interesting natural source to be delivered in neurodegenerative ocular disorders. The incidentally observed amelioration in these two patients deserves further investigation in this respect.
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http://dx.doi.org/10.1155/2018/2381296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6083596PMC
July 2018

State-dependent representation of stimulus-evoked activity in high-density recordings of neural cultures.

Sci Rep 2018 04 3;8(1):5578. Epub 2018 Apr 3.

Neural Computation Laboratory, Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia, Rovereto, Italy.

Neuronal responses to external stimuli vary from trial to trial partly because they depend on continuous spontaneous variations of the state of neural circuits, reflected in variations of ongoing activity prior to stimulus presentation. Understanding how post-stimulus responses relate to the pre-stimulus spontaneous activity is thus important to understand how state dependence affects information processing and neural coding, and how state variations can be discounted to better decode single-trial neural responses. Here we exploited high-resolution CMOS electrode arrays to record simultaneously from thousands of electrodes in in-vitro cultures stimulated at specific sites. We used information-theoretic analyses to study how ongoing activity affects the information that neuronal responses carry about the location of the stimuli. We found that responses exhibited state dependence on the time between the last spontaneous burst and the stimulus presentation and that the dependence could be described with a linear model. Importantly, we found that a small number of selected neurons carry most of the stimulus information and contribute to the state-dependent information gain. This suggests that a major value of large-scale recording is that it individuates the small subset of neurons that carry most information and that benefit the most from knowledge of its state dependence.
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http://dx.doi.org/10.1038/s41598-018-23853-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882875PMC
April 2018

Functionalization of a nanostructured hydroxyapatite with Cu(II) compounds as a pesticide: in situ transmission electron microscopy and environmental scanning electron microscopy observations of treated Vitis vinifera L. leaves.

Pest Manag Sci 2018 Aug 11;74(8):1903-1915. Epub 2018 Apr 11.

Dipartimento di Scienze delle Produzioni Agroalimentari e dell'Ambiente - Sezione Patologia Vegetale ed Entomologia, Università degli Studi di Firenze, Firenze, Italy.

Background: The present study evaluated a biocompatible material for plant protection with the aim of reducing the amount of active substance applied. We used a synthetic hydroxyapatite (HA) that has been studied extensively as a consequence of its bioactivity and biocompatibility. An aggregation between HA nanoparticles and four Cu(II) compounds applied to Vitis vinifera L. leaves as a pesticide was studied. Formulations were characterized by X-ray diffraction (XRD), dynamic light scattering (DLS) and electron microscopy and applied in planta to verify particle aggregation and efficiency in controlling the pathogen Plasmopara viticola.

Results: The XRD patterns showed different crystalline phases dependig on the Cu(II) compound formulated with HA particles, DLS showed that nanostructured particles are stable as aggregates out of the nanometer range and, in all formulations, transmission electron microscopy (TEM) and environmental scanning electron microscopy (ESEM) microscopy showed large aggregates which were partially nanostructured and were recognized as stable in their micrometric dimensions. Such particles did not show phytotoxic effects after their application in planta.

Conclusion: A formulation based on HA and a soluble Cu(II) compound showed promising results in the control of the fungal pathogen, confirming the potential role of HA as an innovative delivery system of Cu(II) ions. The present work indicates the possibility of improving the biological activity of a bioactive substance by modifying its structure through an achievable formulation with a biocompatible material. © 2018 Society of Chemical Industry.
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http://dx.doi.org/10.1002/ps.4892DOI Listing
August 2018

Recurrently connected and localized neuronal communities initiate coordinated spontaneous activity in neuronal networks.

PLoS Comput Biol 2017 Jul 27;13(7):e1005672. Epub 2017 Jul 27.

Neuroscience and Brain Technologies Dept., Fondazione Istituto Italiano di Tecnologia, Genoa, Italy.

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.
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http://dx.doi.org/10.1371/journal.pcbi.1005672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549760PMC
July 2017

RECQ5 Helicase Cooperates with MUS81 Endonuclease in Processing Stalled Replication Forks at Common Fragile Sites during Mitosis.

