Neural circuit activity representing sensorimotor experiences trigger molecular mechanisms that drive long-lasting changes in brain circuits underlying learning and memory. Recent advancements in molecular genetics have led to development of rich toolboxes, e.g. optogenetics and CRISPR, that enable precise temporal and cell type-specific control of neural circuit activity and downstream activity-dependent mechanisms. One such molecular mechanism, the organization of three-dimensional (3D) genome architecture, has emerged as a powerful regulator of rapid and coordinated gene expression in response to neural circuit activity. Here, we describe how to perform optogenetic stimulation of granule neurons at the input layer of the cerebellar cortex in mice and how to profile activity-dependent changes in neuronal genome architecture. In addition, we will discuss how to genetically knock out chromatin regulators specifically in granule neurons in adult mice to study the functions of genome organization in activity-dependent gene expression and cerebellar-dependent motor learning.