There is a gap in knowledge of how loss of 50-80% of cone photoreceptors produces almost no change in visual acuity or sensitivity. While contributions from cortex have been examined, those from retina have been underappreciated. The long-term goal to understand how the retina functions robustly in the face of photoreceptor death will generate transformative insights into how neural plasticity compensates for cell death. Understanding this compensation is likely to lead to earlier diagnostics and more effective treatments. The overall objective of this proposal is to elucidate the fundamental synaptic and circuit-level mechanisms that allow the retina to function while compensating for photoreceptor death. This proposal focuses on the well-characterized circuit of the ON sustained alpha ganglion cell in mouse retina, a strong model circuit with identified cell types, maps of specific connections, accessibility to genetic manipulation, and quantifiable structure and function. Following genetic ablation of 50-75% of cones in adult retina with the diphtheria toxin receptor, these ganglion cells adjust receptive field structures and spike responses. The observations are congruent with adaptation, which adjusts integration and gain for stimulus statistics, e.g., greater integration and gain at lower light levels, or homeostatic plasticity, which involves remodeling circuitry or channel expression. The central hypothesis is that the retina can compensate for cone loss via mechanisms of adaptation and/or homeostatic plasticity that we will determine in two specific aims:
(Aim 1) identify the extent and sites of compensation within the retinal circuit following partial cone loss in the adult and (Aim 2) determine the contributions of partial stimulation, mean adaptation and homeostatic plasticity to the retina's reaction to cone loss. The results of the first aim will identify the structural and functional consequences of cone loss on the direct excitatory pathway from cones to type 6 cone bipolar cells to ON alpha ganglion cells. The results of the second aim will determine how adaptation, changes in excitatory and inhibitory circuits, and intrinsic excitability contribute to changes in ganglion cell spatial and intensity encoding following partial cone loss. The approach is innovative for the genetic control over cone ablation in mature retina, the stage at which most human retinal diseases occur; functional and structural examination with cell-type specific resolution; and focus on synaptic and circuit mechanisms underlying a well known discrepancy between photoreceptor loss and visual function. The research is significant for (1) uncovering mechanisms that may mask visual deficits in early stages of photoreceptor loss; (2) suggesting diagnostics that could detect earlier onset of diseases causing cone loss; (3) establishing knowledge about the flexibility of a sensory circuit and how this flexibility pertains to a surviving circuit; (4) providing direct measures of how retinal function after partial cone loss is distinct from or similar to that in control retina?thus potentially influencing the design of treatments to restore retinal function following photoreceptor loss.

Public Health Relevance

The proposed research is relevant to public health because it will elucidate the fundamental synaptic and circuit-level mechanisms that allow the retina to function while compensating for photoreceptor death. Such information will be critical to optimizing diagnostics and treatments for injury or degenerative outer retinal diseases where photoreceptors die first, such as macular dystrophy or retinitis pigmentosa.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY029772-02
Application #
9849284
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Greenwell, Thomas
Project Start
2019-02-01
Project End
2024-01-31
Budget Start
2020-02-01
Budget End
2021-01-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118