It is widely accepted that experience-dependent plasticity is required for memory formation. However, underlying transcriptional and epigenetic changes are poorly understood.This project aims to deepen our understanding of the gene regulatory dynamics underpinning memory formation and how it is orchestrated with synaptic plasticity.To this end, we first characterized the immediate early genes (IEGs) and the secondary response genes (SRGs) at several time points after aversive learning from FACS-isolated cFOS-expressing mouse amygdalar nuclei. We performed RNA-seq to investigate the experience-dependent IEGs-SRGs cascade. As a control for the learning experience, a group of mice was presented to tone only.Next, to understand how epigenetic mechanisms of gene regulatory elements are coupled with synaptic plasticity, we combine single-cell Multiome (i.e., RNA-seq and ATAC-seq) with synapse-specific manipulation. We enhanced the synaptic strength by optical high-frequency stimulation (HFS) of the thalamic and cortical inputs to the amygdala in behaving animals. We verified with in vivo electrophysiology that our HFS protocol induced long-term potentiation in the amygdala neurons. This approach allows us to compare the IEGs-SRGs cascade induced by synapse-specific potentiation to the cascade induced by aversive learning in a cell-type-specific manner. Furthermore, we aim to specifically manipulate target genes that emerged from our genomics analysis to provide causal links between gene regulatory changes and synaptic plasticity in aversive memory formation. Our multidisciplinary approach combining single-cell genomics and optogenetic synapse-specific manipulation will expand our understanding of how memory is formed by orchestrating gene regulation and synaptic plasticity.