ProjThe human brain is characterized by dense neuronal connectivity, protracted maturation, and unique circuit architecture. These features are thought to be critical for our higher cognitive functions, but may also uniquely contribute to the pathology of neuropsychiatric and neurodevelopmental disorders in humans. However, how these human-specific traits of neuronal connectivity affect the function of neuronal circuits remains unknown. Interestingly, the candidate?s rich preliminary work shows that the human-specific gene SRGAP2C induces human-specific traits in neuronal circuit organization in mice. By studying SRGAP2C and building on these findings, the candidate will leverage this unique opportunity to investigate the yet unknown impact of human-specific gene expression on neuronal circuit function. The candidate will train to use wide-field optical mapping, 2-photon microscopy, and optogenetics, to investigate in vivo how SRGAP2C affects circuit function cortex-wide and at a cellular level. Finally, using a sensory-discrimination task, the candidate will test whether SRGAP2C-mediated changes in circuit architecture affect behavior and learning. Candidate and career goals: The candidate has a strong background in molecular and cellular neurobiology, having spent his PhD studying the mechanisms underlying neuronal circuit formation. Dr. Schmidt has a deep interest in understanding the mechanisms that shape neuronal circuit architecture. His long-term career goal is to establish an independent laboratory focused on uncovering the relationship between neuronal circuit structure, function, and behavior. He is particularly interested in determining the mechanisms underlying unique aspects of human brain development and evolution. His unpublished work has already revealed remarkable effects of the human-specific genetic modifier SRGAP2C on neuronal circuit organization. The goal of this proposal is to uncover the role SRGAP2C plays in regulating cortical circuit function and behavioral performance. Career development plan: The candidate will work with two internationally renowned mentors, Drs. Franck Polleux and Rui Costa. Dr. Polleux is an expert in using genetic, molecular, cellular, and imaging techniques to study cortical connectivity. Dr. Costa is an expert in combining in vivo microscopy and optogenetics with behavioral approaches. In addition, the candidate has assembled a unique team of collaborators, consisting of Drs. Elizabeth Hillman, Randy Bruno, and Darcy Peterka, who will be instrumental in training him in the use of in vivo microscopy and setting up the sensory-discrimination task. The candidate?s excellent mentors and collaborators will advise and guide him in both his research and his transition towards an independent career. As part of the neuroscience community of Columbia University, Dr. Schmidt will work within an exceptional research environment. He will benefit from excellent facilities and all needed equipment for the proposed research. Moreover, he will work in a highly supportive training setting that offers extensive opportunities to present and receive feedback on his research, and resources for transitioning to an independent research career.
SRGAP2C is a human-specific gene that regulates neuronal circuit architecture, but it remains unknown how it impacts the functional properties of neuronal circuits. Using a multimodal in vivo imaging approach, this proposal aims to uncover how SRGAP2C controls neuronal circuit function, and consequently affects cognition and behavior. Results obtained in this study will provide novel insights into the role human-specific genes such as SRGAP2C modify the functional properties of cortical circuits, and ultimately provide insight into how these genes may contribute to the pathophysiology of neuropsychiatric and neurodevelopmental disorders in humans.
