The Modulation by the Locus Coeruleus of Recent and Remote Memory Retrieval is Activity-Dependent

The hippocampus plays a crucial role in acquiring, storing, and retrieving associative experience. Whereas neuromodulatory control of the hippocampus by the locus coeruleus (LC) enhances memory acquisition and consolidation, less is known about its influence on memory retrieval. The LC fires at tonic (0.5-8 Hz) and phasic frequencies (10-25 Hz), relative to arousal and affective states. Here, we explored to what extent LC stimulation at different frequencies (2-100 Hz) and respective stimulation patterns, before retrieval of recently acquired or remote spatial memory, alter working memory (WM) or reference memory (RM) in male rats. Here, animals learned a spatial memory task in an eight-arm radial maze over a period of 15 days. LC stimulation before recent memory testing did not affect WM. However, LC stimulation at 20 or 100 Hz, but not 5-10 Hz, impaired retrieval of recently consolidated RM. These frequency-dependent impairments were abolished by intracerebral β-adrenergic receptor (β-AR), but not D1/D5 receptor, antagonism. When memory retrieval was assessed 4 weeks after initial consolidation (Day 34), RM was significantly impaired compared to the final day of recent memory testing (on Day 6). RM was not altered by LC stimulation before remote memory retrieval. However, LC stimulation at 2-100 Hz improved WM. Taken together, these data suggest that frequency-dependent NA release from the LC disrupts retrieval of recently acquired RM via activation of β-AR. Strikingly, increasing LC activity in general improves WM of a remotely acquired spatial learning task, assessed 4 weeks after the recent memory testing, suggesting that the increased effort of sustaining WM of a task learned in the past requires higher LC engagement.