scholarly journals Eszopiclone and Zolpidem Produce Opposite Effects on Hippocampal Ripple Density

2022 ◽  
Vol 12 ◽  
Author(s):  
Logan A. Becker ◽  
Hector Penagos ◽  
Francisco J. Flores ◽  
Dara S. Manoach ◽  
Matthew A. Wilson ◽  
...  
Keyword(s):  
Memory Consolidation ◽  
Spike Activity ◽  
Pyramidal Cells ◽  
Memory Deficits ◽  
Human Studies ◽  
Sleep Spindles ◽  
Extracellular Recordings ◽  
Neuronal Ensembles ◽  
Ca1 Region ◽  
Spike Firing

Clinical populations have memory deficits linked to sleep oscillations that can potentially be treated with sleep medications. Eszopiclone and zolpidem (two non-benzodiazepine hypnotics) both enhance sleep spindles. Zolpidem improved sleep-dependent memory consolidation in humans, but eszopiclone did not. These divergent results may reflect that the two drugs have different effects on hippocampal ripple oscillations, which correspond to the reactivation of neuronal ensembles that represent previous waking activity and contribute to memory consolidation. We used extracellular recordings in the CA1 region of rats and systemic dosing of eszopiclone and zolpidem to test the hypothesis that these two drugs differentially affect hippocampal ripples and spike activity. We report evidence that eszopiclone makes ripples sparser, while zolpidem increases ripple density. In addition, eszopiclone led to a drastic decrease in spike firing, both in putative pyramidal cells and interneurons, while zolpidem did not substantially alter spiking. These results provide an explanation of the different effects of eszopiclone and zolpidem on memory in human studies and suggest that sleep medications can be used to regulate hippocampal ripple oscillations, which are causally linked to sleep-dependent memory consolidation.

scholarly journals Location of Sialoglycoconjugates Containing the Siaα2–3Gal and Siaα2–6Gal Groups in the Rat Hippocampus and the Effect of Aging on Their Expression

2001 ◽  
Vol 49 (10) ◽  
pp. 1311-1319 ◽  
Author(s):  
Yuji Sato ◽  
Yoshihiro Akimoto ◽  
Hayato Kawakami ◽  
Hiroshi Hirano ◽  
Tamao Endo
Keyword(s):  
Electron Microscopy ◽  
Plasma Membranes ◽  
Pyramidal Cells ◽  
Staining Intensity ◽  
Rat Hippocampus ◽  
Maackia Amurensis ◽  
Ca1 Region ◽  
Old Rats ◽  
Maackia Amurensis Lectin ◽  
Stratum Lacunosum Moleculare

The histochemical distribution of sialoglycoconjugates in the CA1 region in the hippocampus formation of 9-week-old rats and 30-month-old rats was examined using electron microscopy in combination with two lectins, Maackia amurensis lectin, specific for Siaα2–3Gal, and Sambucus sieboldiana agglutinin, specific for Siaα2–6Gal. Each lectin stained the plasma membranes of pyramidal cells, indicating that the Siaα2–3Gal and Siaα2–6Gal groups were expressed on their plasma membranes. These lectins also bound to synapses in the stratum lacunosum moleculare. The staining intensity of the lectins in the synapses in these layers was downregulated in the 30-month-old rats. These results indicated that both the Siaα2–3Gal and Siaα2–6Gal groups are expressed on these synapses and that the expression of these sialyl linkages decreases in the aged brain.

scholarly journals Shining a Light on the Mechanisms of Sleep for Memory Consolidation

2021 ◽  
Author(s):  
Michelle A. Frazer ◽  
Yesenia Cabrera ◽  
Rockelle S. Guthrie ◽  
Gina R. Poe
Keyword(s):  
Rem Sleep ◽  
Neural Activity ◽  
Memory Consolidation ◽  
Strong Support ◽  
Nrem Sleep ◽  
Future Research ◽  
Sleep Spindles ◽  
Slow Oscillations ◽  
Theta Waves ◽  
Learning Tasks

