ABSTRACT
Autophagy is a lysosomal degradation pathway that maintains cellular homeostasis under basal and
stress conditions by catabolizing cellular constituents to produce energy and building blocks. Although
autophagy is common to all eukaryotic cells, highly specialized cells exploit this pathway to support their
unique physiological functions. One such example is cone photoreceptors, where autophagy promotes
survival during periods of metabolic or light-induced stress. The function of cones as our daytime
photoreceptors depends critically on the rapid recovery of their sensitivity after exposure to bright light, a
process known as dark adaptation. This metabolically-demanding process is driven by the turnover of
chromophore for the regeneration of cone visual pigment and by the resetting of the efficiency of synaptic
transmission between cones and cone bipolar cells. As autophagy is intimately involved in cellular
metabolism, we will test the novel hypothesis that autophagy modulates the cone-driven photopic dark
adaptation. We will perform experiments to determine the physiological conditions that activate autophagy
in cones, focusing on bright light exposure, fasting, and physical exercise. We will also determine the
subcellular compartments in cones where autophagy is upregulated in response to a range of stress
conditions. To investigate the role of autophagy in cone-driven photopic dark adaptation, we will perform
electrophysiological experiments to determine how fasting, exercise, or genetic block of autophagy affect
the recovery of photopic function following exposure to bright light. Finally, we will evaluate two alternative
mechanisms by which autophagy could be modulating photopic dark adaptation, either by accelerating
the turnover of visual chromophore or by enhancing synaptic transmission. These experiments will
establish autophagy as a novel mechanism for regulating the function of mammalian cone photoreceptors
and photopic vision. They will also pave the way for future translational studies with humans seeking to
prevent vision loss and enhance photopic vision by intermittent fasting or exercise.