Comprehensive quantification of cone dynamics

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Cone photoreceptors in the retina mediate the vast majority of day-to-day visual percepts in humans, and their responses represent the initial visual signals processed by downstream neurons. As a result, characterizing the response properties of human cone photoreceptors is key to addressing gaps in our knowledge of retinal physiology, and ultimately, the neural basis of human vison. Most studies of mammalian cone electrophysiology have been conducted in vitro. Although this allows extensive control, evidence suggests differences exist in cone behavior under in vivo and in vitro preparations. To approach this issue in vivo, our lab developed a technique in which cone response properties can be elucidated in vivo using single-cone targeted retinal stimulation with an adaptive optics scanning laser ophthalmoscope (AOSLO) in conjunction with physiological recordings from downstream neurons. In addition to using normal single photon stimuli, we will utilize 2-photon stimuli to examine the nature of direct 2-photon stimulation of cone photopigment using the AOSLO system. Though there exists evidence suggesting direct 2-photon stimulation of cones occurs (Palczewska et al. 2014), there remains the possibility that such percepts arise from secondary fluorescence of endogenous retinal fluorophores. By interleaving single and 2-photon stimulation of cones, we will also be able to quantify the differences in light capture between the two stimuli. Data gathered over the course of this project will also be used to examine neural encoding in the optic tract and the lateral geniculate nucleus (LGN) as it relates to psychophysical luminance threshold. Because LGN neurons receive many more spikes than they produce, the LGN must selectively relays certain spikes (Sincich et al. 2007, Rathbun et al. 2010). How the LGN spike patterning at a given stimulus detection probability leads to perceptual threshold is not understood, particularly in response to single cone stimulation. The goal of this proposal is to characterize the response properties of macaque cone photoreceptors in vivo and determine if spike coding in retinal ganglion cells or the LGN set the bounds for human psychophysical luminance threshold performance. In Aim 1, we will use cone-targeted stimuli to measure cone intensity response functions, time course of recovery to a flash, and adaptation to repeated stimuli. By incorporating 2-photon stimuli, we will quantify the extent of indirect excitation of cones when nearby endogenous fluorophores emit light following 2-photon excitation. In Aim 2, analysis of the spike trains recorded in Aim 1 will be used to determine how the neurometric response function relates to psychophysical response functions. The findings of this study will address fundamental gaps in our understanding of neural activity in the early visual system and the mechanisms underlying 2-photon perception.