Interregional synaptic maps among engram cells underlie memory formation

Abstract

Memory resides in engram cells distributed across the brain. However, the site-specific substrate within these engram cells remains theoretical, even though it is generally accepted that synaptic plasticity encodes memories. We developed the dual-eGRASP (green fluorescent protein reconstitution across synaptic partners) technique to examine synapses between engram cells to identify the specific neuronal site for memory storage. We found an increased number and size of spines on CA1 engram cells receiving input from CA3 engram cells. In contextual fear conditioning, this enhanced connectivity between engram cells encoded memory strength. CA3 engram to CA1 engram projections strongly occluded long-term potentiation. These results indicate that enhanced structural and functional connectivity between engram cells across two directly connected brain regions forms the synaptic correlate for memory formation.

Brain-wide mapping of contextual fear memory engram ensembles supports the dispersed engram complex hypothesis

“…The concept that a given memory is stored not just in a single engram cell ensemble but in learning-induced enduring changes in functionally connected multiple neuronal ensembles was predicted by Richard Semon ("engram complex") (Semon, 1904) and Donald Hebb ("neurons that fire together wire together") (Hebb, 1949). The experimental evidence for this concept came from an analysis of engram cells from multiple hippocampal subfields and the amygdala (Choi et al, 2018;Redondo et al, 2014;Ryan et al, 2015) and has since been supported by activity mapping studies (DeNardo et al, 2019;Renier et al, 2016;Vetere et al, 2017;Ye et al, 2016).…”

Septal GABAergic Inputs to CA1 Govern Contextual Memory Retrieval

“…In this paradigm, retrieval is reliably inferred from the rapid freezing behavior upon re-exposure, triggering contextspecific signatures at the cell firing 7 or molecular levels 8 . Considerable progress has linked CA1 pyramidal cell activation with afferences in CA3 or entorhinal cortex [9][10][11] , and with downstream circuits in the subiculum 12 or neocortex 13 during contextual recall. However, the hippocampus also receives long-range GABAergic projections from the subcortical medial septum / diagonal band (i.e.…”

Freeze-frame imaging of synaptic activity using SynTagMA

“…Expressing the two halves of split-GFP on the extracellular surface of pre-and postsynaptic neurons (mGRASP) labels contact points between the neurons as green fluorescent puncta (Feinberg et al, 2008). Refined transsynaptic labeling methods with multiple colors have led to remarkable insights about network connectivity (Choi et al, 2018;Macpherson et al, 2015). Whereas mGRASP and eGRASP report anatomical proximity, SynTagMA photoconversion is Ca 2+dependent and therefore sensitive to synaptic activity.…”