Hippocampal cholecystokinin-expressing interneurons regulate temporal coding and contextual learning.

Cholecystokinin-expressing interneurons (CCKIs) are hypothesized to shape pyramidal cell-firing patterns and regulate network oscillations and related network state transitions. To directly probe their role in the CA1 region, we silenced their activity using optogenetic and chemogenetic tools in mice. Opto-tagged CCKIs revealed a heterogeneous population, and their optogenetic silencing triggered wide disinhibitory network changes affecting both pyramidal cells and other interneurons. CCKI silencing enhanced pyramidal cell burst firing and altered the temporal coding of place cells: theta phase precession was disrupted, whereas sequence reactivation was enhanced. Chemogenetic CCKI silencing did not alter the acquisition of spatial reference memories on the Morris water maze but enhanced the recall of contextual fear memories and enabled selective recall when similar environments were tested. This work suggests the key involvement of CCKIs in the control of place-cell temporal coding and the formation of contextual memories.

Hippocampal ripples coincide with "up-state" and spindles in retrosplenial cortex.

During NREM sleep, hippocampal sharp-wave ripple (SWR) events are thought to stabilize memory traces for long-term storage in downstream neocortical structures. Within the neocortex, a set of distributed networks organized around retrosplenial cortex (RS-network) interact preferentially with the hippocampus purportedly to consolidate those traces. Transient bouts of slow oscillations and sleep spindles in this RS-network are often observed around SWRs, suggesting that these two activities are related and that their interplay possibly contributes to memory consolidation. To investigate how SWRs interact with the RS-network and spindles, we combined cortical wide-field voltage imaging, Electrocorticography, and hippocampal LFP recordings in anesthetized and sleeping mice. Here, we show that, during SWR, "up-states" and spindles reliably co-occur in a cortical subnetwork centered around the retrosplenial cortex. Furthermore, retrosplenial transient activations and spindles predict slow gamma oscillations in CA1 during SWRs. Together, our results suggest that retrosplenial-hippocampal interaction may be a critical pathway of information exchange between the cortex and hippocampus.

Rescue of sharp wave-ripples and prevention of network hyperexcitability in the ventral but not the dorsal hippocampus of a rat model of fragile X syndrome.

Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder characterized by intellectual disability and is related to autism. FXS is caused by mutations of the fragile X messenger ribonucleoprotein 1 gene (Fmr1) and is associated with alterations in neuronal network excitability in several brain areas including hippocampus. The loss of fragile X protein affects brain oscillations, however, the effects of FXS on hippocampal sharp wave-ripples (SWRs), an endogenous hippocampal pattern contributing to memory consolidation have not been sufficiently clarified. In addition, it is still not known whether dorsal and ventral hippocampus are similarly affected by FXS. We used a Fmr1 knock-out (KO) rat model of FXS and electrophysiological recordings from the CA1 area of adult rat hippocampal slices to assess spontaneous and evoked neural activity. We find that SWRs and associated multiunit activity are affected in the dorsal but not the ventral KO hippocampus, while complex spike bursts remain normal in both segments of the KO hippocampus. Local network excitability increases in the dorsal KO hippocampus. Furthermore, specifically in the ventral hippocampus of KO rats we found an increased effectiveness of inhibition in suppressing excitation and an upregulation of α1GABAA receptor subtype. These changes in the ventral KO hippocampus are accompanied by a striking reduction in its susceptibility to induced epileptiform activity. We propose that the neuronal network specifically in the ventral segment of the hippocampus is reorganized in adult Fmr1-KO rats by means of balanced changes between excitability and inhibition to ensure normal generation of SWRs and preventing at the same time derailment of the neural activity toward hyperexcitability.

Trajectories through semantic spaces in schizophrenia and the relationship to ripple bursts.

