Project Abstract This proposal to investigate the impact of the bioenergetically-regulated, metabolic environment on the sensitivity and signaling of retinal ganglion cells blends two converging lines of inquiry. The first arises from evidence that neuronal metabolic stress is accommodated within diverse and complex solutions. The second stems from our extensive knowledge of ganglion cell signaling functions, some of which we now interpret as adaptions to the consequences of fluctuating energy requirements. The focus of this proposal is on identified ganglion cell responses to light and how changes to specific response features are modulated by intrinsic metabolic activity. There is a gap in our understanding of how the different response-forming functions of cellular excitability may be changed during metabolic stress as well as the degree of the consequences of these changes to ganglion cell sensitivity and visual function overall, especially during the pathological conditions that lead to ganglion cell loss. Our investigations will test hypotheses that intersect at the bioenergetic state of the retina and its effects on the signaling of ganglion cells. In Specific Aim 1, we will define how the normal environmental conditions of the outer retina contribute to the response features of ganglion cells. We will test the hypothesis that intrinsic metabolic activity has a key influence on ganglion cell light responses by comparing controlled oxidant modulation of the cells' response waveforms. In Specific Aim 2, we will characterize the oxidant sensitivity of the cells' excitability mechanisms responsible for ganglion cell action potential generation. We will test the hypothesis that the metabolic activity of each ganglion cell and its neighbors influences these signaling mechanisms via oxidant production. In Specific Aim 3, we will examine the net influence of metabolic modulation caused by light intensity changes (contrast adaptation) on ganglion cell output. We will test how the actions of oxidants on specific features of the ganglion cell responses reflect the cell's metabolic state, and how they adjust retinal output in normal and pathophysiological conditions. These proposed studies will further our understanding of the cellular mechanisms that underlie ganglion cell responses and retinal output. Our objectives are consistent with the health-related goals of the National Eye Institute for understanding neuroprotective mechanisms in retinal neurons to prevent neurodegeneration, including that induced by excessive levels of metabolic byproducts, as well as understanding the origin of dysfunctional retinal signals that are detected with clinical tools essential for diagnosing and assessing the progression of retinal disease.