Mol Cell 2017 Jun;66(5):658-671.e8

Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland. Electronic address:

The MUS81-EME1 endonuclease cleaves late replication intermediates at common fragile sites (CFSs) during early mitosis to trigger DNA-repair synthesis that ensures faithful chromosome segregation. Here, we show that these DNA transactions are promoted by RECQ5 DNA helicase in a manner dependent on its Ser727 phosphorylation by CDK1. Upon replication stress, RECQ5 associates with CFSs in early mitosis through its physical interaction with MUS81 and promotes MUS81-dependent mitotic DNA synthesis. RECQ5 depletion or mutational inactivation of its ATP-binding site, RAD51-interacting domain, or phosphorylation site causes excessive binding of RAD51 to CFS loci and impairs CFS expression. This leads to defective chromosome segregation and accumulation of CFS-associated DNA damage in G1 cells. Biochemically, RECQ5 alleviates the inhibitory effect of RAD51 on 3'-flap DNA cleavage by MUS81-EME1 through its RAD51 filament disruption activity. These data suggest that RECQ5 removes RAD51 filaments stabilizing stalled replication forks at CFSs and hence facilitates CFS cleavage by MUS81-EME1.
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http://dx.doi.org/10.1016/j.molcel.2017.05.006DOI Listing
June 2017

A promoter-proximal transcript targeted by genetic polymorphism controls E-cadherin silencing in human cancers.

Nat Commun 2017 05 30;8:15622. Epub 2017 May 30.

Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research (IOR), and Oncology Institute of Southern Switzerland (IOSI), Bellinzona 6500, Switzerland.

Long noncoding RNAs are emerging players in the epigenetic machinery with key roles in development and diseases. Here we uncover a complex network comprising a promoter-associated noncoding RNA (paRNA), microRNA and epigenetic regulators that controls transcription of the tumour suppressor E-cadherin in epithelial cancers. E-cadherin silencing relies on the formation of a complex between the paRNA and microRNA-guided Argonaute 1 that, together, recruit SUV39H1 and induce repressive chromatin modifications in the gene promoter. A single nucleotide polymorphism (rs16260) linked to increased cancer risk alters the secondary structure of the paRNA, with the risk allele facilitating the assembly of the microRNA-guided Argonaute 1 complex and gene silencing. Collectively, these data demonstrate the role of a paRNA in E-cadherin regulation and the impact of a noncoding genetic variant on its function. Deregulation of paRNA-based epigenetic networks may contribute to cancer and other diseases making them promising targets for drug discovery.
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http://dx.doi.org/10.1038/ncomms15622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5459991PMC
May 2017

Fluorescent light induces neurodegeneration in the rodent nigrostriatal system but near infrared LED light does not.

Brain Res 2017 05 2;1662:87-101. Epub 2017 Mar 2.

Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, 67100 L'Aquila, Italy.

We investigated the effects of continuous artificial light exposure on the mouse substantia nigra (SN). A three month exposure of C57Bl/6J mice to white fluorescent light induced a 30% reduction in dopamine (DA) neurons in SN compared to controls, accompanied by a decrease of DA and its metabolites in the striatum. After six months of exposure, neurodegeneration progressed slightly, but the level of DA returned to the basal level, while the metabolites increased with respect to the control. Three month exposure to near infrared LED light (∼710nm) did not alter DA neurons in SN, nor did it decrease DA and its metabolites in the striatum. Furthermore mesencephalic cell viability, as tested by [H]DA uptake, did not change. Finally, we observed that 710nm LED light, locally conveyed in the rat SN, could modulate the firing activity of extracellular-recorded DA neurons. These data suggest that light can be detrimental or beneficial to DA neurons in SN, depending on the source and wavelength.
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http://dx.doi.org/10.1016/j.brainres.2017.02.026DOI Listing
May 2017

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

Nat Mater 2017 06 6;16(6):681-689. Epub 2017 Mar 6.

Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Genoa, Italy.

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.
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http://dx.doi.org/10.1038/nmat4874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446789PMC
June 2017

Modulation of Type-1 and Type-2 Cannabinoid Receptors by Saffron in a Rat Model of Retinal Neurodegeneration.

PLoS One 2016 18;11(11):e0166827. Epub 2016 Nov 18.

Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy.

