How do we distinguish motion in the world from similar retinal image displacements due to eye movements? This problem has special importance in diseases such as vertigo and a variety of spatial orientation disorders, where deficits in motion perception—including the suppression of self-motion—lead to devastating conse- quences. Impaired balance and motion perception substantially impact people’s daily lives, hindering spatial judgments and impeding performance during bodily motion tasks, such as ambulating or driving a vehicle. Until we know how the brain differentiates self-motion from external motion, we will be unable to develop therapeutic advances to address such disorders. Pioneering research in the 1960's - 90's—indeed the first published awake non-human primate (NHP) vision study—asked whether early cortical neurons discerned ocular from external motion, with the majority concluding that primary visual cortex (V1) neurons responded similarly to either type of motion. These studies used different tasks for self-generated vs external motion conditions, however, meaning that the respective neural responses evoked by either motion were not directly comparable. Thus, no research to date has developed a model for how neurons in V1 respond to external vs. self-generated motion. Recent work from the MPIs' labs, and others, has begun to use novel methods to directly compare self- vs real-motion responses in V1. We propose a transformative study to leverage these new techniques to evaluate the responses of V1 neurons to saccadic eye movements of all sizes under equivalent stimuli motions, with directly comparable viewing tasks in all conditions, in all layers of V1 simultaneously, and to develop a model that links the specific contributions of V1 circuits to perception. Our preliminary data suggests that V1 neurons can differentiate be- tween self-generated and external motion, driving our hypotheses: 1) V1 neurons distinguish between self- generated ocular motion vs. external retinal image motion, 2) an inhibitory feedback signal occurs during re- sponses to self-generated motion to drive the discrimination process, and 3) V1 responses to eye movements interact with responses driven by external motion in a nonlinear—though predictable—fashion, leading to both physiological and perceptual effects on the detection of retinal motion. By comparing neurophysiological re- sponses directly to perception in behaving NHPs, we will determine the contribution of V1 neurons to discerning external vs self-generated motion, as well as the provenance of any feedback (and/or perhaps feedforward) signals, using laminar analysis. These studies will establish the contributions of signals arriving to (or arising within) different V1 layers, so as to dissociate external vs self- motion. We will create quantitative models (based on our previously established models) using the new ground truth measurements from the proposed research, to determine the precise neural and ...