Hippocampus-dependent Memory Consolidation Research Articles

Mitochondrial dysfunction following repeated administration of alprazolam causes attenuation of hippocampus-dependent memory consolidation in mice.

The frequently repeated administration of alprazolam (Alp), a highly effective benzodiazepine sedative-hypnotic agent, in anxiety, insomnia, and other diseases is closely related to many negative adverse reactions that are mainly manifested as memory impairment. However, the exact molecular mechanisms underlying these events are poorly understood. Therefore, we conducted a proteomic analysis on the hippocampus in mice that received repeated administration of Alp for 24 days. A total of 439 significantly differentially expressed proteins (DEPs) were identified in mice with repeated administration of Alp compared to the control group, and the GO and KEGG analysis revealed the enrichment of terms related to mitochondrial function, cycle, mitophagy and cognition. In vitro experiments have shown that Alp may affect the cell cycle, reduce the mitochondrial membrane potential (MMP) to induce apoptosis in HT22 cells, and affect the progress of mitochondrial energy metabolism and morphology in the hippocampal neurons. Furthermore, in vivo behavioral experiments including IntelliCage System (ICS) and nover object recognition (NOR), hippocampal neuronal pathological changes with HE staining, and the expression levels of brain-deprived neuron factor (BDNF) with immunohistochemistry showed a significant decrease in memory consolidation in mice with repeated administration of Alp, which could be rescued by the co-administration of the mitochondrial protector NSI-189. To the best of our knowledge, this is the first study to identify a link between repeated administration of Alp and mitochondrial dysfunction and that mitochondrial impairment directly causes the attenuation of memory consolidation in mice.

Entorhinal cortical delta oscillations drive memory consolidation

Long-term memories are formed by creating stable memory representations via memory consolidation, which mainly occurs during sleep following the encoding of labile memories in the hippocampus during waking. The entorhinal cortex (EC) has intricate connections with the hippocampus, but its role in memory consolidation is largely unknown. Using cell-type- and input-specific invivo neural activity recordings, here we show that the temporoammonic pathway neurons in the EC, which directly innervate the output area of the hippocampus, exhibit potent oscillatory activities during anesthesia and sleep. Using invivo individual and populational neuronal activity recordings, we demonstrate that a subpopulation of the temporoammonic pathway neurons, which we termed sleep cells, generate delta oscillations via hyperpolarization-activated cyclic-nucleotide-gated channels during sleep. The blockade of these oscillations significantly impaired the consolidation of hippocampus-dependent memory. Together, our findings uncover a key driver of delta oscillations and memory consolidation that are found in the EC.

KHSRP loss increases neuronal growth and synaptic transmission and alters memory consolidation through RNA stabilization

The KH-type splicing regulatory protein (KHSRP) is an RNA-binding protein linked to decay of mRNAs with AU-rich elements. KHSRP was previously shown to destabilize Gap43 mRNA and decrease neurite growth in cultured embryonic neurons. Here, we have tested functions of KHSRP in vivo. We find upregulation of 1460 mRNAs in neocortex of adult Khsrp−/− mice, of which 527 bind to KHSRP with high specificity. These KHSRP targets are involved in pathways for neuronal morphology, axon guidance, neurotransmission and long-term memory. Khsrp−/− mice show increased axon growth and dendritic spine density in vivo. Neuronal cultures from Khsrp−/− mice show increased axon and dendrite growth and elevated KHSRP-target mRNAs, including subcellularly localized mRNAs. Furthermore, neuron-specific knockout of Khsrp confirms these are from neuron-intrinsic roles of KHSRP. Consistent with this, neurons in the hippocampus and infralimbic cortex of Khsrp−/− mice show elevations in frequency of miniature excitatory postsynaptic currents. The Khsrp−/− mice have deficits in trace conditioning and attention set-shifting tasks compared Khsrp+/+ mice, indicating impaired prefrontal- and hippocampal-dependent memory consolidation with loss of KHSRP. Overall, these results indicate that deletion of KHSRP impairs neuronal development resulting in alterations in neuronal morphology and function by changing post-transcriptional control of neuronal gene expression.