Experimental studies demonstrated that saffron (Crocus sativus) given as a dietary supplement counteracts the effects of bright continuous light (BCL) exposure in the albino rat retina, preserving both morphology and function and probably acting as a regulator of programmed cell death [1]. The purpose of this study was to ascertain whether the neuroprotective effect of saffron on rat retina exposed to BCL is associated with a modulation of the endocannabinoid system (ECS). To this aim, we used eight experimental groups of Sprague-Dawley rats, of which six were exposed to BCL for 24 hours. Following retinal function evaluation, retinas were quickly removed for biochemical and morphological analyses. Rats were either saffron-prefed or intravitreally injected with selective type-1 (CB1) or type-2 (CB2) cannabinoid receptor antagonists before BCL. Prefeeding and intravitreally injections were combined in two experimental groups before BCL. BCL exposure led to enhanced gene and protein expression of retinal CB1 and CB2 without affecting the other ECS elements. This effect of BCL on CB1 and CB2 was reversed by saffron treatment. Selective CB1 and CB2 antagonists reduced photoreceptor death, preserved morphology and visual function of retina, and mitigated the outer nuclear layer (ONL) damage due to BCL. Of interest, CB2-dependent neuroprotection was more pronounced than that conferred by CB1. These data suggest that BCL modulates only distinct ECS elements like CB1 and CB2, and that saffron and cannabinoid receptors could share the same mechanism in order to afford retinal protection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0166827PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5115823PMC
June 2017

Rank Order Coding: a Retinal Information Decoding Strategy Revealed by Large-Scale Multielectrode Array Retinal Recordings.

eNeuro 2016 May-Jun;3(3). Epub 2016 Jun 3.

Faculty of Medical Sciences, Institute of Neuroscience, Newcastle University , Newcastle-upon-Tyne NE2 4HH, United Kingdom.

How a population of retinal ganglion cells (RGCs) encodes the visual scene remains an open question. Going beyond individual RGC coding strategies, results in salamander suggest that the relative latencies of a RGC pair encode spatial information. Thus, a population code based on this concerted spiking could be a powerful mechanism to transmit visual information rapidly and efficiently. Here, we tested this hypothesis in mouse by recording simultaneous light-evoked responses from hundreds of RGCs, at pan-retinal level, using a new generation of large-scale, high-density multielectrode array consisting of 4096 electrodes. Interestingly, we did not find any RGCs exhibiting a clear latency tuning to the stimuli, suggesting that in mouse, individual RGC pairs may not provide sufficient information. We show that a significant amount of information is encoded synergistically in the concerted spiking of large RGC populations. Thus, the RGC population response described with relative activities, or ranks, provides more relevant information than classical independent spike count- or latency- based codes. In particular, we report for the first time that when considering the relative activities across the whole population, the wave of first stimulus-evoked spikes is an accurate indicator of stimulus content. We show that this coding strategy coexists with classical neural codes, and that it is more efficient and faster. Overall, these novel observations suggest that already at the level of the retina, concerted spiking provides a reliable and fast strategy to rapidly transmit new visual scenes.
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http://dx.doi.org/10.1523/ENEURO.0134-15.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891767PMC
October 2017

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

Adv Healthc Mater 2016 09 30;5(17):2271-82. Epub 2016 May 30.

Center for Synaptic Neuroscience and Technology, Fondazione Istituto Italiano di Tecnologia, Largo Giovanna Benzi 10, 16132, Genova, Italy.

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. The results indicate a good stability of the subretinal implants over time, with preservation of the physical properties of the polymeric layer and a tight contact with the outer retina. Immunoinflammatory markers detect only a modest tissue reaction to the surgical insult and the foreign body that peaks shortly after surgery and progressively decreases with time to normal levels at five months after implantation. Importantly, the integrity of the polymeric layer in direct contact with the retinal tissue is preserved after five months of implantation. The recovery of the foreign-body tissue reaction is also associated with a normal b-wave in the electroretinographic response. The results demonstrate that the device implanted in nondystrophic eyes is well tolerated, highly biocompatible, and suitable as retinal prosthesis in case of photoreceptor degeneration.
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http://dx.doi.org/10.1002/adhm.201600318DOI Listing
September 2016

High-density MEA recordings unveil the dynamics of bursting events in Cell Cultures.