Human cognition is underpinned by structured internal representations that encode relationships between entities in the world (cognitive maps). Clinical features of schizophrenia-from thought disorder to delusions-are proposed to reflect disorganization in such conceptual representations. Schizophrenia is also linked to abnormalities in neural processes that support cognitive map representations, including hippocampal replay and high-frequency ripple oscillations. Here, we report a computational assay of semantically guided conceptual sampling and exploit this to test a hypothesis that people with schizophrenia (PScz) exhibit abnormalities in semantically guided cognition that relate to hippocampal replay and ripples. Fifty-two participants [26 PScz (13 unmedicated) and 26 age-, gender-, and intelligence quotient (IQ)-matched nonclinical controls] completed a category- and letter-verbal fluency task, followed by a magnetoencephalography (MEG) scan involving a separate sequence-learning task. We used a pretrained word embedding model of semantic similarity, coupled to a computational model of word selection, to quantify the degree to which each participant's verbal behavior was guided by semantic similarity. Using MEG, we indexed neural replay and ripple power in a post-task rest session. Across all participants, word selection was strongly influenced by semantic similarity. The strength of this influence showed sensitivity to task demands (category > letter fluency) and predicted performance. In line with our hypothesis, the influence of semantic similarity on behavior was reduced in schizophrenia relative to controls, predicted negative psychotic symptoms, and correlated with an MEG signature of hippocampal ripple power (but not replay). The findings bridge a gap between phenomenological and neurocomputational accounts of schizophrenia.

Awake hippocampal synchronous events are incorporated into offline neuronal reactivation.

Learning novel experiences reorganizes hippocampal neuronal circuits, represented as coordinated reactivation patterns in post-experience offline states for memory consolidation. This study examines how awake synchronous events during a novel run are related to post-run reactivation patterns. The disruption of awake sharp-wave ripples inhibited experience-induced increases in the contributions of neurons to post-experience synchronous events. Hippocampal place cells that participate more in awake synchronous events are more strongly reactivated during post-experience synchronous events. Awake synchronous neuronal patterns, in cooperation with place-selective firing patterns, determine cell ensembles that undergo pronounced increases and decreases in their correlated spikes. Taken together, awake synchronous events are fundamental for identifying hippocampal neuronal ensembles to be incorporated into synchronous reactivation during subsequent offline states, thereby facilitating memory consolidation.

Postnatal Maturation of Membrane Potential Dynamics during in Vivo Hippocampal Ripples.

Sharp-wave ripples (SWRs) are transient high-frequency oscillations of local field potentials (LFPs) in the hippocampus and play a critical role in memory consolidation. During SWRs, CA1 pyramidal cells exhibit rapid spike sequences that often replay the sequential activity that occurred during behavior. This temporally organized firing activity gradually emerges during 2 weeks after the eye opening; however, it remains unclear how the organized spikes during SWRs mature at the intracellular membrane potential (Vm) level. Here, we recorded Vm of CA1 pyramidal cells simultaneously with hippocampal LFPs from anesthetized immature mice of either sex after the developmental emergence of SWRs. On postnatal days 16 and 17, Vm dynamics around SWRs were premature, characterized by prolonged depolarizations without either pre- or post-SWR hyperpolarizations. The biphasic hyperpolarizations, features typical of adult SWR-relevant Vm, formed by approximately postnatal day 30. This Vm maturation was associated with an increase in SWR-associated inhibitory inputs to pyramidal cells. Thus, the development of SWR-relevant inhibition restricts the temporal windows for spikes of pyramidal cells and allows CA1 pyramidal cells to organize their spike sequences during SWRs.SIGNIFICANCE STATEMENT Sharp-wave ripples (SWRs) are prominent hippocampal oscillations and play a critical role in memory consolidation. During SWRs, hippocampal neurons synchronously emit spikes with organized temporal patterns. This temporal structure of spikes during SWRs develops during the third and fourth postnatal weeks, but the underlying mechanisms are not well understood. Here, we recorded in vivo membrane potentials from hippocampal neurons in premature mice and suggest that the maturation of SWR-associated inhibition enables hippocampal neurons to produce precisely controlled spike times during SWRs.

