The initial steps of vision, the transduction and encoding of physical light stimuli into neural signals, occur in the retina, an out-pocketing of the diencephalon of the brain that lines the back of the eye. Retinal circuits are reconfigured according to the prevailing illumination conditions through the action of modulatory retinal neurotransmitters such as dopamine. The long-term goal of the line of research proposed here, is to elucidate the underlying cellular and molecular mechanisms by which retinal function is reconfigured by neuromodulatory signals. For the upcoming award period, we propose to focus on two critical questions in retinal neurobiology related to feedback circuits in the retina - How retinal dopaminergic neurons, the source of retinal dopamine, are regulated by light, and whether connexin hemichannels may contribute to feedback at the first visual synapse. We propose the following 2 specific aims:
Aim I. Using a transgenic mouse model developed in our laboratory that enables in situ recording from dopaminergic amacrine neurons (DA neurons), we will further define the synaptic mechanisms regulating sustained, transient and resting DA neuron activity and dopamine neuron heterogeneity.
Aim II : Using the zebrafish molecular genetic model system we will combine electrophysiological analysis of native horizontal cell hemichannel currents and horizontal cell feedback to cones with connexin gene manipulation to decisively test the participation of hemichannels in feedback. Completion of these aims will provide information fundamental for understanding normal retinal function and contribute to our understanding of clinically relevant dopaminergic mechanisms associated with photoreceptor degeneration, myopia, and visual deficits in Parkinsonism and diabetic retinopathy.

Public Health Relevance

The initial steps of vision, the transduction and encoding of physical light stimuli into neural signals, occur in the retina, an out-pocketing of the diencephalon of the brain that lines the back of the eye. Disruption of retinal circuits and cells can lead to visual deficits, including blindness. Research in this proposal focuses on two critical feedback circuits in the retina - how retinal dopaminergic neurons are regulated by light and act to reconfigure retinal circuits according to the prevailing illumination, and how connexin membrane ion channels may contribute to the function of retinal horizontal cells and their regulation of the first visual synapse. Completion of this research will provide information fundamental for understanding normal retinal function and contribute to our understanding of clinically relevant dopaminergic mechanisms associated with photoreceptor degeneration, myopia, and visual deficits in Parkinsonism and diabetic retinopathy.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY009256-22
Application #
8500284
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Greenwell, Thomas
Project Start
1991-08-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
22
Fiscal Year
2013
Total Cost
$341,072
Indirect Cost
$113,072
Name
Vanderbilt University Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Sun, Ziyi; Risner, Michael L; van Asselt, Jorrit B et al. (2012) Physiological and molecular characterization of connexin hemichannels in zebrafish retinal horizontal cells. J Neurophysiol 107:2624-32
Klaassen, Lauw J; Sun, Ziyi; Steijaert, Marvin N et al. (2011) Synaptic transmission from horizontal cells to cones is impaired by loss of connexin hemichannels. PLoS Biol 9:e1001107
Sun, Ziyi; Zhang, Dao-Qi; McMahon, Douglas G (2009) Zinc modulation of hemi-gap-junction channel currents in retinal horizontal cells. J Neurophysiol 101:1774-80
Zhang, Dao-Qi; Zhou, Tongrong; Ruan, Guo-Xiang et al. (2005) Circadian rhythm of Period1 clock gene expression in NOS amacrine cells of the mouse retina. Brain Res 1050:101-9
Zhang, Dao-Qi; Ribelayga, Christophe; Mangel, Stuart C et al. (2002) Suppression by zinc of AMPA receptor-mediated synaptic transmission in the retina. J Neurophysiol 88:1245-51
Zhang, D Q; McMahon, D G (2001) Gating of retinal horizontal cell hemi gap junction channels by voltage, Ca2+, and retinoic acid. Mol Vis 7:247-52
Zhang, D Q; McMahon, D G (2000) Direct gating by retinoic acid of retinal electrical synapses. Proc Natl Acad Sci U S A 97:14754-9