Thalamus control of memory engram storage in the retroplenial cortex – ThalaGram

Current views on systems memory consolidation posit that long-term memories are reliant on the neocortex. However, the circuit-level and cellular mechanisms allowing to allocate these memories to specific cortical neural assemblies, the so-called engram cells, are still elusive. Recent data indicate that anterior thalamic nuclei (ATN) functionally connect the hippocampal formation with the retrosplenial cortex (RSC), which is thought to act as a permanent repository for remote memories. In ThalaGram, we propose that a dynamic interplay between the ATN and the RSC is required for the formation of cortical engram cells. To test this functional hypothesis, we have built a 3-partner consortium within Bordeaux Neurocampus with complementary expertise aimed at addressing the functional dynamics of thalamocortical interactions during the course of memory formation. We will first clarify the functional architecture of the ATN-RSC circuit by revealing the cellular identity of cortical cells contacted by thalamic inputs and their synaptic and cellular properties, as well as the returning connections from cortical layer 5/6 neurons to the ATN. We will pay special attention to presynaptic plasticity at the output ATN-RSC synapses and take advantage of a mouse model to conditionally suppress synaptic facilitation, therefore targeting selectively information transfer at cortico-thalamic connections. We will next systematically assess the effects of specific acute/opto- or chronic/chemogenetic inhibition of projection-defined ATN and RSC neurons at each phase (encoding, consolidation, retrieval) of a contextual fear paradigm. We will then track the formation of cortical engram cells and will address how they connect with the ATN by using genetically encoded activity reporters. Finally, we will question how new contextual memories can be assimilated into existing knowledge by relying on an innovative behavioral paradigm enabling the animal to form pre-existing cortical mental schemas. We will address the contribution of ATN-RSC interactions in this process and explore whether thalamic inputs influence the content (gist-like or richly detailed) of the cortical memory being retrieved. Altogether, we hope to unravel a novel role for the ATN-RSC circuit in the dynamics of memory engram formation and organization.