Mechanisms of cross-modal plasticity in the brain: optogenetics, electrophysiology, and behavior
The study of how information from different senses is integrated in the brain crosses boundaries between different scientific disciplines, such as perceptual psychology, cognitive science, neuroscience, biology, and a number of clinical disciplines such as neurology, neurosurgery, and psychiatry. Thus, an important goal in modern neuroscience is to understand how single neurons in the nervous system encode information derived from more than one sensory system. This issue has long been studied in the superior colliculus, an integration centre of visual and auditory information. The laboratory, instead, addresses the poorly known function of multisensory processes in the visual system. The aim of this research project is to investigate the involvement of different physiological mechanisms in processes of cross-modal cortical plasticity by using environmental and optogenetic stimulation (Journal of Experimental Neuroscience 2017, 11: 1179069517703354). To test this issue, we use the monocular deprivation (MD) paradigm in rodents: a classical model for experience-dependent modifications of visual cortical circuitries (Nature Reviews Neuroscience 2005, 6: 877) while stimulating other sensory areas. We work with both (i) wild type and (ii) transgenic animals expressing opsins sensitive to light in a cell-specific manner. Plasticity in the cortex after sensory stimulation is evaluated by means of in vivo electrophysiology in awake rodents analyzing modifications of ocular dominance in response to MD with a multi-channel approach. This analysis is accompanied by behavioural assessments of vision in freely moving animals (e.g., light sensitivity and spatial resolution) using (i) the light-dark box test and (ii) the optomotor response. This is paralleled by analyses of epigenetic modifications of chromatin structure by ChIP, gene expression patterns by RT-PCR and immunohistochemistry (European Journal of Neuroscience 2011, 33: 49; Journal of Physiology 590: 4777). The identification of epigenetic mechanisms and gene expression in the context of cross-modal plasticity is an issue of high interest in the field of modern neuroscience. It has potential clinical applications in pathological states where a reorganization of neuronal circuitries may be beneficial.
Nano-technological strategies and non-invasive environmental approaches to treat neurodegenerative blindness
The purpose of the research project is to promote the development of novel therapeutic strategies for human blindness using animal models of genetic retinal illnesses. We direct our attention to non-invasive approaches that aim to modulate endogenous physiological processes at the basis of brain plasticity (i.e., environmental enrichment). In collaboration with Fabio Benfenati, Guglielmo Lanzani, and Grazia Pertile, we have also used a fully organic three-layered prosthetic device for in vivo subretinal implantation in the eye of Royal College of Surgeons rats, a widely recognized model of Retinitis Pigmentosa (Advanced Healthcare Materials 2016, 5: 2271). Electrophysiological and behavioural analyses revealed a significant and prosthesis-dependent recovery of light-sensitivity and spatial resolution that persists up to 6 months after surgical implant. The rescue of visual functions was accompanied by an increase in the basal metabolic activity of the primary visual cortex, as demonstrated by positron emission tomography imaging (Nature Materials 2017, 16(6): 681). This line of translational research is of clinical relevance in retinal diseases with an incidence of 1 in every 4000 people worldwide, for which there is currently no medical treatment. In addition, we are working with an artificial retina specially designed for the swine eye (Front Bioeng Biotech 2020, 8: 1188). We are implanting such photovoltaic device in pigs bearing photoreceptor degeneration, to evaluate the rescue of visual functions and to develop the surgical technique of implantation in an eye that resembles that of humans as the last experimental step before the phase-1 experimentation in man. We are also testing novel polymeric interfaces based on new materials and geometries to develop more advanced, next-generation retinal interfaces (Nature Nanotechology 2020, 15(4): 296). An innovative issue we have also been working with is the development and application of “liquid” artificial devices that can be repeatedly microinjected in the subretinal space of the eye. One of such devices consists of a suspension of nanoparticles that greatly improve the coverage of the afflicted retina and therefore enhances the recovery of visual functions. This novel strategy has been successfully applied in an animal model of retinal degeneration (Nature Nanotechnology 2020, 15(8): 698). At the moment, we are using intravitreal injections of FDA approved biodegradable PLGA nano-particles that slowly realease a potent anti-inflammatory and antioxidant molecule to treat early stage neurodegenerative blindness.
Major Collaborations:
- Prof. Fabio Benfenati, MD, Neuroscientist, Italian Institute of Technology, Genova, Italy
- Prof. Guglielmo Lanzani, PhD, Physicist, Polytechnic Institute of Milan, Milan, Italy
- Dr. Grazia Pertile, MD, Ophthalmologist, Sacrocuore Don Calabria Hospital, Verona, Italy
- Prof. Maurizio Mete, MD, Ophthalmologist, University of Bologna, Bologna, Italy
- Prof. Eero Castren, MD, Neuroscientist, University of Helsinki, Helsinki, Finland
- Prof. Stéphane Molotchnikoff, PhD, Neuroscientist, University of Montreal, Montreal, Canada
- Dr. Miguel Skirzewski, PhD, Neuroscientist, Bar Harbor, Maine, USA
- Prof. Luis Hernandez, MD, Neuroscientist, Bascom Palmer Eye Institute, Florida, USA
- Prof. Gaetano Valenza, PhD, Electronic Engineer, University of Pisa, Pisa, Italy
- Prof. Dario Puppi, PhD, Chemical Engineering, University of Pisa, Pisa, Italy