PROJECT SUMMARY - This K08 career development award will facilitate the advancement of Dr. Eric Kaiser as an independent physician-scientist focused on the neural mechanisms of pain from light in migraine and related disorders. He is currently a clinical fellow in headache medicine but will return to the University of Pennsylvania as an Instructor in the Department of Neurology. The career development plan builds upon his prior expertise in rodent behavior while refining essential scientific skills and teaching new technical skills to prepare him for an independent, cutting-edge career in neuroscience. This will be accomplished by gaining hands-on technical experience using tailored light stimuli in rodents, applying mouse genetics to study neurologic disorders, and performing immunohistochemistry to dissect neural circuits. This will be complimented by formal didactics in mouse genetics, ethics, biostatistics, and grant writing. These efforts will be supported by three mentors including Dr. Frances Jensen, a renowned physician-scientist in neural plasticity and network hyperexcitability, Dr. Geoffrey Aguirre, a physician scientist with expertise in visual perception, and Dr. Wenqin Luo, a neuroscientist with expertise in somatosensation. Dr. Kaiser will also work with Dr. Maria Geffen, a neuroscientist at the University of Pennsylvania that will act a consultant on optogenetic techniques. The PI will also greatly benefit from the unparalleled resources and faculty at the University of Pennsylvania and headache experts at the affiliated Children's Hospital of Philadelphia. The objective of this project is to examine the pathologic interaction of the visual and trigeminal sensory systems. Photophobia is a canonical and debilitating feature of migraine, which is a disabling neurologic disorder. Bright light perception involves the cones, which project to the classical retinal ganglion cells (RGCs), and the melanopsin-containing, intrinsically photosensitive RGCs (ipRGCs). Recent human studies by Drs. Kaiser and Aguirre demonstrate that both melanopsin and cone stimulation in isolation and in combination can trigger visual discomfort in individuals with migraine. Dr. Kaiser's central hypothesis is that ipRCG signals potentiate trigeminal activation leading to the aversive perception of light in migraine. To investigate these interactions, the PI proposes to use a mouse model of migraine in which a neuropeptide, calcitonin gene-related peptide (CGRP), induces light aversion. Using tailored light stimuli to isolate cone and melanopsin activity, the PI will test their relative contribution to CGRP-induced light aversion. To establish how trigeminal and retinal signals interact in a migraine-like state, Dr. Kaiser will examine c-fos activation as a marker of neuronal activity in the trigeminal and retinal pathways following CGRP and light stimulation as well as determine if primary trigeminal afferents are required for CGRP-induced light aversion.