Abstract Purpose of review This paper reviews all optogenetic studies that directly test various sleep states, traits, and circuit-level activity profiles for the consolidation of different learning tasks. Recent findings Inhibiting or exciting neurons involved either in the production of sleep states or in the encoding and consolidation of memories reveals sleep states and traits that are essential for memory. REM sleep, NREM sleep, and the N2 transition to REM (characterized by sleep spindles) are integral to memory consolidation. Neural activity during sharp-wave ripples, slow oscillations, theta waves, and spindles are the mediators of this process. Summary These studies lend strong support to the hypothesis that sleep is essential to the consolidation of memories from the hippocampus and the consolidation of motor learning which does not necessarily involve the hippocampus. Future research can further probe the types of memory dependent on sleep-related traits and on the neurotransmitters and neuromodulators required.

Pharmacologically Increasing Sleep Spindles Enhances Recognition for Negative and High-arousal Memories

2013 ◽  
Vol 25 (10) ◽  
pp. 1597-1610 ◽  
Author(s):  
Erik J. Kaestner ◽  
John T. Wixted ◽  
Sara C. Mednick
Keyword(s):  
Rem Sleep ◽  
Memory Consolidation ◽  
Declarative Memory ◽  
Memory Performance ◽  
Emotional Memory ◽  
Limited Range ◽  
Sleep Spindles ◽  
Sleep Spindle ◽  
Emotional Stimuli ◽  
Valence And Arousal

Sleep affects declarative memory for emotional stimuli differently than it affects declarative memory for nonemotional stimuli. However, the interaction between specific sleep characteristics and emotional memory is not well understood. Recent studies on how sleep affects emotional memory have focused on rapid eye movement sleep (REM) but have not addressed non-REM sleep, particularly sleep spindles. This is despite the fact that sleep spindles are implicated in declarative memory as well as neural models of memory consolidation (e.g., hippocampal neural replay). Additionally, many studies examine a limited range of emotional stimuli and fail to disentangle differences in memory performance because of variance in valence and arousal. Here, we experimentally increase non-REM sleep features, sleep spindle density, and SWS, with pharmacological interventions using zolpidem (Ambien) and sodium oxybate (Xyrem) during daytime naps. We use a full spread of emotional stimuli to test all levels of valence and arousal. We find that increasing sleep spindle density increases memory discrimination (da) for highly arousing and negative stimuli without altering measures of bias (ca). These results indicate a broader role for sleep in the processing of emotional stimuli with differing effects based on arousal and valence, and they raise the possibility that sleep spindles causally facilitate emotional memory consolidation. These findings are discussed in terms of the known use of hypnotics in individuals with emotional mood disorders.

P384 The role of sleep spindles in overnight verbal memory consolidation in temporal lobe epilepsy patients

2017 ◽  
Vol 128 (9) ◽  
pp. e302-e303
Author(s):  
Márta Virág ◽  
Róbert Bódizs ◽  
Ferenc Gombos ◽  
Anna Kelemen ◽  
Dániel Fabó
Keyword(s):  
Temporal Lobe Epilepsy ◽  
Temporal Lobe ◽  
Memory Consolidation ◽  
Verbal Memory ◽  
Sleep Spindles

Hyperexcitability of entorhinal cortex and hippocampus after application of aminooxyacetic acid (AOAA) to layer III of the rat medial entorhinal cortex in vitro

1996 ◽  
Vol 76 (5) ◽  
pp. 2986-3001 ◽  
Author(s):  
H. E. Scharfman
Keyword(s):  
Nmda Receptor ◽  
Evoked Potentials ◽  
Entorhinal Cortex ◽  
Pyramidal Cells ◽  
Aminooxyacetic Acid ◽  
Field Potentials ◽  
Medial Entorhinal Cortex ◽  
Extracellular Recordings ◽  
Extracellular Potentials