0110 Nap-Related Change in Memory Precision may be Related to Slow-Wave Sleep in Early Childhood

Abstract Introduction In early childhood (3-5 years), naps comprise part of children’s 24-hr sleep. Naps support some types of learning (declarative, emotional), enhancing children’s ability to correctly identify previously seen items. During this time, children’s ability to form precise memories also improves, likely due to ongoing hippocampal development and maturation of processes allowing for pattern separation. Whether naps support the ability to form precise memory representations, allowing children to discriminate between previously seen vs. similar but novel items, is unclear. Here, we used a mnemonic similarity task to examine whether daytime naps support children’s recall of specific images more so than a period of wake. Further, we tested whether this nap-related improvement persists across overnight sleep. We hypothesized that task improvement would be associated with slow-wave sleep (SWS), as this stage has been shown to support episodic memory in preschool-aged children. Methods Participants (N=7, 4 females, Mage=56.1 mos) encoded items in the morning, verbally categorizing each image as something they would find “inside” or “outside”. They recalled items at three time points: immediately following encoding, after their nap/wake period, and the following morning after overnight sleep. Recall involved being shown a single image and responding whether it had been previously seen or not. Recall items included targets, foils, and lures. PSG was recorded during the nap and overnight sleep bouts. Results When controlling for age, children forgot fewer target items following a nap than a comparable period of wake (p=.05). Following a nap and overnight sleep, children also exhibited marginally less forgetting of target items than following a period of wake and overnight sleep (p=.102). Lure discrimination index (LDI; false alarm lures minus false alarm foils) did not differ between nap and wake conditions. Change in target recall following the nap was associated with SWS% during the nap (r=.96, p=.01), but not nap duration (p=.27). Conclusion Napping supported children’s ability to recall target items, but not to correctly reject lures, suggesting naps’ benefit towards more generalized memory. Nap SWS% was associated with less forgetting of target items, supporting its role in hippocampal-dependent memory consolidation. Analyses of overnight sleep data and inclusion of more participants may help better elucidate the relationship between preschool children’s sleep and memory development. Support (If Any) NSF BCS 1749280 NIH R21 HD094758 NIH R01 HL111695

P 87 Slow wave sleep of a 90-minute nap relates to hippocampus-dependent spatial memory consolidation

Introduction : The hippocampus is critical for learning and consolidation of behaviourally-relevant spatial information. During spatial learning, spatially-related firing patterns of hippocampal place cells reflecting the subjects‘ location can be detected. It is widely acknowledged that the stabilization of newly encoded memory traces during active system consolidation is promoted by post-learning slow wave sleep (SWS). Here, hippocampal neural sequences are reactivated (“replay”) accompanied by neocortical slow oscillations thereby synchronizing spindle-ripple events originating from hippocampal and thalamic regions. Studies in rodents and humans reported a facilitation of spatial memories after full nights of sleep, in particular in early sleep SWS (i.e., sharp-wave ripples and slow waves). In this ongoing study, we investigated the effect of a 90-min nap on sleep-associated memory consolidation of spatial information. The advantage of an isolated nap condition is the possibility to selectively study the effect of SWS on memory consolidation. Patients & Methods: Forty healthy students between 21 and 32 years were divided into a sleep group (24±1,64 years, 55% female) and a wake group (24±2,68 years, 55% female). For testing spatial learning, the Virtual Water Maze (VWM), a digitalised version of the established Morris Water Maze Test for hippocampus-dependent place learning was used. Here, students had to find a treasure box hidden in the same position on a virtual island. Between learning and the recall sessions of the VWM (90 minutes), students either performed a mid-day nap accompanied by polysomnography (sleep condition) or watched emotionally neutral documentaries (wake condition). The improvement in the recall session was then compared between the groups and the influence of EEG sleep measures was analysed. Results: We found a significant positive correlation between spatial memory consolidation and time spent in SWS (SWS [min]: r=0,612, p=0,004). Accordingly, there was a tendency of a stronger consolidation when amounts of slow oscillations and sleep spindles were higher. When directly compared, there was no significant difference in the various consolidation measures of VWM between the groups . Conclusion: We found that consolidation of hippocampus-dependent spatial memory in a young healthy population was related to longer time spent in SWS as well as the amount of sleep spindles and slow oscillations during NonREM sleep of a 90-minute nap. Our data support the notion that the efficacy of hippocampus-dependent spatial memory consolidation depends on the duration of SWS.

Development of a Novel, Small-Molecule Brain-Penetrant Histone Deacetylase Inhibitor That Enhances Spatial Memory Formation in Mice.

