Kang Dae-Si, Koo Ja Wook
Emotion, Cognition and Behavior Research Group, Korea Brain Research Institute, Daegu, 41062, Republic of Korea.
Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, 42988, Republic of Korea.
Mol Brain. 2025 May 19;18(1):45. doi: 10.1186/s13041-025-01216-8.
Fear memory formation is crucial for survival, with the hippocampus playing a central role. This study investigates the behavioral and molecular aspects of fear memory formation, focusing on Dual-specificity tyrosine phosphorylation-regulated kinase 1 A (DYRK1A), a protein known to be critical for cognitive functions. Our results demonstrate that DYRK1A expression in hippocampal CA1 pyramidal neurons is downregulated after contextual fear conditioning (CFC). We also observed a decrease in DYRK1A binding to the Maoa promoter, suggesting its involvement in transcriptional regulation during fear memory formation. In subsequent experiments, we modulated DYRK1A expression using viral vectors. DYRK1A overexpression reduced freezing behavior, while knockdown enhanced it. At the molecular level, DYRK1A overexpression resulted in elevated H3K4me3 levels, while knockdown decreased it. These findings indicate that DYRK1A regulates fear memory formation via epigenetic modifications, altering H3K4me3 levels and influencing Maoa transcription in the hippocampus. This research highlights the nuclear role of DYRK1A and suggests its potential as a therapeutic target for neuropsychiatric disorders related to fear and memory.
恐惧记忆的形成对生存至关重要，海马体起着核心作用。本研究调查了恐惧记忆形成的行为和分子方面，重点关注双特异性酪氨酸磷酸化调节激酶1A（DYRK1A），一种已知对认知功能至关重要的蛋白质。我们的结果表明，在情境恐惧条件反射（CFC）后，海马CA1锥体神经元中DYRK1A的表达下调。我们还观察到DYRK1A与Maoa启动子的结合减少，表明其在恐惧记忆形成过程中参与转录调控。在随后的实验中，我们使用病毒载体调节DYRK1A的表达。DYRK1A过表达减少了僵住行为，而敲低则增强了僵住行为。在分子水平上，DYRK1A过表达导致H3K4me3水平升高，而敲低则降低了该水平。这些发现表明，DYRK1A通过表观遗传修饰调节恐惧记忆的形成，改变H3K4me3水平并影响海马体中Maoa的转录。这项研究突出了DYRK1A的核作用，并表明其作为与恐惧和记忆相关的神经精神疾病治疗靶点的潜力。
