Development of Inter- and Intra-cellular Components of Direction Selectivity in The Mammalian Retina
The mouse brain contains over 70 million neurons that form around a trillion connections, or synapses, with one another. Different synaptically connected networks of neurons are organized with varying circuit motifs to receive information and transform that information into a relevant output for the animal. The visual system, and in particular the retina, has served as a classic model for elucidating how neuronal circuits perform these computations. The focus of this dissertation was to understand how the inter-neuronal and sub-neuronal aspects of the direction selective circuit in the retina develop and operate to extract the directions of object motion from the milieu of information in the visual scene. The key neuron in this circuit is the starburst amacrine cell. The dendrites of starburst cells exhibit specific responses to motion in the visual scene that depend upon the dendrite’s orientation within the retina. These signals are then propagated through a stereotyped asymmetric arrangement of synaptic connections from multiple starburst cells onto direction selective ganglion cells, which transmit this directional information to the brain. I begin by summarizing the current understanding of how the direction selective circuit develops and operates in Chapter I. Then, experimental evidence is provided that seeks to answer outstanding questions regarding the development of direction selective circuit components and their roles within the mature circuit. First, in Chapter II, I investigate how the asymmetric synaptic connections between starburst cells and direction selective ganglion cells develop. I find that the mature direction selective circuit wiring diagram results from a subcellularly specified synaptogenesis program, rather than synaptic pruning or strengthening. Next, in Chapter III I investigate how the direction selective responses within the starburst cell dendrites are generated. I find that a skewed distribution of excitatory inputs onto the dendrite is sufficient to produce these responses. In Chapter IV, I explore how starburst cell dendritic morphology influences direction selective circuit computations. I find that starburst cell morphology aligns the subcellular starburst cell computation with the appropriate post-synaptic ganglion cell and that the dense plexus of starburst dendrites is required to produce directionally discriminate responses in the ganglion cell. In addition, I find that the subcellular directional computation in starburst cells is performed at the end of the bipolar cell input distribution along the dendrite identified in Chapter III. In Chapter V I seek to identify the molecular determinants of the asymmetric wiring program identified in Chapter II. These preliminary results will provide a basis for further exploration of direction selective circuit development. Together, these results reveal how the morphology, connectivity, and biophysical properties of neurons are arranged during development to generate the amazing computational abilities of neuronal circuits.