Experience alters hippocampal and cortical network communication via a KIBRA-dependent mechanism.

Synaptic plasticity is hypothesized to underlie "replay" of salient experience during hippocampal sharp-wave/ripple (SWR)-based ensemble activity and to facilitate systems-level memory consolidation coordinated by SWRs and cortical sleep spindles. It remains unclear how molecular changes at synapses contribute to experience-induced modification of network function. The synaptic protein KIBRA regulates plasticity and memory. To determine the impact of KIBRA-regulated plasticity on circuit dynamics, we recorded in vivo neural activity from wild-type (WT) mice and littermates lacking KIBRA and examined circuit function before, during, and after novel experience. In WT mice, experience altered population activity and oscillatory dynamics in a manner consistent with incorporation of new information content in replay and enhanced hippocampal-cortical communication. While baseline SWR features were normal in KIBRA conditional knockout (cKO) mice, experience-dependent alterations in SWRs were absent. Furthermore, intra-hippocampal and hippocampal-cortical communication during SWRs was disrupted following KIBRA deletion. These results indicate molecular mechanisms that underlie network-level adaptations to experience.

Selective serotonin reuptake inhibitors suppress sharp wave ripples in the ventral hippocampus.

Biased memory processing contributes to the development and exacerbation of depression, and thus could represent a potential therapeutic target for stress-induced mental disorders. Synchronized spikes in hippocampal neurons, corresponding to sharp wave ripples (SWRs), may play a crucial role in memory reactivation. In this study, we showed that the frequency of SWRs increased in the ventral hippocampus, but not in the dorsal hippocampus, after stress exposure. Administration of the selective serotonin reuptake inhibitors (SSRIs) fluoxetine and fluvoxamine inhibited the generation of ventral hippocampal SWRs and reduced locomotor activity and local field potential power in the gamma bands. These results suggest that the antidepressant effects of SSRIs may be mediated by the suppression of ventral hippocampal SWRs.

Alterations in theta-gamma coupling and sharp wave-ripple, signs of prodromal hippocampal network impairment in the TgF344-AD rat model.

Alzheimer's disease (AD) is a severe neurodegenerative disorder caused by the accumulation of toxic proteins, amyloid-beta (Aß) and tau, which eventually leads to dementia. Disease-modifying therapies are still lacking, due to incomplete insights into the neuropathological mechanisms of AD. Synaptic dysfunction is known to occur before cognitive symptoms become apparent and recent studies have demonstrated that imbalanced synaptic signaling drives the progression of AD, suggesting that early synaptic dysfunction could be an interesting therapeutic target. Synaptic dysfunction results in altered oscillatory activity, which can be detected with electroencephalography and electrophysiological recordings. However, the majority of these studies have been performed at advanced stages of AD, when extensive damage and cognitive symptoms are already present. The current study aimed to investigate if the hippocampal oscillatory activity is altered at pre-plaque stages of AD. The rats received stereotactic surgery to implant a laminar electrode in the CA1 layer of the right hippocampus. Electrophysiological recordings during two consecutive days in an open field were performed in 4-5-month-old TgF344-AD rats when increased concentrations of soluble Aß species were observed in the brain, in the absence of Aß-plaques. We observed a decreased power of high theta oscillations in TgF344-AD rats compared to wild-type littermates. Sharp wave-ripple (SWR) analysis revealed an increased SWR power and a decreased duration of SWR during quiet wake in TgF344-AD rats. The alterations in properties of SWR and the increased power of fast oscillations are suggestive of neuronal hyperexcitability, as has been demonstrated to occur during presymptomatic stages of AD. In addition, decreased strength of theta-gamma coupling, an important neuronal correlate of memory encoding, was observed in the TgF344-AD rats. Theta-gamma phase amplitude coupling has been associated with memory encoding and the execution of cognitive functions. Studies have demonstrated that mild cognitive impairment patients display decreased coupling strength, similar to what is described here. The current study demonstrates altered hippocampal network activity occurring at pre-plaque stages of AD and provides insights into prodromal network dysfunction in AD. The alterations observed could aid in the detection of AD during presymptomatic stages.

