Project

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Brain rewiring after vision loss and rehabilitation

Applicant Trenholm Stuart
Number 168213
Funding scheme Ambizione
Research institution Friedrich Miescher Institute for Biomedical Research
Institution of higher education Institute Friedrich Miescher - FMI
Main discipline Neurophysiology and Brain Research
Start/End 01.09.2016 - 31.08.2017
Approved amount 196'964.00
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Keywords (9)

In vivo calcium imaging; Neuronal plasticity; Viral circuit tracing; Vision loss; Optogenetics; Vision rehabilitation; Behavioral testing; Retina; Visual cortex

Lay Summary (French)

Lead
Plasticité cérébrale après une perte visuelle et restauration de la vue.
Lay summary

Les circuits cérébraux sont plastiques. La plasticité permet aux circuits neuronaux de s’adapter aux changements et aux altérations de l’environnement. La plasticité est aussi nécessaire pour permettre de restaurer un sens perdu. Cependant, les atteintes de la vue peuvent aussi entrainer un remodelage de circuits cérébraux visuels et non visuels. Par conséquent, il reste incertain quelles capacités visuelles réellement utiles peuvent être atteints par les patients après restauration de la vue. En effet, la capacité des circuits réactivés à intégrer de façon fonctionnelle ces nouvelles informations visuelles dans un cerveau précédemment aveugle n’a pas été étudiée en détail. Ce projet a pour but 1) d’examiner comment les circuits visuels se remodèlent fonctionnellement après une perte visuelle 2) tenter d’améliorer la qualité de la vue atteignable à la suite d’une stratégie de restauration visuelle.

Direct link to Lay Summary Last update: 12.08.2016

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Abstract

Background: Brain circuits are plastic. Plasticity allows neuronal circuits to adapt to characteristics of and alterations to the environment, and is also important for permitting rehabilitation after sensory loss. Vision loss has been shown to promote rewiring of both visual and non-visual brain circuits. However, it is currently unclear how effective vision rehabilitation strategies can be at restoring useful visual capabilities to vision impaired patients, as the ability of re-activated visual circuits to functionally integrate into previously vision-deprived brain circuits has not been studied in detail. Furthermore, while the extent of plasticity is known to change throughout the course of a lifetime, a systematic examination of vision-loss induced circuit rewiring in congenital, early-onset and late-onset blindness is missing. Main goals: I plan to examine, in mice, how visual brain circuits functionally rewire following 1) vision loss and 2) the implementation of vision rehabilitation strategies.Focus 1: I will make a comprehensive map of the circuit rewiring that occurs in visual cortex, at single cell resolution, in congenitally, early-onset and late-onset blind mice. I will use well-defined mouse models in which vision loss occurs at different time points and I will cross these mice with cortical layer-specific Cre-expressing mice. Using viral tracing techniques I will map the inputs and outputs of each layer of primary visual cortex in these different mouse lines. These results could help predict how well these different mouse models will respond to vision rehabilitation strategies.Focus 2: I will examine the effects of restoring light sensitivity to blind retinae on the functional wiring of visual brain areas. I will use optogenetics to restore light-sensing capabilities to retinae that have become blind due to photoreceptor dystrophies, using adeno-associated viruses to deliver light-activated channels to remaining retinal neurons. I will perform these experiments in congenitally, early-onset and late-onset blind mice. After restoring light-sensing capabilities to the retinae of these mice, I will examine how the input/output wiring of primary visual cortex is altered compared to that of wild type mice. I will also assess the functionality of this ‘restored vision’ with a set of visually-driven behavioral tasks and test whether certain mice show better outcomes than other mice (for instance, it is possible that late-onset blind mice will recover better functional vision than congenitally blind mice). Finally, I will experimentally enhance the plasticity of visual brain circuits and test whether these manipulations boost recovery of functional vision when combined with optogenetic retinal treatments.Focus 3: I will test whether blind mice can be used as a model system for studying visual-to-auditory sensory substitution. In visually impaired humans, it has been shown that other senses, including hearing, can be used as a proxy for detecting environmental cues that previously required the visual system, and that such sensory substitution paradigms drive activity in brain areas normally driven by vision. First, I will examine whether there is enhanced functional cross-modal auditory input to visual cortex in congenitally, early-onset and late-onset blind mice. Next I will place blind mice in a virtual reality environment and train them to navigate through a virtual maze using auditory signals that describe the visual environment. I will then examine whether ‘visual’ brain areas are activated during these auditory tasks. Finally, I will test whether sensory-substitution training leads to rewiring of visual cortex, paying particular attention to the connectivity of auditory inputs to visual cortex. Outcomes: Together, these studies will have direct translational implications for vision rehabilitation strategies and will provide insights into the brain’s capacity to recover functional sensory processing abilities following both sensory deafferentation and sensory reafferentation.
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