Stability of synaptic memory engrams

• Applicant: Dr. Alessio Attardo
• Subject Area: Cognitive, Systems and Behavioural Neurobiology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 531274710

Memories are thought to be encoded as enduring physi¬cal changes in the brain. Several studies in murine models have identified subpopulations of neurons throughout various brain regions showing increased neuronal activity during memory formation and shown that manipulation of these cells can induce either artificial retrieval or loss of stored memories. This demonstrates that memory storage and retrieval are mediated by specific populations of neurons which are thus believed to be cellular engrams. Engrams, however, can be identified at different spatial scales, ranging from the systems to the synaptic levels. According to the Hebbian postulate connections between neurons with highly correlated activity patterns are strengthened while connections between neurons whose activity patterns are weakly correlated are depressed or even lost. Increase in synaptic strength between co-active neurons thus increases the likelihood that the same spatial-temporal pattern of neural activity that occurred dur¬ing encoding will occur again at a later time, during retrieval. This hypothesis suggests that synaptic strengthening between coactivated neurons forms the neural substrate of memory, or a synaptic engram. It has recently become possible to label synapses between engram neurons and study their properties, thanks to the Green fluorescent protein Reconstitution Across Synaptic Partners (mGRASP) technique. This technique allows to label with GFP expression synapses between neurons expressing the presynaptic and the postsynaptic mGRASP components. Combining this system with established methods to label engram neurons based on Immediate-Early genes, finally offers the concrete possibility to visualize the engram at the synaptic level. In this project I propose to investigate the stability of structural synaptic engrams in the CA1 by using longitudinal two-photon deep-brain optical imaging in mice. First, We will label structural CA1 synaptic engrams by using mGRASP to highlight synapses between CA3 and CA1 neurons and by using the promoter of the immediate early gene Arc to target the pre- and post-mGRASP constructs to CA3 and CA1 engram neurons. Second, we will employ optical imaging to track the long-term stability of CA1 synaptic fear engrams under baseline, extinction and reinforcement. This will enable us to investigate for the first time the effects of continued learning on structural synaptic engrams.

• DFG Programme: Research Grants