Understanding how memories are formed, stored, and updated in the brain remains a fundamental challenge in neuroscience. Disruptions in these processes contribute to neuropsychiatric disorders like post-traumatic stress disorder (PTSD), where traumatic memories become rigid and uncontrollable. To tackle this, researchers need precise tools to manipulate specific proteins *within* the neurons actively engaged in memory formation, and a deeper understanding of the molecular pathways that enable memories to be flexibly updated.
This project aims to revolutionize our ability to study memory at the molecular level by achieving two interconnected goals:
1. Developing Molecular Tools: We are engineering novel "molecular switches", called conformational integrators, which are genetically encoded modules that can be inserted into specific proteins. Crucially, they act like an "AND gate": the target protein becomes active *only* when the neuron is both illuminated by blue light and experiences the calcium surge associated with neural activity. This provides unprecedented, millisecond-precision control over protein function exclusively in neurons active during defined experiences (e.g. learning). Unlike existing methods, which work slowly at the gene level, our tools directly control protein activity, enabling real-time causal experiments within neural circuits. They also hold potential as ultra-precise "activity recorders" to label these active neurons.
2. Decoding Memory Mechanisms: We are investigating a newly discovered signalling pathway (involving proteins like YTHDC1) that links neuronal activity to changes in gene regulation within the nucleus. Our initial findings revealed that YTHDC1, an RNA-binding protein, plays a critical and unexpected role in memory in excitatory hippocampal neurons. We aim to unravel how this pathway, triggered by neuronal activity, coordinates changes in both RNA processing and chromatin state to allow healthy memory updating.
Expected Impact:
New Research Capabilities: The conformational integrator platform will provide neuroscientists worldwide with a powerful, versatile toolbox to probe the function of any protein in active neurons during behavior with unmatched precision, accelerating discovery across brain research.
Fundamental Insights: Uncovering the YTHDC1 pathway's role in memory offers a completely new molecular explanation for how memories remain adaptable, filling a critical knowledge gap.
Therapeutic Potential: Identifying key molecules like YTHDC1 and its downstream effectors provides novel targets for developing treatments for disorders characterized by maladaptive, inflexible memories, such as PTSD and possibly dementia.
Interdisciplinary Advancements: The work integrates cutting-edge protein engineering, genomics, and behavioral neuroscience, fostering innovation across these fields.
By bridging the gap between precise molecular control and circuit-level memory processes, this research aims to provide fundamental knowledge and powerful new technologies to understand and ultimately treat memory-related brain disorders.
