The objective of our research is to understand how the retina of mammals analyzes the visual world and encodes its spatial, temporal and chromatic contrast into a message of action potentials which is sent to the brain. In the retina, dopamine is the modulator responsible for many of the events that lead to neural adaptation to light. To identify the mechanisms and neural networks that control the release of dopamine, we labeled genetically dopaminergic amacrine cells (DA cells) in the mouse and could therefore investigate their physiology in vitro after dissociation of the retina. We also developed a technique to study global gene expression in single neurons. The present application has the following aims: (i) we will test the hypothesis that DA cells, in addition to dopamine, release GABA by exocytosis both over their entire surface and at their synapses with AII amacrine cells, the neuron that transfer rod signals to cone bipolar cells. (ii) We will investigate the light responses of DA cells by intracellular recordings in the intact mouse retina. (iii) By profiling gene expression on high-density arrays of oligonucleotide probes covering the transcribed mouse genome, we will compile a comprehensive list of the transcripts contained in DA cells. Knowledge of the repertory of ion channels, transmitter receptors, components of G-protein-coupled second messenger pathways and secreted neuroactive molecules that are contained in DA cells will allow us to formulate meaningful hypotheses about novel functions that can be tested experimentally. Finally, we will compare the transcriptome of DA cells with that of two other types of retinal neurons, type 2 catecholaminergic amacrines and rod bipolars. In addition to the presence of novel molecules, we will be searching for answers to questions that are at the very heart of the concept neuronal cell type: we want to uncover cell-type specific molecules and identify a """"""""molecular signature"""""""" for the unique functions that are carried out by the three types of neurons in the processing of light signals. (iv) We will identify by electron microscopy the neurons that control the activity of DA cells in light and darkness. These studies are crucial to the understanding of the mechanism of vision in the retina.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology and Diseases of the Posterior Eye Study Section (BDPE)
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Greenwell, Thomas
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Harvard University
Schools of Medicine
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Hirasawa, Hajime; Contini, Massimo; Raviola, Elio (2015) Extrasynaptic release of GABA and dopamine by retinal dopaminergic neurons. Philos Trans R Soc Lond B Biol Sci 370:
Hirasawa, Hajime; Betensky, Rebecca A; Raviola, Elio (2012) Corelease of dopamine and GABA by a retinal dopaminergic neuron. J Neurosci 32:13281-91
Contini, Massimo; Lin, Bin; Kobayashi, Kazuto et al. (2010) Synaptic input of ON-bipolar cells onto the dopaminergic neurons of the mouse retina. J Comp Neurol 518:2035-50
Hirasawa, Hajime; Puopolo, Michelino; Raviola, Elio (2009) Extrasynaptic release of GABA by retinal dopaminergic neurons. J Neurophysiol 102:146-58
Dorenbos, Ronald; Contini, Massimo; Hirasawa, Hajime et al. (2007) Expression of circadian clock genes in retinal dopaminergic cells. Vis Neurosci 24:573-80
Storch, K-F; Paz, C; Signorovitch, J et al. (2007) Physiological importance of a circadian clock outside the suprachiasmatic nucleus. Cold Spring Harb Symp Quant Biol 72:307-18
Puopolo, Michelino; Raviola, Elio; Bean, Bruce P (2007) Roles of subthreshold calcium current and sodium current in spontaneous firing of mouse midbrain dopamine neurons. J Neurosci 27:645-56
Puopolo, Michelino; Bean, Bruce P; Raviola, Elio (2005) Spontaneous activity of isolated dopaminergic periglomerular cells of the main olfactory bulb. J Neurophysiol 94:3618-27
MacNeil, Margaret A; Heussy, John K; Dacheux, Ramon F et al. (2004) The population of bipolar cells in the rabbit retina. J Comp Neurol 472:73-86
Gustincich, Stefano; Contini, Massimo; Gariboldi, Manuela et al. (2004) Gene discovery in genetically labeled single dopaminergic neurons of the retina. Proc Natl Acad Sci U S A 101:5069-74

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