1. Injection of aminooxyacetic acid (AOAA) into the entorhinal cortex in vivo produces acute seizures and cell loss in medial entorhinal cortex. To understand these effects, AOAA was applied directly to the medial entorhinal cortex in slices containing both the entorhinal cortex and hippocampus. Extracellular and intracellular recordings were made in both the entorhinal cortex and hippocampus to study responses to angular bundle stimulation and spontaneous activity. 2. AOAA was applied focally by leak from a micropipette or by pressure ejection. Evoked potentials increased gradually within 5 min of application, particularly the late, negative components. Evoked potentials continued to increase for up to 1 h, and these changes persisted for the remainder of the experiment (up to 5 h after drug application). 3. Paired pulse facilitation (100-ms interval) was also enhanced after AOAA application. Increasing stimulus frequency to 1-10 Hz increased evoked potentials further, and after several seconds of such stimulation multiple field potentials occurred. When stimulation was stopped at this point, repetitive field potentials occurred spontaneously for 1-2 min. These recordings, and simultaneous extracellular recordings in different layers, indicated that spontaneous synchronous activity occurred in entorhinal neurons. Intracellularly labeled cortical pyramidal cells depolarized and discharged during spontaneous and evoked field potentials. 4. The effects of AOAA were blocked reversibly by bath application of the N-methyl-D-aspartate (NMDA) receptor antagonist D-amino-5-phosphonovalerate (D-APV; 25 microM) or focal application of D-APV to the medial entorhinal cortex. 5. Simultaneous extracellular recordings from the entorhinal cortex and hippocampus demonstrated that spontaneous synchronous activity in layer III was often followed within several milliseconds by negative field potentials in the terminal zones of the perforant path (stratum moleculare of the dentate gyrus and stratum lacunosum-moleculare of area CA1). The extracellular potentials recorded in the dentate gyrus corresponded to excitatory postsynaptic potentials and action potentials in dentate granule cells. However, extracellular potentials in area CA1 were small and rarely correlated with discharge in CA1 pyramidal cells. 6. The results demonstrate that AOAA application leads to an NMDA-receptor-dependent enhancement of evoked potentials in medial entorhinal cortical neurons, which appears to be irreversible. The potentials can be facilitated by repetitive stimulation, and lead to synchronized discharges of entorhinal neurons. The discharges invade other areas such as the hippocampus, indicating how seizure activity may spread after AOAA injection in vivo. These data suggest that AOAA may be a useful tool to study longlasting changes in NMDA receptor function that lead to epileptiform activity and neurodegeneration.

scholarly journals Selection of stimulus parameters for enhancing slow wave sleep events with a Neural-field theory thalamocortical computational model

2021 ◽  
Author(s):  
Felipe A. Torres ◽  
Patricio Orio ◽  
María-José Escobar
Keyword(s):  
Computational Model ◽  
Slow Wave ◽  
Memory Consolidation ◽  
Closed Loop ◽  
Slow Wave Sleep ◽  
Brain Activity ◽  
Sensory Stimulation ◽  
Sleep Spindles ◽  
Slow Oscillations ◽  
Closed Loop Stimulation

