In a population of neurons activated by plastic stimuli triggered during memory formation, synaptic inputs cause CREB-dependent transcriptional activation in the nucleus. We first showed that synaptic input not only induces neuroplasticity signals at the synaptic site, but also co-activates activity-dependent neuroplasticity mechanisms linking the synapse and the nucleus, thereby controlling long-term memory and long-term plasticity. Furthermore, by deciphering the synapses-nucleus communication, we have revealed multiple CREB pathways from the synapses to the nucleus and an inverse synaptic tagging mechanism governed by a CREB-target gene Arc. These biological discoveries led to the identification of genomic and protein structural module information responsible for the mechanism of bidirectional coupling between synaptic plasticity and Arc transcriptional plasticity. This led to a technological breakthrough that helped create the next-generation Ca²⁺ indicator suite XCaMP, which can record rapid action potential kinetics, and a synthetic promoter, E-SARE, which labels activated neuronal populations. These innovations in neural circuit measurement and labeling technologies, triggered by the elucidation of Ca²⁺ signaling, now contributes to further elucidating novel in vivo mechanisms of brain function regulation.