Annu Int Conf IEEE Eng Med Biol Soc 2015 Aug;2015:3763-6

High density multielectrode arrays (MEAs) based on CMOS technology (CMOS-MEAs) can simultaneously record extracellular spiking activity in neuronal cultures from 4096 closely spaced microelectrodes. This allows for a finer investigation of neuronal network activity compared to conventional MEAs with a few tens of electrodes. However, the sensing properties of these devices differ. To highlight this aspect, here we investigate and discuss the differences observed when quantifying spontaneous synchronized bursting events (SBEs) in datasets acquired with conventional MEAs and high-density MEAs from comparable hippocampal cultures. We found that datasets acquired with high-density MEAs exhibit collective dynamics similar to conventional arrays, but are characterized by a higher percentage of random spikes, i.e. spikes that are not part of a burst, most probably resulting from the larger recording capability. Additionally, the percentage of electrodes that record a burst is remarkably small on high-density MEAs compared to what can be observed on conventional MEAs and SBEs appear to be propagating in time across the electrode array, by involving shorter sequences of spikes per electrode. Overall, these results highlight a lower level of network synchronization involved in SBEs compared to what has been debated for several decades based on conventional MEA recordings from cell cultures.
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http://dx.doi.org/10.1109/EMBC.2015.7319212DOI Listing
August 2015

Investigating cell culture dynamics combining high density recordings with dimensional reduction techniques.

Annu Int Conf IEEE Eng Med Biol Soc 2015 Aug;2015:3759-62

High density multielectrode array recordings with CMOS-MEAs allow to monitor cell culture activity with unprecedent details respect to previous recording techniques. This is clarifying how network activity develops and is motivating the development of novel data analysis tools. Here, in order to advance in the exploitation of the richness of these large-scale array recordings, we introduce a principal component analysis approach that aims at improving on existing methodologies to describe neural activity events within large networks.
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http://dx.doi.org/10.1109/EMBC.2015.7319211DOI Listing
August 2015

Cerium Oxide Nanoparticles Reduce Microglial Activation and Neurodegenerative Events in Light Damaged Retina.

PLoS One 2015 15;10(10):e0140387. Epub 2015 Oct 15.

Department of Applied Clinical Science and Biotechnology, University of L'Aquila, Via Vetoio, Coppito II, 67100 L'Aquila, Italy.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0140387PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4607482PMC
June 2016

Microelectronics, bioinformatics and neurocomputation for massive neuronal recordings in brain circuits with large scale multielectrode array probes.

Brain Res Bull 2015 Oct 29;119(Pt B):118-26. Epub 2015 Jul 29.

NetS3 Laboratory, Neuroscience and Brain Technologies, Fondazione Istituto Italiano di Tecnologia, Genova, Italy.

Deciphering neural network function in health and disease requires recording from many active neurons simultaneously. Developing approaches to increase their numbers is a major neurotechnological challenge. Parallel to recent advances in optical Ca(2+) imaging, an emerging approach consists in adopting complementary-metal-oxide-semiconductor (CMOS) technology to realize MultiElectrode Array (MEA) devices. By implementing signal conditioning and multiplexing circuits, these devices allow nowadays to record from several thousands of single neurons at sub-millisecond temporal resolution. At the same time, these recordings generate very large data streams which become challenging to analyze. Here, at first we shortly review the major approaches developed for data management and analysis for conventional, low-resolution MEAs. We highlight how conventional computational tools cannot be easily up-scaled to very large electrode array recordings, and custom bioinformatics tools are an emerging need in this field. We then introduce a novel approach adapted for the acquisition, compression and analysis of extracellular signals acquired simultaneously from 4096 electrodes with CMOS MEAs. Finally, as a case study, we describe how this novel large scale recording platform was used to record and analyze extracellular spikes from the ganglion cell layer in the wholemount retina at pan-retinal scale following patterned light stimulation.
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http://dx.doi.org/10.1016/j.brainresbull.2015.07.008DOI Listing
October 2015

RNAi-mediated silencing of Myc transcription inhibits stem-like cell maintenance and tumorigenicity in prostate cancer.

Cancer Res 2013 Nov 24;73(22):6816-27. Epub 2013 Sep 24.

Authors' Affiliations: Institute of Oncology Research; Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; and Molecular Oncology Unit, CIEMAT, Madrid, Spain.