AbstractSlow-wave sleep cortical brain activity, conformed by slow-oscillations and sleep spindles, plays a key role in memory consolidation. The increase of the power of the slow-wave events, obtained by auditory sensory stimulation, positively correlates to memory consolidation performance. However, little is known about the experimental protocol maximizing this effect, which could be induced by the power of slow-oscillation, the number of sleep spindles, or the timing of both events’ co-occurrence. Using a mean-field model of thalamocortical activity, we studied the effect of several stimulation protocols, varying the pulse shape, duration, amplitude, and frequency, as well as a target-phase using a closed-loop approach. We evaluated the effect of these parameters on slow-oscillations (SO) and sleep-spindles (SP), considering: (i) the power at the frequency bands of interest, (ii) the number of SO and SP, (iii) co-occurrences between SO and SP, and (iv) synchronization of SP with the up-peak of the SO. The first three targets are maximized using a decreasing ramp pulse with a pulse duration of 50 ms. Also, we observed a reduction in the number of SO when increasing the stimulus energy by rising its amplitude. To assess the target-phase parameter, we applied closed-loop stimulation at 0º, 45º, and 90º of the phase of the narrow-band filtered ongoing activity, at 0.85 Hz as central frequency. The 0º stimulation produces better results in the power and number of SO and SP than the rhythmic or aleatory stimulation. On the other hand, stimulating at 45º or 90º change the timing distribution of spindles centers but with fewer co-occurrences than rhythmic and 0º phase. Finally, we propose the application of closed-loop stimulation at the rising zero-cross point using pulses with a decreasing ramp shape and 50 ms of duration for future experimental work.Author summaryDuring the non-REM (NREM) phase of sleep, events that are known as slow oscillations (SO) and spindles (SP) can be detected by EEG. These events have been associated with the consolidation of declarative memories and learning. Thus, there is an ongoing interest in promoting them during sleep by non-invasive manipulations such as sensory stimulation. In this paper, we used a computational model of brain activity that generates SO and SP, to investigate which type of sensory stimulus –shape, amplitude, duration, periodicity– would be optimal for increasing the events’ frequency and their co-occurrence. We found that a decreasing ramp of 50 ms duration is the most effective. The effectiveness increases when the stimulus pulse is delivered in a closed-loop configuration triggering the pulse at a target phase of the ongoing SO activity. A desirable secondary effect is to promote SPs at the rising phase of the SO oscillation.

scholarly journals Removal of KCNQ2 from Parvalbumin-expressing Interneurons Improves Anti-Seizure Efficacy of Retigabine

2020 ◽  
Author(s):  
Corrinne Dunbar ◽  
Junzhan Jing ◽  
Alina Sonesra ◽  
Suhyeorn Park ◽  
Heun Soh ◽  
...  
Keyword(s):  
Spike Activity ◽  
Drug Targets ◽  
Spectral Power ◽  
Pyramidal Cells ◽  
Suppressive Effect ◽  
Conditional Knockout ◽  
Heat Sensitivity ◽  
Anticonvulsant Effect ◽  
List Type ◽  
Membrane Excitability

AbstractMost anti-seizure drugs (ASDs) achieve their effects by suppressing neuronal excitability through various drug targets. However, these drug targets are widely expressed in both excitatory and inhibitory neurons. Here, we investigate whether the efficacy of the ASD retigabine (RTG) is altered after removal of the potassium channel subunit KCNQ2, one of its drug targets, from parvalbumin-expressing interneurons (PV-INs). Parvalbumin-Cre (PV-Cre) mice were crossed with Kcnq2-floxed (Kcnq2fl/fl) mice to conditionally delete Kcnq2, the gene encoding KCNQ2, from PV-INs. The efficacy of RTG (10 mg/kg, i.p.) in preventing seizures induced by picrotoxin (PTX, 10 mg/kg, i.p.) and kainic acid (KA, 30mg/kg, i.p.) in conditional knockout mice (cKO, PV-Kcnq2fl/fl) was tested. Immunostaining for KCNQ2 and KCNQ3 and in vitro pharmacological studies with whole-cell recordings were also performed. The cKO mice had no significant change in appearance, body mass, balance, heat sensitivity, depressive behavior, mortality, or EEG spectral power. RTG significantly delayed the onset of PTX- and KA-induced convulsive seizures in cKO mice, but not in wild-type littermates (WT). The expression of both KCNQ2 and KCNQ3 subunits was specifically enriched at the distal axon initial segments (AISs) of hippocampal CA1 PV-INs. In cKO mice, this specific expression and the potassium currents mediated by these subunits were greatly reduced in PV-INs, while their expression in CA1 pyramidal cells (CA1-PCs) remained unchanged. Accordingly, while the ability of RTG to suppress CA1-PC spike activity was unchanged in cKO mice, its suppressive effect on high-frequency spike activity of CA1 PV-INs (elicited by >540pA depolarizing currents) was significantly reduced compared with WT mice. In addition, the RTG-induced suppressive effect on intrinsic membrane excitability of PV-INs in WT mice became absent or decreased in cKO mice. These findings suggest that reducing the suppression of PV-INs by RTG improves its anticonvulsant effect.Key Points(3-5 bullets, no longer than 85 characters each)RTG was effective for seizures only after Kcnq2 was removed from PV-INs.KCNQ2/KCNQ3 was enriched at PV-IN AISs, sites of AP initiation.Kcnq2 removal greatly reduced KCNQ2/KCNQ3 expression and function in CA1 PV-INs.The suppressive effect of RTG on hippocampal PV-INs was blunted in cKO mice.Therefore, the efficacy of RTG may improve with partial sparing of interneurons.