Histone acetylation is a prominent epigenetic modification linked to the memory loss symptoms associated with neurodegenerative disease. The use of existing histone deacetylase inhibitor (HDACi) drugs for treatment is precluded by their weak blood-brain barrier (BBB) permeability and undesirable toxicity. Here, we address these shortcomings by developing a new class of disulfide-based compounds, inspired by the scaffold of the FDA-approved HDACi romidepsin (FK288). Our findings indicate that our novel compound MJM-1 increases the overall level of histone 3 (H3) acetylation in a prostate cancer cell line. In mice, MJM-1 injected intraperitoneally (i.p.) crossed the BBB and could be detected in the hippocampus, a brain region that mediates memory. Consistent with this finding, we found that the post-training i.p. administration of MJM-1 enhanced hippocampus-dependent spatial memory consolidation in male mice. Therefore, MJM-1 represents a potential lead for further optimization as a therapeutic strategy for ameliorating cognitive deficits in aging and neurodegenerative diseases.

Acute pre-learning stress selectively impairs hippocampus-dependent fear memory consolidation: Behavioral and molecular evidence

Despite compelling evidence that stress or stress-related hormones influence fear memory consolidation processes, the understanding of molecular mechanisms underlying the effects of stress is still fragmentary. The release of corticosterone in response to pre-learning stress exposure has been demonstrated to modulate positively or negatively memory encoding and/or consolidation according to many variables such as stress intensity, the emotional valence of the learned material or the interval between stressful episode and learning experience. Here, we report that contextual but not cued fear memory consolidation was selectively impaired in male mice exposed to a 50 min-period of restraint stress just before the unpaired fear conditioning session. In addition to behavioral impairment, acute stress down-regulated activated/phosphorylated ERK1/2 (pERK1/2) in dorsal hippocampal area CA1 in mice sacrificed 60 min and 9 h after unpaired conditioning. In lateral amygdala, although acute stress by itself increased the level of pERK1/2 it nevertheless blocked the peak of pERK1/2 that was normally observed 15 min after unpaired conditioning. To examine whether stress-induced corticosterone overflow was responsible of these detrimental effects, the corticosterone synthesis inhibitor, metyrapone, was administered 30 min before stress exposure. Metyrapone abrogated the stress-induced contextual fear memory deficits but did not alleviate the effects of stress on pERK1/2 and its downstream target phosphorylated CREB (pCREB) in hippocampus CA1 and lateral amygdala. Collectively, our observations suggest that consolidation of hippocampus-dependent memory and the associated signaling pathway are particularly sensitive to stress. However, behavioral normalization by preventive metyrapone treatment was not accompanied by renormalization of the canonical signaling pathway. A new avenue would be to consider surrogate mechanisms involving proper metyrapone influence on both nongenomic and genomic actions of glucocorticoid receptors.

Sleep loss drives acetylcholine- and somatostatin interneuron–mediated gating of hippocampal activity to inhibit memory consolidation

Sleep loss disrupts consolidation of hippocampus-dependent memory. To characterize effects of learning and sleep loss, we quantified activity-dependent phosphorylation of ribosomal protein S6 (pS6) across the dorsal hippocampus of mice. We find that pS6 is enhanced in dentate gyrus (DG) following single-trial contextual fear conditioning (CFC) but is reduced throughout the hippocampus after brief sleep deprivation (SD; which disrupts contextual fear memory [CFM] consolidation). To characterize neuronal populations affected by SD, we used translating ribosome affinity purification sequencing to identify cell type-specific transcripts on pS6 ribosomes (pS6-TRAP). Cell type-specific enrichment analysis revealed that SD selectively activated hippocampal somatostatin-expressing (Sst+) interneurons and cholinergic and orexinergic hippocampal inputs. To understand the functional consequences of SD-elevated Sst+ interneuron activity, we used pharmacogenetics to activate or inhibit hippocampal Sst+ interneurons or cholinergic input from the medial septum. The activation of either cell population was sufficient to disrupt sleep-dependent CFM consolidation by gating activity in granule cells. The inhibition of either cell population during sleep promoted CFM consolidation and increased S6 phosphorylation among DG granule cells, suggesting their disinhibition by these manipulations. The inhibition of either population across post-CFC SD was insufficient to fully rescue CFM deficits, suggesting that additional features of sleeping brain activity are required for consolidation. Together, our data suggest that state-dependent gating of DG activity may be mediated by cholinergic input and local Sst+ interneurons. This mechanism could act as a sleep loss-driven inhibitory gate on hippocampal information processing.

