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. In the rabbit retina, preliminary evidence indicates that a circadian (24-hour) clock regulates rod and cone input to ganglion cells and cone-connected horizontal cells, a type of second order cell that receives synaptic contact from cones. 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). The circadian factors that regulate the light responses of ganglion cells and cone-connected horizontal cells are not known. Preliminary evidence suggests that a clock in the retina regulates the release of endogenous dopamine and adenosine and that these neuromodulators mediate the clock effects on rod and cone pathways in the inner and outer retina. We will use electrophysiological, neurochemical and anatomical techniques to determine whether a circadian clock affects the light responses of outer and inner retinal neurons in the mammalian retina (i.e. horizontal, ganglion and All amacrine cells) and whether and how the clock utilizes dopamine, adenosine, and melatonin to achieve its effects. We will also determine whether there is a clock in the mammalian retina that regulates endogenous dopamine and adenosine release and extracellular pH and whether this clock is in the outer or inner retina. Finally, we will characterize the mechanisms by which the mammalian clock regulates the release of dopamine and adenosine. The light responses and tracer coupling of cone-connected horizontal cells and All amacrine cells, as well as the light responses of ganglion cells will be studied under conditions of constant darkness in the day and night, using in vitro rabbit and mouse retinal preparations. Disruption of circadian clock processes in the retina may mediate photoreceptor cell degeneration. Thus, increased understanding of circadian clock processes and pathways and of transmitter function 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, increased knowledge of the action of dopamine and adenosine in the retina may aid in the understanding and treatment of Parkinson's disease and schizophrenia.
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