Inhibition is a prevalent mode of activity in the neocortex around awake hippocampal ripples in mice.

Coordinated peri-ripple activity in the hippocampal-neocortical network is essential for mnemonic information processing in the brain. Hippocampal ripples likely serve different functions in sleep and awake states. Thus, the corresponding neocortical activity patterns may differ in important ways. We addressed this possibility by conducting voltage and glutamate wide-field imaging of the neocortex with concurrent hippocampal electrophysiology in awake mice. Contrary to our previously published sleep results, deactivation and activation were dominant in post-ripple neocortical voltage and glutamate activity, respectively, especially in the agranular retrosplenial cortex (aRSC). Additionally, the spiking activity of aRSC neurons, estimated by two-photon calcium imaging, revealed the existence of two subpopulations of excitatory neurons with opposite peri-ripple modulation patterns: one increases and the other decreases firing rate. These differences in peri-ripple spatiotemporal patterns of neocortical activity in sleep versus awake states might underlie the reported differences in the function of sleep versus awake ripples.

Ripples in macaque V1 and V4 are modulated by top-down visual attention.

Sharp-wave ripples (SWRs) are highly synchronous neuronal activity events. They have been predominantly observed in the hippocampus during offline states such as pause in exploration, slow-wave sleep, and quiescent wakefulness. SWRs have been linked to memory consolidation, spatial navigation, and spatial decision-making. Recently, SWRs have been reported during visual search, a form of remote spatial exploration, in macaque hippocampus. However, the association between SWRs and multiple forms of awake conscious and goal-directed behavior is unknown. We report that ripple activity occurs in macaque visual areas V1 and V4 during focused spatial attention. The occurrence of ripples is modulated by stimulus characteristics, increased by attention toward the receptive field, and by the size of the attentional focus. During attention cued to the receptive field, the monkey's reaction time in detecting behaviorally relevant events was reduced by ripples. These results show that ripple activity is not limited to hippocampal activity during offline states, rather they occur in the neocortex during active attentive states and vigilance behaviors.

Relationship Between Replay-Associated Ripples and Hippocampal N-Methyl-D-Aspartate Receptors: Preliminary Evidence From a PET-MEG Study in Schizophrenia.

Background and Hypotheses: Hippocampal replay and associated high-frequency ripple oscillations are among the best-characterized phenomena in resting brain activity. Replay/ripples support memory consolidation and relational inference, and are regulated by N-methyl-D-aspartate receptors (NMDARs). Schizophrenia has been associated with both replay/ripple abnormalities and NMDAR hypofunction in both clinical samples and genetic mouse models, although the relationship between these 2 facets of hippocampal function has not been tested in humans. Study Design: Here, we avail of a unique multimodal human neuroimaging data set to investigate the relationship between the availability of (intrachannel) NMDAR binding sites in hippocampus, and replay-associated ripple power, in 16 participants (7 nonclinical participants and 9 people with a diagnosis of schizophrenia, PScz). Each participant had both a [18F]GE-179 positron emission tomography (PET) scan (to measure NMDAR availability, V T ) and a magnetoencephalography (MEG) scan (to measure offline neural replay and associated high-frequency ripple oscillations, using Temporally Delayed Linear Modeling). Study Results: We show a positive relationship between hippocampal NMDAR availability and replay-associated ripple power. This linkage was evident across control participants (r(5) = .94, P = .002) and PScz (r(7) = .70, P = .04), with no group difference. Conclusions: Our findings provide preliminary evidence for a relationship between hippocampal NMDAR availability and replay-associated ripple power in humans, and haverelevance for NMDAR hypofunction theories of schizophrenia.