Coupling between slow waves and sharp-wave ripples engages distributed neural activity during sleep in humans.

Hippocampal-dependent memory consolidation during sleep is hypothesized to depend on the synchronization of distributed neuronal ensembles, organized by the hippocampal sharp-wave ripples (SWRs, 80 to 150 Hz), subcortical/cortical slow-wave activity (SWA, 0.5 to 4 Hz), and sleep spindles (SP, 7 to 15 Hz). However, the precise role of these interactions in synchronizing subcortical/cortical neuronal activity is unclear. Here, we leverage intracranial electrophysiological recordings from the human hippocampus, amygdala, and temporal and frontal cortices to examine activity modulation and cross-regional coordination during SWRs. Hippocampal SWRs are associated with widespread modulation of high-frequency activity (HFA, 70 to 200 Hz), a measure of local neuronal activation. This peri-SWR HFA modulation is predicted by the coupling between hippocampal SWRs and local subcortical/cortical SWA or SP. Finally, local cortical SWA phase offsets and SWR amplitudes predicted functional connectivity between the frontal and temporal cortex during individual SWRs. These findings suggest a selection mechanism wherein hippocampal SWR and cortical slow-wave synchronization governs the transient engagement of distributed neuronal populations supporting hippocampal-dependent memory consolidation.

028 Sleep loss disrupts hippocampal memory consolidation via an acetylcholine- and somatostatin interneuron-mediated inhibitory gate

Abstract Introduction Sleep loss profoundly disrupts consolidation of hippocampus-dependent memory. To better characterize effects of learning and sleep loss on the hippocampal circuit, we quantified activity-dependent phosphorylation of ribosomal subunit S6 (pS6) across the dorsal hippocampus of mice. Methods We first measured pS6 throughout the hippocampus after learning (single trial contextual fear conditioning; CFC), and after subsequent sleep or sleep deprivation (SD). To characterize cell populations with activity affected by SD, we used translating ribosome affinity purification (TRAP)-seq to identify cell type-specific transcripts on pS6 ribosomes after SD vs. sleep. We next used pharmacogenetics to mimic the effects of SD, selectively activating hippocampal Sst+ interneurons or cholinergic inputs to hippocampus from the medial septum (MS) while mice slept in the hours following CFC. We also inhibited these neuronal populations to assess effects on memory consolidation. Results We find that pS6 in enhanced in the dentate gyrus (DG) following single-trial CFC, but is reduced throughout the hippocampus after brief SD – a manipulation which disrupts contextual fear memory (CFM) consolidation. Cell type-specific enrichment analysis (CSEA) of these transcripts revealed that hippocampal somatostatin-expressing (Sst+) interneurons, and cholinergic and orexinergic inputs to hippocampus, are selectively activated after SD. We used TRAP targeted to hippocampal Sst+ interneurons to identify cellular mechanisms mediating SD-driven Sst+ interneuron activation. . We find that activation of Sst+ interneurons is sufficient to disrupt CFM consolidation, by gating activity in surrounding pyramidal neurons, while inhibition of Sst+ interneurons enhances memory consolidation. Similarly, pharmacogenetic activation of cholinergic input to hippocampus from the MS disrupted CFM. Inhibition of MS cholinergic neurons promoted CFM consolidation and disinhibited neurons in the DG, increasing pS6 expression among DG granule cells. Conclusion Our data suggest that state-dependent gating of DG activity during SD is mediated by cholinergic input. Together these data provide evidence for an inhibitory gate on hippocampal information processing, which is activated by sleep loss. Support (if any) R01-NS118440 to SJA from NINDS, DP2-MH104119 to SJA from the NIH Director’s Office, and a Human Frontiers Science Program Young Investigator Award

Contrasting Functions of Mitogen- and Stress-activated Protein Kinases 1 and 2 in Recognition Memory and In Vivo Hippocampal Synaptic Transmission

