mTORC1-Dependent Signaling in Layer 5b Neurons Is Required for Memory Consolidation

Abstract Memory consolidation relies on activity-dependent neuronal plasticity, particularly in deep-layer cortical neurons that integrate long-range inputs from medial temporal lobe (MTL) structures. In the neocortex, apical tuft dendrites of layer 5b pyramidal neurons receive direct input from the MTL within cortical layer 1, and their activation is critical for associative learning. However, the molecular mechanisms that enable learning-induced plasticity in these neurons remain poorly understood. Here, we demonstrate that activity-dependent, mTORC1-regulated translation in layer 5b neurons contributes to learning and memory. Using in vivo paradigms such as exposure to an enriched environment (EE) and in vitro models of network activation by chemical long-term potentiation (cLTP), combined with cell type-specific translational profiling (RiboTag), we identify candidate mRNAs associated with experience-dependent plasticity. We further show that pharmacological inhibition of canonical mTORC1 signaling during memory-relevant tasks abrogated memory consolidation. Our findings identify the mTORC1 pathway as a central regulator of learning-induced protein translation and cortical plasticity. Competing Interest Statement The authors have declared no competing interest. Footnotes ↵# shared first authorship