Characterizing learning-induced remodeling of cortical circuitry and computation during the critical period - PROJECT SUMMARY Neuronal plasticity is a fundamental ability for survival, and impaired plasticity underlies numerous neuro- developmental and neurodegenerative disorders, including autism spectrum disorder and Alzheimer's disease. While brain plasticity persists through life, brains are particularly malleable and sensitive to external stimuli during developmental critical periods. Critical period plasticity has been extensively studied using sensory deprivation, which induces dramatic and persistent alterations in circuitry and function, including in humans; however, the impact of sensory enhancement, for instance by learning, remains underexplored. During her postdoctoral work, Dr. Bissen showed that prey capture learning, a complex and ethologically relevant vision-dependent paradigm, enhances visual function and profoundly rewires L5 circuitry in the visual cortex of critical period mice – but not in adult hunters, suggesting that these changes are mediated by critical period-specific mechanisms. The proposed research will recontextualize learning-induced rewiring within its network during the critical period of the visual system and investigate the roles of genetically defined L5 subtypes and their associated circuitry during learning. Depending on their afferents and projections, subtypes of L5 pyramidal neurons, a main output layer of the cortex, are proposed to mediate different phases (i.e. movement preparation or execution) during adult behavior and learning. In Aim 1, Dr. Bissen will assess whether these subtypes play similarly distinct roles during the critical period and will characterize their behavioral contributions to vision-dependent learning and their underlying structural plasticity. Aim 2 will determine the impact of vision-dependent learning on neuronal computation in these neurons, i.e. how they process and integrate their myriads of sensory and non-sensory (e.g. contextual or motivational) inputs into a single firing stream. Finally, Aim 3 will identify the driving forces behind learning-induced changes in L5 neurons by assessing the behavioral and structural contributions of major L5 afferents to vision-dependent learning. Together, these aims will characterize the learning-induced, afferent- specific remodeling of cortical circuitry and computation during the critical period and lay the foundation for a comprehensive model of the mechanisms mediating enhanced plasticity during this window. To complete these aims, the scientific training plan will capitalize on Dr. Bissen’s expertise in structural plasticity and develop crucial skills in novel methods for fine behavioral analysis and cutting-edge dendritic and axonal calcium imaging and computation, thanks to technical and conceptual advice from her advisory committee, Drs. Mark Andermann, Christine Grienberger and Mark Harnett. Dr. Bissen will also benefit from the guidance of her mentor, Dr. Gina Turrigiano, as well as from the highly innovative, collaborative, and supportive neuroscience community at Brandeis. Finally, an extensive and personalized career development plan will focus on honing her communication, mentoring, leadership and lab management skills, to fully prepare Dr. Bissen to lead an independent lab addressing innovative and impactful research questions in the field of neuronal plasticity.