The mitogen-activated protein kinases (MAPK) are major signaling components of intracellular pathways required for memory consolidation. Mitogen- and stress-activated protein kinases 1 and 2 (MSK1 and MSK2) mediate signal transduction downstream of MAPK. MSKs are activated by Extracellular-signal Regulated Kinase 1/2 (ERK1/2) and p38 MAPK. In turn, they can activate cyclic AMP-response-element-binding protein (CREB), thereby modulating the expression of immediate early genes crucial for the formation of long-term memories. While MSK1 has been previously implicated in certain forms of learning and memory, little is known concerning MSK2. Our goal was to explore the respective contribution of MSK1 and MSK2 in hippocampal synaptic transmission and plasticity and hippocampal-dependent recognition memory. In Msk1- and Msk2-knockout mice, we evaluated object and object-place recognition memory, basal synaptic transmission, paired-pulse facilitation (PPF) and inhibition (PPI), and the capacity to induce and sustain long-term potentiation (LTP) in vivo. We also assessed the level of two proteins downstream in the MAPK/ERK1/2 pathway crucial for long-term memory, CREB and the immediate early gene (IEG) Early growth response 1 (EGR1). Loss of Msk1, but not of Msk2, affected excitatory synaptic transmission at perforant path-to-dentate granule cell synapses, altered short-term presynaptic plasticity, impaired selectively long-term spatial recognition memory, and decreased basal levels of CREB and its activated form. LTP in vivo and LTP-induced CREB phosphorylation and EGR1 expression were unchanged after Msk1 or Msk2 deletion. Our findings demonstrate a dissimilar contribution of MSKs proteins in cognitive processes and suggest that Msk1 loss-of-function only has a deleterious impact on neuronal activity and hippocampal-dependent memory consolidation.

Recognition Memory in Noonan Syndrome

Noonan syndrome (NS) and the clinically related NS with multiple lentiginous (NMLS) are genetic conditions characterized by upregulated RAS mitogen activated protein kinase (RAS–MAPK) signaling, which is known to impact hippocampus-dependent memory formation and consolidation. The aim of the present study was to provide a detailed characterization of the recognition memory of children and adolescents with NS/NMLS. We compared 18 children and adolescents affected by NS and NMLS with 22 typically developing (TD) children, matched for chronological age and non-verbal Intelligence Quotient (IQ), in two different experimental paradigms, to assess familiarity and recollection: a Process Dissociation Procedure (PDP) and a Task Dissociation Procedure (TDP). Differences in verbal skills between groups, as well as chronological age, were considered in the analysis. Participants with NS and NSML showed reduced recollection in the PDP and impaired associative recognition in the TDP, compared to controls. These results indicate poor recollection in the recognition memory of participants with NS and NSML, which cannot be explained by intellectual disability or language deficits. These results provide evidence of the role of mutations impacting RAS–MAPK signaling in the disruption of hippocampal memory formation and consolidation.

Pharmacological inhibition of phosphodiesterase 7 enhances consolidation processes of spatial memory

Augmentation of cAMP signaling through inhibition of phosphodiesterases (PDE) is known to enhance plasticity and memory. Inhibition of PDE4 enhances consolidation into memory, but less is known about the role of other cAMP specific PDEs. Here, we tested the effects of oral treatment with a selective inhibitor of PDE7 of nanomolar potency on spatial and contextual memory. In an object location task, doses of 0.3–3 mg/kg administered 3 h after training dose-dependently attenuated time-dependent forgetting in rats. Significant enhancement of memory occurred at a dose of 3 mg/kg with corresponding brain levels consistent with PDE7 inhibition. The same dose given prior to training augmented contextual fear conditioning. In mice, daily dosing before training enhanced spatial memory in two different incremental learning paradigms in the Barnes Maze. Drug treated mice made significantly less errors locating the escape in a probe-test 24 h after the end of training, and they exhibited hippocampal-dependent spatial search strategies more frequently than controls, which tended to show serial sampling of escape locations. Acquisition and short-term memory, in contrast, were unaffected. Our data provide evidence for a role of PDE7 in the consolidation of hippocampal-dependent memory. We suggest that targeting PDE7 for memory enhancement may provide an alternative to PDE4 inhibitors, which tend to have undesirable gastrointestinal side-effects.

