Sepahvand Tayebeh, Qin Tian, Hasan Zia, Power Kyron D, Carew Samantha J, Nazari Negar, Janes Alyssa M, Salman Ali, Xia Yue, Benoukraf Touati, Yuan Qi
Biomedical Sciences, Faculty of Medicine, Memorial University, St. John's, NL, A1B 3V6, Canada.
Commun Biol. 2025 Jun 2;8(1):846. doi: 10.1038/s42003-025-08287-2.
Fear, while crucial for survival, is a component of a myriad of psychiatric illnesses in its extreme. Persistent fear memories can form through processes such as second-order conditioning (SOC), during which a second-order conditioned stimulus (CS2) acquires significance by associating with a first-order conditioned stimulus (CS1). The neural circuitry underlying SOC, particularly the roles of sensory cortices, remains poorly understood. Here we explore the mechanisms of olfactory SOC in rats, focusing on the basolateral amygdala (BLA) and posterior piriform cortex (pPC). Our results demonstrate that NMDAR-dependent plasticity in both regions is essential for SOC. The BLA mediates the CS2-CS1 association, while the pPC, receiving inputs from the locus coeruleus and BLA, is critical for memory acquisition and retrieval. Single-nucleus multiomics analysis of Fos ensembles in both regions reveals distinct yet overlapping gene activation profiles in excitatory neurons, accompanied by global chromatin remodeling. These findings highlight the specific yet coordinated roles of these structures in supporting learning and memory.
恐惧虽然对生存至关重要，但在极端情况下却是众多精神疾病的一个组成部分。持续性恐惧记忆可通过二阶条件作用（SOC）等过程形成，在此过程中，二阶条件刺激（CS2）通过与一阶条件刺激（CS1）关联而获得意义。SOC背后的神经回路，尤其是感觉皮层的作用，仍知之甚少。在这里，我们探索大鼠嗅觉SOC的机制，重点关注基底外侧杏仁核（BLA）和梨状后皮质（pPC）。我们的结果表明，这两个区域中依赖NMDAR的可塑性对于SOC至关重要。BLA介导CS2-CS1关联，而接受来自蓝斑和BLA输入的pPC对于记忆获取和检索至关重要。对这两个区域中Fos集落的单核多组学分析揭示了兴奋性神经元中不同但重叠的基因激活谱，并伴有全局染色质重塑。这些发现突出了这些结构在支持学习和记忆方面的特定但协调的作用。
