This research project is an experimental study that seeks to understand how neuronal networks change or adapt due to the influence of an intrinsic circadian oscillator. Recent published evidence indicates that a circadian (24-hour) clock in the mammalian retina regulates rod and cone input to cone-connected horizontal cells, a type of second order cell that receives synaptic contact from cones, by controlling rod-cone gap junctional coupling via dopamine D2 receptors. Preliminary evidence suggests that the retinal clock also regulates rod and cone input to ganglion cells, the output neurons of the retina. A circadian clock is a type of biological oscillator that has persistent rhythmicity with a period of approximately 24 hours in the absence of external timing cues (e.g. constant darkness). Preliminary evidence suggests that the retinal clock uses the intracellular signaling molecules cyclic AMP and protein kinase A and the neuromodulators melatonin and adenosine, in addition to dopamine, to regulate rod and cone input to cone-connected horizontal cells and to ganglion cells in part via Connexin36-containing gap junctions. We will use electrophysiological, neurochemical and anatomical techniques to determine whether the circadian clock utilizes adenosine and melatonin, and the intracellular signaling molecules cyclic AMP and protein kinase A to control rod and cone input to cones and cone-connected horizontal cells in part by modulating Connexin36- containing rod-cone gap junctions. We will also determine whether the clock utilizes dopamine, adenosine, and melatonin to control rod and cone input to ganglion cells and AII amacrine cells in part by modulating Connexin36-containing gap junctions. The light responses and tracer coupling of neurons in in vitro rabbit, mouse and goldfish retina preparations will be studied in the day and night under conditions of constant darkness.
Disruption of circadian clock processes in the retina may mediate photoreceptor cell degeneration. Thus, increased understanding of circadian clock processes and pathways and of the neuromodulators dopamine, adenosine and melatonin, which are used by the circadian clock in the retina to achieve its effects, will aid in the understanding of human retinal processes and dysfunction, as well as provide the basis for drug therapy for retinal disorders. In addition, adenosine and dopamine have been implicated in the neuronal death that occurs in Parkinson's disease, ischemic brain injury, Huntington's disease, multiple sclerosis, Alzheimer's disease, and HIV-associated dementia. Thus, increased knowledge of the actions of dopamine and adenosine in the retina may aid in the understanding and treatment of these brain diseases.
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