Several studies link disease progression, recurrence, and treatment failures to the cancer stem-like cell (CSC) subpopulation within the heterogeneous tumor cell population. Myc is a transcription factor having a central function in stem cell biology and in human cancers. Hence, Myc represents an attractive target to develop CSC-specific therapies. Recent findings suggest that Myc transcription can be silenced using an RNA interference (RNAi)-based strategy that targets noncoding promoter-associated RNA (paRNA) overlapping the transcription start site. In this study, we investigated the effects of silencing Myc transcription on prostate CSC in cell culture and xenograft models of human prostate cancer. Treatment with an effective promoter-targeting siRNA reduced the fraction of CSCs, leading to reduced self-renewal, tumor-initiating, and metastatic capability. Combined analysis of stem-like cells and senescence markers indicated that Myc silencing triggered a phenotypic shift and senescence in the CSC subpopulation. Notably, systemic delivery of the promoter-targeting siRNA in the xenograft model produced a striking suppression in the development of prostate tumors. Our results support a pivotal role for Myc in CSC maintenance and show that Myc targeting via RNAi-based transcriptional silencing can trigger CSC senescence and loss of their tumor-initiating capability. More generally, our findings demonstrate the efficacy of RNAi-based transcriptional strategies and the potential to target regulatory noncoding paRNAs for therapeutic applications.
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http://dx.doi.org/10.1158/0008-5472.CAN-13-0615DOI Listing
November 2013

Excitatory and inhibitory contributions to receptive fields of alpha-like retinal ganglion cells in mouse.

J Neurophysiol 2013 Sep 10;110(6):1426-40. Epub 2013 Jul 10.

ARC Centre of Excellence in Vision Science, The University of Sydney, Sydney, Australia;

The ON and OFF pathways that emerge at the first synapse in the retina are generally thought to be streamed in parallel to higher visual areas, but recent work shows cross talk at the level of retinal ganglion cells. The ON pathway drives inhibitory inputs onto some OFF ganglion cells, such that these neurons show "push-pull" convergence of OFF-excitation and ON-disinhibition. In this study we measure the spatial receptive field of excitatory and inhibitory inputs to OFF-sustained (OFF-S) retinal ganglion cells of mouse, establish how contrast adaptation modulates excitatory and inhibitory synaptic inputs, and show the pharmacology of the inhibitory inputs. We find that the spatial tuning properties of excitatory and inhibitory inputs are sufficient to determine the spatial profile of the spike output and that high spatial acuity may be particularly reliant on disinhibitory circuits. Contrast adaptation reduced excitation to OFF-S ganglion cells, as expected, and also unmasked an asymmetry in inhibitory inputs: disinhibition at light-off was immune to contrast adaptation, but inhibition at light-on was substantially reduced. In pharmacological experiments we confirm that inhibitory inputs are partly mediated by glycine, but our measurements also suggest a substantial role for GABA. Our observations therefore reveal functional diversity in the inhibitory inputs to OFF ganglion cells and suggest that in addition to enhancing operational range these inputs help shape the spatial receptive fields of ganglion cells.
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http://dx.doi.org/10.1152/jn.01097.2012DOI Listing
September 2013

An isolated semi-intact preparation of the mouse vestibular sensory epithelium for electrophysiology and high-resolution two-photon microscopy.

J Vis Exp 2013 Jun 13(76):e50471. Epub 2013 Jun 13.

Discipline of Biomedical Science, School of Medical Sciences, Sydney Medical School, University of Sydney.

Understanding vestibular hair cells function under normal conditions, or how trauma, disease, and aging disrupt this function is a vital step in the development of preventative approaches and/or novel therapeutic strategies. However, the majority of studies looking at abnormal vestibular function have not been at the cellular level but focused primarily on behavioral assays of vestibular dysfunction such as gait analyses and vestibulo-ocular reflex performance. While this work has yielded valuable data about what happens when things go wrong, little information is gleaned regarding the underlying causes of dysfunction. Of the studies that focus on the cellular and subcellular processes that underlie vestibular function, most have relied on acutely isolated hair cells, devoid of their synaptic connections and supporting cell environment. Therefore, a major technical challenge has been access to the exquisitely sensitive vestibular hair cells in a preparation that is least disrupted, physiologically. Here we demonstrate a semi-intact preparation of the mouse vestibular sensory epithelium that retains the local micro-environment including hair cell/primary afferent complexes.
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http://dx.doi.org/10.3791/50471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3729247PMC
June 2013