Department of Neurobiology and Anatomy; W.M. Keck Center for the Neurobiology of Learning and Memory; The University of Texas Medical School at Houston, Houston, Texas, United States of America.
Center for Neural Science, New York University, New York City, New York, United States of America.
PLoS Comput Biol. 2022 Jun 27;18(6):e1010239. doi: 10.1371/journal.pcbi.1010239. eCollection 2022 Jun.
Key features of long-term memory (LTM), such as its stability and persistence, are acquired during processes collectively referred to as consolidation. The dynamics of biological changes during consolidation are complex. In adult rodents, consolidation exhibits distinct periods during which the engram is more or less resistant to disruption. Moreover, the ability to consolidate memories differs during developmental periods. Although the molecular mechanisms underlying consolidation are poorly understood, the initial stages rely on interacting signaling pathways that regulate gene expression, including brain-derived neurotrophic factor (BDNF) and Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα) dependent feedback loops. We investigated the ways in which these pathways may contribute to developmental and dynamical features of consolidation. A computational model of molecular processes underlying consolidation following inhibitory avoidance (IA) training in rats was developed. Differential equations described the actions of CaMKIIα, multiple feedback loops regulating BDNF expression, and several transcription factors including methyl-CpG binding protein 2 (MeCP2), histone deacetylase 2 (HDAC2), and SIN3 transcription regulator family member A (Sin3a). This model provides novel explanations for the (apparent) rapid forgetting of infantile memory and the temporal progression of memory consolidation in adults. Simulations predict that dual effects of MeCP2 on the expression of bdnf, and interaction between MeCP2 and CaMKIIα, play critical roles in the rapid forgetting of infantile memory and the progress of memory resistance to disruptions. These insights suggest new potential targets of therapy for memory impairment.
长期记忆（LTM）的主要特征，例如其稳定性和持久性，是在被统称为巩固的过程中获得的。巩固过程中生物变化的动态是复杂的。在成年啮齿动物中，巩固表现出明显的时期，在此期间，记忆痕迹或多或少不易受到破坏。此外，在发育期间，巩固记忆的能力也不同。尽管巩固的分子机制尚不清楚，但初始阶段依赖于相互作用的信号通路，这些信号通路调节基因表达，包括脑源性神经营养因子（BDNF）和 Ca2+/钙调蛋白依赖性蛋白激酶 IIα（CaMKIIα）依赖性反馈环。我们研究了这些途径如何有助于巩固的发育和动态特征。开发了一种用于描述大鼠抑制回避（IA）训练后巩固分子过程的计算模型。微分方程描述了 CaMKIIα 的作用、调节 BDNF 表达的多个反馈环，以及几种转录因子，包括甲基化-CpG 结合蛋白 2（MeCP2）、组蛋白去乙酰化酶 2（HDAC2）和 SIN3 转录调节因子家族成员 A（Sin3a）。该模型为婴儿记忆的快速遗忘和成人记忆巩固的时间进展提供了新的解释。模拟预测，MeCP2 对 bdnf 表达的双重影响，以及 MeCP2 和 CaMKIIα 之间的相互作用，在婴儿记忆的快速遗忘和记忆对破坏的抵抗力的进展中起着关键作用。这些见解为记忆障碍的治疗提供了新的潜在靶点。
