Dopaminergic neurons are widely distributed throughout the CNS and play vital roles in sensory functions, motor control, cognition, and motivation. The most accessible dopaminergic neurons of the CNS are located in the vertebrate retina. These neurons are a specialized subpopulation of amacrine cells that play critical roles in modulating retinal circuits, synchronizing the retinal clock, and influencing eye growth. Dopaminergic amacrine neurons are regulated by several factors including light; however, mechanisms involved are mostly unknown. The long-term goal of the proposed study is to understand the mechanisms by which dopaminergic amacrine neurons are regulated by light. We have developed novel strategies and reagents to achieve this goal. Our published studies have revealed that dopaminergic amacrine neurons comprise at least two functional subtypes, transient and sustained responders, which appear to be tuned to distinct aspects of environmental light. In this application, we will extend our previous studies by addressing four specific aims.
Aim 1 will test the hypothesis that dopaminergic amacrine neurons are depolarized with persistent increased activity by rods through distinct neural pathways.
In Aim 2, we will test the hypothesis that cone-driven dopaminergic amacrine neurons comprise two distinct morphological and functional subtypes (transient ON and ON-OFF).
Aim 3 will determine the morphology of sustained dopaminergic amacrine neurons driven by the melanopsin-expressing intrinsically photosensitive retinal ganglion cells and the mechanisms of glutamatergic transmission from the intrinsically photosensitive retinal ganglion cells to dopaminergic amacrine neurons.
In Aim 4, we will define the relative contributions of rod, cone, and melanopsin signaling to dopaminergic amacrine neurons across a wide range of light intensities. Successful completion of these aims will provide novel information regarding dopaminergic amacrine neuron subtypes, each subtype's light response characteristics, the neural pathways conveying photosensitive cell signals to dopaminergic amacrine neurons, and a framework for how dopaminergic amacrine neurons encode light stimuli through the three photosensitive cell classes over the entire visual range. This information will advance our understanding of the regulation of retinal dopamine release by light and have important implications for the roles of dopamine in visual information processing, gene expression, and eye development. These studies will also have the potential to yield new insight into the cellular and synaptic mechanisms responsible for pathogenesis of eye and brain disorders associated with dopaminergic abnormalities such as diabetic retinopathy and Parkinson's disease, and to suggest novel preventive and therapeutic strategies for these disorders.
Retinal dopamine acts as a neurotransmitter and plays critical roles in modulating retinal circuits, synchronizing the retinal clock, and influencing eye growth. As a result, dopamine deficiency in neurodegenerative diseases such as diabetic retinopathy, retinitis pigmentosa, and Parkinson's disease leads to a number of visual defects involved in spatial and temporal vision, as well as absolute visual sensitivity. The proposed studies will have the potential to yield new insights into the cellular and synaptic mechanisms responsible for pathogenesis of these neurodegenerative diseases, and to suggest novel preventive and therapeutic strategies for them.
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