The overall objective of this research program is to provide a better understanding of the development of retinal ganglion cells (RGCs) and their eye-specific projections to the dorsal lateral geniculate nucleus (dlgn).
Five specific aims are proposed designed to fill major gaps in our current knowledge.
In specific aim 1 we will employ multiple morphometric measures and quantitative methods to classify mouse RGCs into distinct classes. The mouse offers a powerful model to assess the effects of genetic variations on neuronal development, and for this reason it is vitally important to have a sound basis for assessing the salient properties of RGCs in the normal mouse retina. A cluster analysis of multiple morphometric measures obtained on a preliminary sample of cells suggests that the mouse ganglion cell population is comprised of 14 distinct classes, In specific aim 2 we will test the hypothesis that cholinergic inputs and/or neural circuitry play a key role in the morphological differentiation of mouse RGCs. For this purpose, we will perform the same morphometric measures as in the normal mouse in three different groups of animals: (i) genetically altered animals, lacking the nicotinic acetylcholine receptor;(ii) those in which the cholinergic cells have been depleted by intraocular injection of an immunotoxin targeting these neurons;and (iii) those in which cholinergic synaptic inputs have been chronically blocked during development by pharmacological treatment.
In specific aims 3 we will make multi-array recordings from the developing ferret retina, in which neuronal discharges have been perturbed pharmacologically, to define the key features of retinal activity essential for the formation of segregated left and right eye inputs to the dlgn.
In specific aim 4 we will define the role of activity in the growth and elaboration of individual retinogeniculate axons during the time that eye-specific projections are normally formed.
In specific aim 5 we will test the hypothesis that cholinergic inputs from the basal forebrain to the dlgn are essential for the formation of eye-specific retinogeniculate projections. The completion of the 5 specific aims of this proposal will extend and clarify our understanding of how neuronal activity serves to regulate the development of two key features of mammalian RGCs, their dendritic morphologies and eye-specific projections to the dlgn. This information will be useful in devising empirically based treatments of the myriad ontogenetic disorders than adversely impact the human visual system.
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