Chemi-Knock: Achieving rapidly inducible loss-of-function in live animal brains during memory consolidation

Memory consolidation is an important process in memory retention, whereby short-term memories are transformed into long-term ones. Memory retention is facilitated when novel or salient experiences occur within 1-2 hours before or after memory encoding. Novelty-induced memory consolidation relies on the locus coeruleus-hippocampus pathway and involves the de novo synthesis of an–as–yet–unidentified group of proteins known as plasticity-related proteins (PRPs) in the hippocampus. These PRPs are thought to play a critical role in memory consolidation by stabilizing synaptic plasticity. However, the precise mechanism through which these newly synthesized PRPs facilitate the consolidation of synaptic plasticity and memory in the hippocampus remains unclear. This uncertainty primarily arises from the limited availability of loss-of-function techniques capable of perturbing the function of the target PRP with a minute temporal resolution and selectively within this memory process. This project aims to develop innovative molecular tool, using chemical-based manipulation, that enable the rapid and precise inactivation of endogenous target proteins in specific cell types during memory consolidation without genetic modification. Specifically, upon a chemical trigger, our new tool is designed to relocate a target PRP from its active site to other subcellular locations within a timeframe of minutes. This relocation can be achieved in specific neuron types in the hippocampus of freely moving rats undergoing memory tasks. To demonstrate the utility of this tool, we have selected activity-regulated cytoskeleton associated protein (ARC), one of the major PRPs, as a model target. Success in this endeavor will not only shed light on the elusive molecular mechanisms of memory consolidation by identifying key PRPs but also potentially reveal new pharmacological targets to improve memory retention. Moreover, the flexible and modular nature of this genetically encoded tool opens the door to its use in a broad range of biological applications beyond memory research. Project Number: 1R21MH138991-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Takanari Inoue (+1 co-PI) | Institution: JOHNS HOPKINS UNIVERSITY, BALTIMORE, MD | Award Amount: $427,625 | Activity Code: R21 | Study Section: Learning, Memory and Decision Neuroscience Study Section[LMDN] View on NIH RePORTER: https://reporter.nih.gov/project-details/11217168