On the accuracy of cell-attached current-clamp recordings from cortical neurons.

Cell-attached current-clamp (CA/CC) recordings have been proposed to measure resting membrane potential and synaptic/agonist responses in neurons without disrupting the cell membrane, thus avoiding the intracellular dialysis that occurs in conventional whole-cell recordings (WC). However, the accuracy of CA/CC recordings in neurons has not been directly assessed. Here, we used concomitant CA and WC current clamp recordings from cortical neurons in brain slices. Resting membrane potential values and slow voltage shifts showed variability and were typically attenuated during CA/CC recordings by ~10-20% relative to WC values. Fast signals were slowed down and their amplitude was greatly reduced: synaptic potentials by nearly 2-fold, and action potentials by nearly 10-fold in CA/CC mode compared to WC. The polarity of GABAergic postsynaptic responses in CA/CC mode matched the responses in WC, and depolarising GABAergic potentials were predominantly observed during CA/CC recordings of intact neonatal CA3 hippocampal pyramidal neurons. Similarly, CA/CC recordings reliably detected neuronal depolarization and excitation during network-induced giant depolarizing potentials in the neonatal CA3 hippocampus, and revealed variable changes, from depolarization to hyperpolarization, in CA1 pyramidal cells during sharp wave ripples in the adult hippocampus. Thus, CA/CC recordings are suitable for assessing membrane potential but signal distortion, probably caused by leakage via the seal contact and RC filtering should be considered.

An open-source, ready-to-use and validated ripple detector plugin for the Open Ephys GUI.

Objective. Sharp wave-ripples (SWRs, 100-250 Hz) are oscillatory events extracellularly recorded in the CA1 subfield of the hippocampus during sleep and quiet wakefulness. Many studies employed closed-loop strategies to either detect and abolish SWRs within the hippocampus or manipulate other relevant areas upon ripple detection. However, the code and schematics necessary to replicate the detection system are not always available, which hinders the reproducibility of experiments among different research groups. Furthermore, information about performance is not usually reported. Here, we sought to provide an open-source, validated ripple detector for the scientific community.Approach. We developed and validated a ripple detection plugin integrated into the Open Ephys graphical user's interface. It contains a built-in movement detector based on accelerometer or electromyogram data that prevents false ripple events (due to chewing, grooming, or moving, for instance) from triggering the stimulation/manipulation device.Main results. To determine the accuracy of the detection algorithm, we first carried out simulations in MATLAB with real ripple recordings. Using a specific combination of detection parameters (amplitude threshold of 5 standard deviations above the mean, time threshold of 10 ms, and root mean square block size of 7 samples), we obtained a 97% true positive rate and 2.48 false positives per minute. Next, an Open Ephys plugin based on the same detection algorithm was developed, and a closed-loop system was set up to evaluate the round trip (ripple onset-to-stimulation) latency over synthetic data. The lowest latency obtained was 34.5 ± 0.5 ms. The embedded movement monitoring was effective in reducing false positives and the plugin's flexibility to detect pathological events was also verified.Significance. Besides contributing to increased reproducibility, we anticipate that the developed ripple detector plugin will be helpful for many closed-loop applications in the field of systems neuroscience.

Alterations of sleep oscillations in Alzheimer's disease: A potential role for GABAergic neurons in the cortex, hippocampus, and thalamus.

