Background: Retinal cell loss due to injury or disease results in disruptions to the structural organization of the visual system with dire consequences for vision.
Hypothesis: Local remodelling in the retina and global remodelling in the brain represent checkpoints for visual circuit repair that could sometimes be maladaptive, but could also support recovery of visual function.
Strategy: We will ablate specific cell-types in the zebrafish retina, monitor structural and functional remodelling across the whole brain in vivo to determine the checkpoints of remodeling and devise strategies to bias them towards recovery.
Vision begins in the retina, a thin neural out-post of the brain that lines the back of the eye. Cell loss results in vision impairments in many retinal diseases. These impairments originate in disruptions to the laminar and mosaic organization of the retina, which are essential for the function of neural circuits. Cell loss triggers remodelling in spared circuits, which is typically maladaptive, augmenting neurite loss, delamination and spurious connectivity. However, the capacity for such plasticity could also be harnessed toward “constructive” rewiring that leads to circuit repair. In regenerative settings, for example, where new cells derive from endogenous sources or transplantations, this capacity for remodelling allows for circuit integration. Retinal lesions also trigger remodelling in higher visual centres in the brain. Here too remodelling can either be maladaptive, leading to further exacerbation of the impairment, or constructive, representing endogenous attempts at functional compensation. Moreover, when such remote remodelling events occur in relation to the initial retinal insult and the local response, it will have implications for whether and by what strategy visual function is restored. Hence, local and global remodelling represent interconnected circuit checkpoints of visual system recovery, potentially also revealing general strategies of central nervous system recovery based on local repair versus global compensation. Here we will use zebrafish to monitor structural (L.G.’s area of expertise) and functional (R.P.’s area of expertise) remodelling locally within the retina and brain-wide in the living animal following partial ablations of retinal cell-types that are particularly vulnerable in disease. Using these approaches together with behavioural assays, we will be able to elucidate the local and global remodelling checkpoints that control circuit repair and restoration of visual function. We will work toward the following specific aims:
Aim ❶ Assess recovery after acute subset ablation of selected retinal cell-types by behavioural assays and whole-brain calcium imaging
Aim ❷ Assess the retinal checkpoints of remodelling that underlie functional recovery
Aim ❸ Assess checkpoints of global remodelling to elucidate compensatory mechanisms