Posttraining noradrenergic stimulation maintains hippocampal engram reactivation and episodic-like specificity of remote memory

Recent findings indicate that noradrenergic arousal maintains long-term episodic-like specificity of memory. However, the neural mechanism of how norepinephrine can alter the temporal dynamics of systems consolidation to maintain hippocampus dependency of remote memory is currently unknown. Memories are stored within ensembles of neurons that become activated during learning and display strengthened mutual plasticity and connectivity. This strengthened connectivity is believed to guide the coordinated reactivation of these neurons upon subsequent memory recall. Here, we used male transgenic FosTRAP2xtdTomato mice to investigate whether the noradrenergic stimulant yohimbine administered systemically immediately after an episodic-like object-in-context training experience maintained long-term memory specificity which was joined by an enhanced reactivation of training-activated cells within the hippocampus during remote retention testing. We found that saline-treated control mice time-dependently lost their episodic-like specificity of memory, which was associated with a shift in neuronal reactivation from the dorsal hippocampus to the prelimbic cortex at a 14-day retention test. Importantly, yohimbine-treated mice maintained episodic-like specificity of remote memory and retained high neuronal reactivation within the dorsal hippocampus, without a time-dependent increase in prelimbic cortex reactivation. These findings suggest that noradrenergic arousal shortly after training maintains episodic-like specificity of remote memory by strengthening the connectivity between training-activated hippocampal cells during consolidation, and provide a cellular model of how emotional memories remain vivid and detailed.