Friday, April 26, 2024
4/26/2024
There is critical need to understand the causes, extent, and mechanisms of reactions to cell death so that effective treatments most appropriate for the state of the remaining circuit can be employed, and so that constructive compensation can be harnessed as a potential treatment in conditions where a portion of the circuit endures. Our long-term goal is to salvage neuronal circuits. Here, we will define the effects of controlled cell death on specific circuits, cell types, synapses, and proteins for the purpose of understanding the conditions that result in constructive (e.g., compensation through increasing synaptic gain) vs. destructive (e.g., aberrant spontaneous activity that corrupts signal) response. The mouse retina is an exceptional platform for this study because the primary sensory neurons, photoreceptors, can be manipulated under genetic control; cell types within specific circuits are identifiable and accessible; and the functional readout can be interpreted as visual sensitivity. We propose to ablate variable populations of rods in mature retina and determine the structural and functional effects on the primary rod bipolar cell pathway, the most sensitive retinal pathway: rods¿rod bipolar cells¿AII amacrine cells¿ON cone bipolar cells¿ON sustained alpha ganglion cells (abbr. ON alpha). ON alpha ganglion cells receive the greatest number of rod inputs, thus would be the most sensitive to rod loss. Our central hypothesis is that the retina has constructive reactions to input loss with the capacity to recover normal function up to an undefined threshold; beyond this threshold, destructive reactions begin. Unknown is this tipping point. Our preliminary data show that despite loss of half the rods, rod- mediated light responses in ON alpha ganglion cell spikes are comparable to control, suggesting compensation within the primary rod bipolar cell pathway. Thus, the premise is strong for constructive compensation within the retina following rod loss, and we will determine the induction parameters, sites, and contributions of this compensation to maintaining function in the following aims: (Aim 1) to determine the degree of input loss that induces constructive vs. destructive structural and functional changes, and (Aim 2) to locate the site(s) and mechanism(s) of compensation within a well-defined neural circuit. The approach is innovative for genetic control over the timing and degree of rod death; synaptic- and cell-type specific structural and functional investigation of a well-defined retinal circuit; and molecular tools to distinguish between cell ablation and synapse disassembly in triggering compensatory mechanisms. The results will be significant for (1) determining the degree of rod death that triggers the remaining circuit to undergo destructive or constructive responses, (2) identifying the sites and contributions of structural and functional compensation to maintaining retinal function, and (3) providing knowledge essential to the optimization and deployment of therapies to treat dysfunctional photoreceptors involving stem cells, genes, and prostheses, all of which rely on a stable retinal circuit and/or extensive knowledge of the state of the surviving retinal circuit.
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