Meijer, E. L. | bioRxiv Science

bioRxiv2026

The phosphodiesterase-5 inhibitor vardenafil reverses sleep deprivation-induced amnesia in mice

Sleep deprivation (SD) disrupts memory processes, particularly those dependent on the hippocampus. Six hours of SD after training in a hippocampus-dependent task typically induces amnesia in mice and impairs performance upon memory testing later. However, we previously demonstrated that object-location memories (OLMs) encoded under SD conditions can be recovered several days later, suggesting that these memories were not lost but suboptimally stored. Given that engrams of a specific memory are distributed across multiple functionally connected brain regions, we hypothesized that SD-induced amnesia arises from disrupted network alterations extending beyond the hippocampus. Consistent with this, brain-wide cFos mapping revealed a widespread reduction in cFos in memory associated regions during recall in SD mice and connectivity analysis identified the hippocampus as a central hub in this network. Since cGMP signaling modulates memory processes, we next tested whether the cGMP-specific PDE5 inhibitor vardenafil could restore access to these latent memories. One day after training, vardenafil reversed SD-induced OLM impairment when administered 30 minutes before testing, but this effect was lost when testing occurred several days later. To achieve persistent access to OLMs formed under SD conditions, we combined vardenafil treatment with optogenetic engram stimulation. This combined approach successfully maintained OLM retrievability for several days post-manipulation. Crucially, successful retrieval in these mice was associated with a significant increase in engram cell reactivation within the dorsal dentate gyrus compared to mice that failed to recall. Collectively, these findings provide novel insight into the molecular and network mechanisms underlying SD-induced amnesia and offer a strong rationale for developing targeted PDE5-mediated therapies to reverse SD-related memory deficits. HighlightsO_LISD-induced amnesia is associated with reduced cFos expression within memory-associative circuitry C_LIO_LIThe phosphodiestarase-5-inhibitor vardenafil can be used to restore memory access C_LIO_LICombining optogenetics with vardenafil treatment sustains memory retrieval over several days C_LIO_LISuccessful retrieval reflects increased reactivation of engram cells in the dentate gyrus C_LI

neuroscience↗

bioRxiv2021

Restoring persistent accessibility to memories after sleep deprivation-induced amnesia

It is well established that sleep deprivation after learning impairs hippocampal memory processes and causes amnesia. It is unknown, however, whether it leads to the actual loss of information or merely suppresses the retrievability of this information stored under suboptimal conditions. Here, we reveal that hippocampal memories formed under sleep deprivation conditions can be successfully retrieved multiple days following training using optogenetic memory engram activation or treatment with the clinically-approved phosphodiesterase 4 (PDE4) inhibitor roflumilast. Moreover, when optogenetic memory engram activation and roflumilast treatment were combined two days following training and subsequent sleep deprivation, it resulted in a more persistent memory trace that allowed for natural (i.e., manipulation free) retrieval several days later. Our studies in mice demonstrate that sleep deprivation does not necessarily cause memory loss, but instead leads to the suboptimal storage of information that is difficult to retrieve. We also provide proof of principle that these suboptimally stored memories can be made accessible again far beyond the learning episode and that the clinically-approved PDE4 inhibitor roflumilast may be used to successfully retrieve information thought to be lost.

neuroscience↗