Sleep abnormalities are widely reported in patients with Alzheimer's disease (AD) and are linked to cognitive impairments. Sleep abnormalities could be potential biomarkers to detect AD since they are often observed at the preclinical stage. Moreover, sleep could be a target for early intervention to prevent or slow AD progression. Thus, here we review changes in brain oscillations observed during sleep, their connection to AD pathophysiology and the role of specific brain circuits. Slow oscillations (0.1-1 Hz), sleep spindles (8-15 Hz) and their coupling during non-REM sleep are consistently reduced in studies of patients and in AD mouse models although the timing and magnitude of these alterations depends on the pathophysiological changes and the animal model studied. Changes in delta (1-4 Hz) activity are more variable. Animal studies suggest that hippocampal sharp-wave ripples (100-250 Hz) are also affected. Reductions in REM sleep amount and slower oscillations during REM are seen in patients but less consistently in animal models. Thus, changes in a variety of sleep oscillations could impact sleep-dependent memory consolidation or restorative functions of sleep. Recent mechanistic studies suggest that alterations in the activity of GABAergic neurons in the cortex, hippocampus and thalamic reticular nucleus mediate sleep oscillatory changes in AD and represent a potential target for intervention. Longitudinal studies of the timing of AD-related sleep abnormalities with respect to pathology and dysfunction of specific neural networks are needed to identify translationally relevant biomarkers and guide early intervention strategies to prevent or delay AD progression.

Ripple-selective GABAergic projection cells in the hippocampus.

Ripples are brief high-frequency electrographic events with important roles in episodic memory. However, the in vivo circuit mechanisms coordinating ripple-related activity among local and distant neuronal ensembles are not well understood. Here, we define key characteristics of a long-distance projecting GABAergic cell group in the mouse hippocampus that selectively exhibits high-frequency firing during ripples while staying largely silent during theta-associated states when most other GABAergic cells are active. The high ripple-associated firing commenced before ripple onset and reached its maximum before ripple peak, with the signature theta-OFF, ripple-ON firing pattern being preserved across awake and sleep states. Controlled by septal GABAergic, cholinergic, and CA3 glutamatergic inputs, these ripple-selective cells innervate parvalbumin and cholecystokinin-expressing local interneurons while also targeting a variety of extra-hippocampal regions. These results demonstrate the existence of a hippocampal GABAergic circuit element that is uniquely positioned to coordinate ripple-related neuronal dynamics across neuronal assemblies.

Spatial Learning Drives Rapid Goal Representation in Hippocampal Ripples without Place Field Accumulation or Goal-Oriented Theta Sequences.

The hippocampus is critical for rapid acquisition of many forms of memory, although the circuit-level mechanisms through which the hippocampus rapidly consolidates novel information are unknown. Here, the activity of large ensembles of hippocampal neurons in adult male Long-Evans rats was monitored across a period of rapid spatial learning to assess how the network changes during the initial phases of memory formation and retrieval. In contrast to several reports, the hippocampal network did not display enhanced representation of the goal location via accumulation of place fields or elevated firing rates at the goal. Rather, population activity rates increased globally as a function of experience. These alterations in activity were mirrored in the power of the theta oscillation and in the quality of theta sequences, without preferential encoding of paths to the learned goal location. In contrast, during brief "offline" pauses in movement, representation of a novel goal location emerged rapidly in ripples, preceding other changes in network activity. These data demonstrate that the hippocampal network can facilitate active navigation without enhanced goal representation during periods of active movement, and further indicate that goal representation in hippocampal ripples before movement onset supports subsequent navigation, possibly through activation of downstream cortical networks.SIGNIFICANCE STATEMENT Understanding the mechanisms through which the networks of the brain rapidly assimilate information and use previously learned knowledge are fundamental areas of focus in neuroscience. In particular, the hippocampal circuit is a critical region for rapid formation and use of spatial memory. In this study, several circuit-level features of hippocampal function were quantified while rats performed a spatial navigation task requiring rapid memory formation and use. During periods of active navigation, a general increase in overall network activity is observed during memory acquisition, which plateaus during memory retrieval periods, without specific enhanced representation of the goal location. During pauses in navigation, rapid representation of the distant goal well emerges before either behavioral improvement or changes in online activity.

A Variable Clock Underlies Internally Generated Hippocampal Sequences.

