Systems and molecular mechanisms of retrieval-dependent memory destabilization

恐惧条件反射是理解大脑如何反应的一个很好的模型系统 威胁。当有机体了解到听觉提示预测危险时，这种现象的形成 情绪记忆需要杏仁核突触的可塑性变化。重要的是， 随后对该记忆的提取和使用涉及到活动依赖型突触 不稳定。记忆失稳在提取过程中的功能意义尚不完全清楚 可以理解，但此过程可能对内存更新和灵活性非常重要。 正常情况下。理解和控制记忆失稳可能开启新的 焦虑症的临床干预途径。我们最近的工作主要集中在 泛素-蛋白酶体系统(UPS)在控制突触稳定性中的关键作用 回想起已有的记忆。虽然杏仁核突触的不稳定有很好的记录， 与控制这一过程的因素有关的数据很少。在这个项目中，我们使用 大鼠记忆提取过程中控制神经活动的光发生沉默和刺激 在量化与不稳定有关的生化信号的同时表现动物 杏仁核。这些信号包括蛋白酶体活性和活性驱动的磷酸化 Rpt6调节亚基。目标1专注于改变特定杏仁核或 关系。Aim 2中的研究评估了前额叶内侧皮质(PL)活动的作用 在触发内存不稳定和解决PL和 杏仁核。在目标3中，我们讨论了腹侧中脑导水管周围灰质的作用及其一些 与杏仁核的相互联系。在这里获得的知识最终可能是 应用于创伤记忆的定向失稳和擦除。

Fear conditioning is an excellent model system for understanding how the brain responds to threat. When organisms learn that an auditory cue predicts danger, the formation of this emotional memory requires plastic changes at synapses in the amygdala. Importantly, the subsequent retrieval and use of this memory involves activity-dependent synaptic destabilization. The functional significance of memory destabilization at retrieval is yet to be fully understood, but this process is likely to be important for memory updating and flexibility under normal conditions. Understanding and control of memory destabilization may open new avenues for clinical interventions in anxiety disorders. Our recent work has focused on the critical role of the ubiquitin-proteasome system (UPS) in controlling synaptic stability when existing memories are recalled. While destabilization is well documented at amygdala synapses, very few data exist related to the factors that control this process. In this project we use optogenetic silencing and stimulation to control neural activity during memory retrieval in behaving animals while quantifying biochemical signals related to destabilization in the amygdala. These signals include proteasome activity and activity-driven phosphorylation of Rpt6 regulatory subunits. Aim 1 is focused on altering activity within specific amygdala nuclei or connections. Studies in Aim 2 assess the role of prelimbic medial prefrontal cortex (PL) activity in triggering memory destabilization and address functional interactions between PL and the amygdala. In Aim 3 we address the role of the ventral periaqueductal gray and some of its reciprocal connections with the amygdala. The knowledge gained here may ultimately be applied to the targeted destabilization and erasure of traumatic memories.