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

新的记忆在海马体中编码，最后储存在新皮层中。人们普遍认为，海马体和大脑皮层之间的交流对于远程记忆的巩固和精确是重要的。虽然，研究表明同步的神经元放电事件，如锐波波纹，支持海马体-皮层通信，潜在的电路机制尚不清楚。这部分是由于缺乏专门操作离散电路元件和评估其在体内因果作用的工具。CA3和CA1抑制性中间神经元被认为是锐波波纹的主要来源，齿状颗粒细胞（DGC）与抑制性中间神经元的连接被认为与记忆精度呈正相关。在这里，我们将利用最近开发的分子工具，以前所未有的控制特异性地操纵DG神经元与抑制性中间神经元的连接。结合行为小鼠的纵向体内钙成像，我们将验证这样一种假设，即随着时间的推移，增加DG神经元对CA3的前馈抑制（FFI）的招募促进了神经元记忆表征的稳定。由于CA3的兴奋-抑制失衡是年龄相关记忆障碍的特征，我们还将评估我们的操作对老年小鼠的影响。提出的研究将阐明DG-CA3回路的一个基本特征，即FFI，如何促进海马-皮层的交流和长期记忆的准确性。

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.