Biology subjects

Havekes, R.

Publications and source records attributed to Havekes, R..

5 recordsLinked to original sources

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↗

bioRxiv2024

Featural and spatial interference with functionally active and passive items in working memory

Functionally active and passive states in working memory have been related to different neural mechanisms. Memoranda in active states might be maintained by persistent neural firing, whereas memoranda in passive states might be maintained through short-term synaptic plasticity. We reasoned that this might make these items differentially susceptible to interference during maintenance, in particular that passively maintained items might be more robust. To test this hypothesis, we gave our participants a working memory task in which one item was prioritised (active) by always probing it first, while the other item was deprioritised (passive) by always probing it second. In two experiments, on half the trials, we presented an interfering task during memory maintenance, in which the stimuli matched either the feature dimension of the memory items (colour or orientation), or their spatial location. Whether the interfering task appeared on a given trial was unpredictable. In a third experiment where participants were given prior knowledge of the interference condition, and finally in a fourth experiment we used a reward-based prioritisation cue. Across experiments, we found that both active and passive memory items were affected by interference to a similar extent, with overall performance being closely matched in all experiments. We further investigated precision and probability of target response parameters from the standard mixture model, which also showed no differences between states. We conclude that active and passive items, although potentially stored in different neuronal states, do not show differential susceptibility to interference. Public significance statementThe ability to briefly remember information is critical to human cognition. Our so-called working memory is nevertheless rather limited, able to hold only a few items at any one time, and prone to forgetting when we are briefly distracted. Yet, there is reason to believe that not all information in working memory is equally vulnerable. Items that are more passively stored, because they will only be required after some time, might be more resilient to interference. Items that are stored actively, for more immediate recall, might be more easily disrupted. Here, we investigated the effect of an interference task on the retention of both active and passive items in working memory. Our results showed that active and passive items are equally affected by interference, suggesting that resilience in working memory does not depend on the functional state of the items therein.

neuroscience↗

bioRxiv2023

Molecular fingerprints in the hippocampus of alcohol seeking during withdrawal

Alcohol use disorder (AUD) is characterized by excessive alcohol seeking and use. Here, we investigated the molecular correlates of impaired extinction of alcohol seeking using a multidimentional mouse model of AUD. We distinguished AUD-prone and AUD-resistant mice, based on the presence of [≥] 2 or < 2 criteria of AUD and utilized RNA sequencing to identify genes that were differentially expressed in the hippocampus and amygdala of mice meeting [≥] 2 or < 2 criteria, as these brain regions are implicated in alcohol motivation, seeking, consumption and the cognitive inflexibility characteristic of AUD. Our findings revealed dysregulation of the genes associated with the actin cytoskeleton, including actin binding molecule cofilin, and impaired synaptic transmission in the hippocampi of mice meeting [≥] 2 criteria. Overexpression of cofilin in the polymorphic layer of the dentate gyrus (PoDG) inhibited ML-DG synapses, increased motivation to seek alcohol and impaired extinction of alcohol seeking, resembling the phenotype observed in mice meeting [≥] 2 criteria. Overall, our study uncovers a novel mechanism linking increased hippocampal cofilin expression with the AUD phenotype. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/554622v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@14b3fadorg.highwire.dtl.DTLVardef@141b1fdorg.highwire.dtl.DTLVardef@c82b8org.highwire.dtl.DTLVardef@15a16ad_HPS_FORMAT_FIGEXP M_FIG C_FIG

animal behavior and cognition↗

bioRxiv2021

Sleep deprivation reduces the density of individual spine subtypes in a branch-specific fashion in CA1 neurons

Sleep deprivation has a negative impact on hippocampus-dependent memory, which are thought to depend on cellular plasticity. We previously found that five hours of sleep deprivation robustly decreases dendritic spine density in the CA1 area of the hippocampus in adult male mice. However, recent work by others suggests that sleep deprivation increases the density of certain spine types on specific dendritic branches. Based on these recent findings and our previous work, we conducted a more in-depth analysis of different spine types on branches 1, 2 and 5 of both apical and basal dendrites to assess whether five hours of sleep deprivation may have previously unrecognized spine-type and branch-specific effects. This analysis shows no spine-type specific changes on branch 1 and 2 of apical dendrites after sleep deprivation. In contrast, sleep deprivation decreases the number of mushroom and branched spines on branch 5. Likewise, sleep deprivation reduces thin, mushroom, and filopodia spine density on branch 5 of the basal dendrites, without affecting spines on branch 1 and 2. Our findings indicate that sleep deprivation leads to local branch-specific reduction in the density of individual spine types, and that local effects might not reflect the overall impact of sleep deprivation on CA1 structural plasticity. Moreover, our analysis underscores that focusing on a subset of dendritic branches may lead to potential misinterpretation of the overall impact of in this case sleep deprivation on structural plasticity.

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↗