Molecular control of ensemble dynamics to govern remote memory precision in adult and aged mice

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New memories are encoded in the hippocampus and finally stored in the neocortex. It is widely recognized that communication between the hippocampus and the cortex is important for the consolidation and precision of remote memories. Although, studies suggest synchronized neuronal firing events such as sharp-wave ripples to support hippocampal-cortical communication, the underlying circuit mechanisms are poorly understood. This is partly due to lack of tools to specifically manipulate discrete circuit elements and assess their causal roles in vivo. CA3 and CA1 inhibitory interneurons are thought to be a main source of sharp-wave ripples and dentate granule cells (DGC) connectivity with inhibitory interneurons has been suggested to positively correlate with memory precision. Here, we will leverage a recently developed molecular tool to specifically manipulate DG neuron connectivity with inhibitory interneurons with unprecedented control. In combination with longitudinal in vivo calcium imaging in behaving mice, we will test the hypothesis that increasing DG neuron recruitment of feedforward inhibition (FFI) onto CA3 promotes stabilization of neuronal representations of memories over time. Since excitation-inhibition imbalance in CA3 characterizes age-associated memory impairments, we will also assess the impact of our manipulation in aged mice. The proposed studies will illuminate how an elemental feature of the DG-CA3 circuit, namely FFI, promotes hippocampal-cortical communication and precision of long-term memories.