In nature, fear memory represents one of the most highly conserved mechanisms across species, enabling animals to recognize and avoid environmental cues associated with potential threats or harmful conditions [1]. This essential adaptive function plays a critical role in survival and has been extensively studied, providing profound insights into the molecular and neural circuits involved in fear memory.

The hippocampus is a pivotal brain region involved in fear memory formation, consolidation, and retrieval [2]. It serves as an integrative hub that processes contextual information and interacts dynamically with other regions, such as the amygdala and prefrontal cortex to regulate cognitive and emotional responses. Emerging evidence suggests that hippocampal gene expression plays a crucial role in modulating its functional capacity, particularly in learning and memory.

DYRK1A has been implicated in various biological processes, including neuronal development and synaptic plasticity. In the hippocampus, DYRK1A plays a critical role in regulating neural activity and synaptic plasticity, influencing long-term potentiation and CFC [3]. Recent studies have linked DYRK1A to cognitive functions, suggesting its potential role in learning and memory. Notably, transcriptomic analysis (GSE214838) reveals that DYRK1A expression is downregulated in the hippocampus following fear conditioning, indicating a possible involvement in memory formation [4, 5].

Cognitive functions, including memory formation, are significantly influenced by epigenetic mechanisms, particularly histone modifications that regulate gene expression [6, 7]. DYRK1A is known to phosphorylate the C-terminal domain of RNA polymerase II, a critical step for transcriptional elongation, indicating its involvement in gene regulation. Given that histone methylation, particularly H3K4me3, serves as a key epigenetic marker linked to transcriptional elongation and memory formation, DYRK1A may modulate chromatin dynamics to influence transcription [8, 9].

We found that DYRK1A regulates transcription of genes involved in neurotransmitter metabolism, supporting this hypothesis. Specifically, our study reveals that DYRK1A binding to the monoamine oxidase A (MAOA) promoter, a key enzyme involved in the metabolism of monoamine neurotransmitters such as serotonin and norepinephrine, regulates gene expression critical for emotional learning and behavior. Given that MAOA deficiency leads to elevated monoamine levels and enhanced fear memory formation [10], DYRK1A may play a role in modulating synaptic plasticity through epigenetic mechanisms. Our results revealed a significant decrease in DYRK1A binding at the MAOA promoter following CFC, indicating that DYRK1A may regulate chromatin accessibility and influence MAOA expression, potentially impacting fear memory formation through modulation of neurotransmitter metabolism. However, the specific role of DYRK1A in epigenetic regulation during fear memory formation remains largely unexplored. This study aims to elucidate the role of DYRK1A in fear memory formation by examining its molecular functions in chromatin remodeling and gene transcription.