Disruption of NREM sleep and sleep-related spatial memory consolidation in mice lacking adult hippocampal neurogenesis

Cellular plasticity at the structural level and sleep at the behavioural level are both essential for memory formation. The link between the two is not well understood. A functional connection between adult neurogenesis and hippocampus-dependent memory consolidation during NREM sleep has been hypothesized but not experimentally shown. Here, we present evidence that during a three-day learning session in the Morris water maze task a genetic knockout model of adult neurogenesis (Cyclin D2−/−) showed changes in sleep macro- and microstructure. Sleep EEG analyses revealed a lower total sleep time and NREM fraction in Cyclin D2−/− mice as well as an impairment of sleep specific neuronal oscillations that are associated with memory consolidation. Better performance in the memory task was associated with specific sleep parameters in wild-type, but not in Cyclin D2−/− mice. In wild-type animals the number of proliferating cells correlated with the amount of NREM sleep. The lack of adult neurogenesis led to changes in sleep architecture and oscillations that represent the dialog between hippocampus and neocortex during sleep. We suggest that adult neurogenesis—as a key event of hippocampal plasticity—might play an important role for sleep-dependent memory consolidation and modulates learning-induced changes of sleep macro- and microstructure.

Loss of Long-Term Potentiation at Hippocampal Output Synapses in Experimental Temporal Lobe Epilepsy.

Patients suffering from temporal lobe epilepsy (TLE) show severe problems in hippocampus dependent memory consolidation. Memory consolidation strongly depends on an intact dialog between the hippocampus and neocortical structures. Deficits in hippocampal signal transmission are known to provoke disturbances in memory formation. In the present study, we investigate changes of synaptic plasticity at hippocampal output structures in an experimental animal model of TLE. In pilocarpine-treated rats, we found suppressed long-term potentiation (LTP) in hippocampal and parahippocampal regions such as the subiculum and the entorhinal cortex (EC). Subsequently we focused on the subiculum, serving as the major relay station between the hippocampus proper and downstream structures. In control animals, subicular pyramidal cells express different forms of LTP depending on their intrinsic firing pattern. In line with our extracellular recordings, we could show that LTP could only be induced in a minority of subicular pyramidal neurons. We demonstrate that a well-characterized cAMP-dependent signaling pathway involved in presynaptic forms of LTP is perturbed in pilocarpine-treated animals. Our findings suggest that in TLE, disturbances of synaptic plasticity may influence the information flow between the hippocampus and the neocortex.

0102 The Relationship Between Overnight Consolidation and Next-Day Learning

Abstract Introduction Contemporary models of sleep-associated consolidation posit that overnight memory processing paves the way for next-day learning in hippocampus. However, the extent to which new hippocampal learning is dependent on overnight consolidation has yet to be investigated. In this study, we compared the impacts of sleep and sleep deprivation on the consolidation and encoding of hippocampus-dependent memories and, importantly, examined whether individual differences in consolidation were associated with individual differences in encoding. Methods Thirty healthy adults (17 females, mean age 20.1±1.65) were trained on a spatial memory task in the evening before a night of sleep or total sleep deprivation (repeated measures). Participants completed a spatial memory test the following morning, and then encoded a novel set of word-image pairs. Two days later (after recovery sleep), memory for the word-image pairs was tested. We predicted that participants’ spatial memory recall would predict performance on the word-image test, suggesting that overnight consolidation lays the groundwork for new encoding in hippocampus. Results Sleep (vs. sleep deprivation) improved spatial memory accuracy the following morning (t(29)=3.93, p<.001, d=0.72) and word-image recall two days later (t(29)=12.19, p<.001, d=2.23), suggesting that sleep facilitated the consolidation and encoding of hippocampus-dependent memories, respectively. However, the benefit of sleep for spatial memory recall was not significantly correlated with the benefit of sleep for word-image encoding (r(28)= 0.01, p=0.971), suggesting that hippocampal encoding was not contingent on foregoing overnight consolidation processes. Conclusion In support of previous findings, overnight sleep improved consolidation and next-day encoding, as compared to an equivalent period of sleep deprivation. However, the present results did not reveal any relationship between an individual’s sleep-associated consolidation and their next-day learning. Support Department of Psychology, University of York scholarship to A.áV.G. Medical Research Council Career Development Award (MR/P020208/1) to S.A.C.

A role for CIM6P/IGF2 receptor in memory consolidation and enhancement.