Humans have the ability to store and retrieve memories with various degrees of specificity, and recent advances in reinforcement learning have identified benefits to learning when past experience is represented at different levels of temporal abstraction. How this flexibility might be implemented in the brain remains unclear. We analyzed the temporal organization of male rat hippocampal population spiking to identify potential substrates for temporally flexible representations. We examined activity both during locomotion and during memory-associated population events known as sharp-wave ripples (SWRs). We found that spiking during SWRs is rhythmically organized with higher event-to-event variability than spiking during locomotion-associated population events. Decoding analyses using clusterless methods further indicate that a similar spatial experience can be replayed in multiple SWRs, each time with a different rhythmic structure whose periodicity is sampled from a log-normal distribution. This variability increases with experience despite the decline in SWR rates that occurs as environments become more familiar. We hypothesize that the variability in temporal organization of hippocampal spiking provides a mechanism for storing experiences with various degrees of specificity.SIGNIFICANCE STATEMENT One of the most remarkable properties of memory is its flexibility: the brain can retrieve stored representations at varying levels of detail where, for example, we can begin with a memory of an entire extended event and then zoom in on a particular episode. The neural mechanisms that support this flexibility are not understood. Here we show that hippocampal sharp-wave ripples, which mark the times of memory replay and are important for memory storage, have a highly variable temporal structure that is well suited to support the storage of memories at different levels of detail.

Reorganization of CA1 dendritic dynamics by hippocampal sharp-wave ripples during learning.

The hippocampus plays a critical role in memory consolidation, mediated by coordinated network activity during sharp-wave ripple (SWR) events. Despite the link between SWRs and hippocampal plasticity, little is known about how network state affects information processing in dendrites, the primary sites of synaptic input integration and plasticity. Here, we monitored somatic and basal dendritic activity in CA1 pyramidal cells in behaving mice using longitudinal two-photon calcium imaging integrated with simultaneous local field potential recordings. We found immobility was associated with an increase in dendritic activity concentrated during SWRs. Coincident dendritic and somatic activity during SWRs predicted increased coupling during subsequent exploration of a novel environment. In contrast, somatic-dendritic coupling and SWR recruitment varied with cells' tuning distance to reward location during a goal-learning task. Our results connect SWRs with the stabilization of information processing within CA1 neurons and suggest that these mechanisms may be dynamically biased by behavioral demands.

Sleep Deprivation Impairs Learning-Induced Increase in Hippocampal Sharp Wave Ripples and Associated Spike Dynamics during Recovery Sleep.

Sleep deprivation (SD) causes deficits in off-line memory consolidation, but the underlying network oscillation mechanisms remain unclear. Hippocampal sharp wave ripple (SWR) oscillations play a critical role in off-line memory consolidation. Therefore, we trained mice to learn a hippocampus-dependent trace eyeblink conditioning (tEBC) task and explored the influence of 1.5-h postlearning SD on hippocampal SWRs and related spike dynamics during recovery sleep. We found an increase in hippocampal SWRs during postlearning sleep, which predicted the consolidation of tEBC in conditioned mice. In contrast, sleep-deprived mice showed a loss of tEBC learning-induced increase in hippocampal SWRs during recovery sleep. Moreover, the sleep-deprived mice exhibited weaker reactivation of tEBC learning-associated pyramidal cells in hippocampal SWRs during recovery sleep. In line with these findings, tEBC consolidation was impaired in sleep-deprived mice. Furthermore, sleep-deprived mice showed augmented fast excitation from pyramidal cells to interneurons and enhanced participation of interneurons in hippocampal SWRs during recovery sleep. Among various interneurons, parvalbumin-expressing interneurons specifically exhibited overexcitation during hippocampal SWRs. Our findings suggest that altered hippocampal SWRs and associated spike dynamics during recovery sleep may be candidate network oscillation mechanisms underlying SD-induced memory deficits.