scholarly journals Telencephalic outputs from the medial entorhinal cortex are copied directly to the hippocampus

2021 ◽  
Author(s):  
Sau Yee Tsoi ◽  
Merve Öncül ◽  
Ella Svahn ◽  
Mark Robertson ◽  
Zuzanna Bogdanowicz ◽  
...  
Keyword(s):  
Entorhinal Cortex ◽  
Memory Consolidation ◽  
Memory Storage ◽  
Medial Entorhinal Cortex ◽  
Ca1 Region ◽  
Deep Layers ◽  
Standard Models

AbstractStandard models for memory storage assume that signals reach the hippocampus from superficial layers of the entorhinal cortex (EC) and are returned to the telencephalon by projections from deep layers of the EC. Here we show that telencephalon-projecting cells in Layer 5a of the medial EC send a copy of their outputs back to the CA1 region of the hippocampus. Our results suggest that rather than serving as a relay, deep EC may coordinate hippocampal-neocortical interactions in memory consolidation.

scholarly journals Separable actions of acetylcholine and noradrenaline on neuronal ensemble formation in hippocampal CA3 circuits

2021 ◽  
Vol 17 (10) ◽  
pp. e1009435
Author(s):  
Luke Y. Prince ◽  
Travis Bacon ◽  
Rachel Humphries ◽  
Krasimira Tsaneva-Atanasova ◽  
Claudia Clopath ◽  
...  
Keyword(s):  
Granule Cells ◽  
Mossy Fiber ◽  
Pyramidal Cells ◽  
Recurrent Network ◽  
Memory Storage ◽  
Neuronal Ensembles ◽  
Hippocampal Ca3 ◽  
Ca3 Pyramidal Cells ◽  
Episodic Memories ◽  
Mossy Fiber Pathway

In the hippocampus, episodic memories are thought to be encoded by the formation of ensembles of synaptically coupled CA3 pyramidal cells driven by sparse but powerful mossy fiber inputs from dentate gyrus granule cells. The neuromodulators acetylcholine and noradrenaline are separately proposed as saliency signals that dictate memory encoding but it is not known if they represent distinct signals with separate mechanisms. Here, we show experimentally that acetylcholine, and to a lesser extent noradrenaline, suppress feed-forward inhibition and enhance Excitatory–Inhibitory ratio in the mossy fiber pathway but CA3 recurrent network properties are only altered by acetylcholine. We explore the implications of these findings on CA3 ensemble formation using a hierarchy of models. In reconstructions of CA3 pyramidal cells, mossy fiber pathway disinhibition facilitates postsynaptic dendritic depolarization known to be required for synaptic plasticity at CA3-CA3 recurrent synapses. We further show in a spiking neural network model of CA3 how acetylcholine-specific network alterations can drive rapid overlapping ensemble formation. Thus, through these distinct sets of mechanisms, acetylcholine and noradrenaline facilitate the formation of neuronal ensembles in CA3 that encode salient episodic memories in the hippocampus but acetylcholine selectively enhances the density of memory storage.

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