Cation-independent mannose-6-phosphate receptor, also called insulin-like growth factor two receptor (CIM6P/IGF2R), plays important roles in growth and development, but is also extensively expressed in the mature nervous system, particularly in the hippocampus, where its functions are largely unknown. One of its major ligands, IGF2, is critical for long-term memory formation and strengthening. Using CIM6P/IGF2R inhibition in rats and neuron-specific knockdown in mice, here we show that hippocampal CIM6P/IGF2R is necessary for hippocampus-dependent memory consolidation, but dispensable for learning, memory retrieval, and reconsolidation. CIM6P/IGF2R controls the training-induced upregulation of de novo protein synthesis, including increase of Arc, Egr1, and c-Fos proteins, without affecting their mRNA induction. Hippocampal or systemic administration of mannose-6-phosphate, like IGF2, significantly enhances memory retention and persistence in a CIM6P/IGF2R-dependent manner. Thus, hippocampal CIM6P/IGF2R plays a critical role in memory consolidation by controlling the rate of training-regulated protein metabolism and is also a target mechanism for memory enhancement.

Manipulating neural activity and sleep-dependent memory consolidation

Abstract Sleep contributes actively to the consolidation of many forms of memory. This review describes the neural oscillations of non-rapid eye movement (NREM) sleep, the structures underlying these oscillations and their relation to hippocampus-dependent memory consolidation. A main focus lies on the relation between inter- and intraregional interactions and their electrophysiological representation. Methods for modulating neural oscillations with the intent of affecting memory consolidation are presented.

Training on an Appetitive Trace-Conditioning Task Increases Adult Hippocampal Neurogenesis and the Expression of Arc, Erk and CREB Proteins in the Dorsal Hippocampus.

Adult hippocampal neurogenesis (AHN) plays an essential role in hippocampal-dependent memory consolidation. Increased neurogenesis enhances learning, whereas its ablation causes memory impairment. In contrast, few reports suggest that neurogenesis reduces after learning. Although the interest in exploring the role of adult neurogenesis in learning has been growing, the evidence is still limited. The role of the trace- and delay-appetitive-conditioning on AHN and its underlying mechanism are not known. The consolidation of trace-conditioned memory requires the hippocampus, but delay-conditioning does not. Moreover, the dorsal hippocampus (DH) and ventral hippocampus (VH) may have a differential role in these two conditioning paradigms. Here, we have investigated the changes in: (A) hippocampal cell proliferation and their progression towards neuronal lineage; and (B) expression of Arc, Erk1, Erk2, and CREB proteins in the DH and VH after trace- and delay-conditioning in the rat. The number of newly generated cells significantly increased in the trace-conditioned but did not change in the delay-conditioned animals compared to the control group. Similarly, the expression of Arc protein significantly increased in the DH but not in the VH after trace-conditioning. Nonetheless, it remains unaltered in the delay-conditioned group. The expression of pErk1, pErk2, and pCREB also increased in the DH after trace-conditioning. Whereas, the expression of only pErk1 pErk2 and pCREB proteins increased in the VH after delay-conditioning. Our results suggest that appetitive trace-conditioning enhances AHN. The increased DH neuronal activation and pErk1, pErk2, and pCREB in the DH may be playing an essential role in learning-induced cell-proliferation after appetitive trace-conditioning.

Elucidating the role of protein synthesis in hippocampus‐dependent memory consolidation across the day and night

It is widely acknowledged that de novo protein synthesis is crucial for the formation and consolidation of long‐term memories. While the basal activity of many signaling cascades that modulate protein synthesis fluctuates in a circadian fashion, it is unclear whether the temporal dynamics of protein synthesis‐dependent memory consolidation vary depending on the time of day. More specifically, it is unclear whether protein synthesis inhibition affects hippocampus‐dependent memory consolidation in rodents differentially across the day (i.e., the inactive phase with an abundance of sleep) and night (i.e., the active phase with little sleep). To address this question, male and female C57Bl6/J mice were trained in a contextual fear conditioning task at the beginning or the end of the light phase. Animals received a single systemic injection with the protein synthesis inhibitor anisomycin or vehicle directly, 4, 8 hr, or 11.5 hr following training, and memory was assessed after 24 hr. Here, we show that protein synthesis inhibition impaired the consolidation of context–fear memories selectively when the protein synthesis inhibitor was administered at the first three time points, irrespective of timing of training. Even though the basal activity of signaling pathways regulating de novo protein synthesis may fluctuate across the 24‐hr cycle, these results suggest that the temporal dynamics of protein synthesis‐dependent memory consolidation are similar for day‐time and night‐time learning.