CA3-SYNGRAM · Synaptic engrams in hippocampal CA3 memory circuits

A fundamental question in neuroscience is how information in brain circuits is stored and retrieved. However, the physical and chemical changes underlying the formation of memories, or “engrams”, are largely elusive. Although recent work identified engram cells, the nanoscopic changes at synapses during engram formation remain unclear. New experimental techniques allow us to probe the subcellular and synaptic components of the engram: functional analysis by multicellular electrophysiology, structural analysis by superresolution light and electron microscopy, and optical recording and stimulation techniques in vivo. Here, we propose to combine these techniques to reveal engrams in the hippocampal CA3 network. This circuit is ideally suited to identify engrams, as it plays a critical role in learning and memory, forms the largest recurrent network throughout the brain, and receives powerful input from hippocampal granule cells, previously defined as engram cells. The project has two main goals. First, we want to identify the physical and chemical changes in the CA3 network during engram formation, especially changes in synaptic transmission and network connectivity. Thus, we will be able to rigorously test cellular, synaptic, and connectomic hypotheses of the engram. Second, we want to probe the rules of synaptic engram storage (“engraphy“), the mechanisms of engram retrieval (“ecphory“), and the behavioral content of the engrams. Hence, we will be able to enrich the classical engram concept with quantitative data on how synaptic engrams are efficiently stored and reliably retrieved. Taken together, the expected results will lead to a substantial increase in our understanding of engrams, advancing it from the cellular to the synaptic level. The proposed experiments will answer a fundamental question in neuroscience and open new avenues for treatment of brain diseases in humans, in which engram formation or retrieval are impaired.