How neuronal circuitry arises in the brain during ontogeny is a central question in neuroscience. My research seeks to define the molecular mechanisms that govern development of connectivity in the mammalian brain. We have extensively probed the mechanisms of axon guidance and synaptogenesis in normal brain, and are keenly interested in defective functioning of neural genes that perturb connectivity in neuropsychiatric disorders such as autism spectrum disorders (ASDs) and schizophrenia. Our approach has been to create novel mouse genetic models designed to reveal how mutation of specific families of neural adhesion molecules (L1, NCAM) perturbs cortical connectivity and leads to abnormal behavioral responses. Notably, our studies of thalamocortical and retino-collicular development have demonstrated that neural cell adhesion molecule signaling plays a vital role in guiding specific axon populations to appropriate synaptic targets in the brain, essential for neurotransmission, sensory functions, and working memory.
Recently, polymorphisms in the NrCAM gene have been linked with ASDs, a disease associated with mis-wiring and hyperexcitability in the prefrontal cortex. Using novel mouse models for NrCAM loss of function, we showed that NrCAM is vital for normal social behavior and controls topographic connectivity in specific neural pathways. An exciting new finding is that NrCAM is a pivotal component of a receptor signaling complex for the repellent axon guidance cue Semaphorin3F. This complex appears to have dual functions regulating topographic axon guidance in amygdalar circuitry (controlling fear/anxiety and social interactions) as well as spine morphogenesis of cortical pyramidal neurons, which provide ”top-down” control of the fear response. We have generated a conditional NrCAM mutant mouse that will be a valuable new genetic tool for discerning distinct cortical and amygdalar functions underlying development of ADS-related behaviors, and for testing the pro-social neuropeptide oxytocin and its derivatives for ameliorating abnormal responses.
As a member of the Carolina Institute for Developmental Disabilities, NIMH-funded UNC Silvio Conte Center for Schizophrenia Research, and UNC Neuroscience Center, I have engaged in productive collaborations with colleagues dedicated to unraveling the neurodevelopmental mechanisms of connectivity. Our recent studies utilize optogenetic strategies to probe the detailed connectivity and function of neural circuits in mouse models, which have been facilitated by collaborations with UNC electrophysiologists Dr. Garret Stuber, Dr. Paul B. Manis, and Dr. Ben Philpot. In addition we work in coordination with with Dr. Sheryl Moy, Director of the UNC Mouse Behavioral Core Facility, on studies of sociability, working memory, and other behaviors relevant to ASD. I serve as advisor to this core for the Carolina Institute for Developmental DisabilitiesTraining Grant.
We are also members of the UNC Neuroscience Center and Neurobiology Curriculum for Graduate Research. Association with the Neuroscience Center enables us to participate in the Neuroscience Mini-Series, weekly neuroscience seminars, and the annual symposium. Students from the Neurobiology Curriculum and BBSP are invited to rotate in the lab.