Sharp-wave Ripple Events Research Articles

Disrupted Hippocampal Theta-Gamma Coupling and Spike-Field Coherence Following Experimental Traumatic Brain Injury.

Traumatic brain injury (TBI) often results in persistent learning and memory deficits, likely due to disrupted hippocampal circuitry underlying these processes. Precise temporal control of hippocampal neuronal activity is important for memory encoding and retrieval and is supported by oscillations that dynamically organize single unit firing. Using high-density laminar electrophysiology, we discovered a loss of oscillatory power across CA1 lamina, with a profound, layer-specific reduction in theta-gamma phase amplitude coupling in injured rats. Interneurons from injured animals were less strongly entrained to theta and gamma oscillations, suggesting a mechanism for the loss of coupling, while pyramidal cells were entrained to a later phase of theta. During quiet immobility, we report decreased ripple amplitudes from injured animals during sharp-wave ripple events. These results reveal deficits in information encoding and retrieval schemes essential to cognition that likely underlie TBI-associated learning and memory impairments, and elucidate potential targets for future neuromodulation therapies.

CA3 Circuit Model Compressing Sequential Information in Theta Oscillation and Replay.

The hippocampus plays a critical role in the compression and retrieval of sequential information. During wakefulness, it achieves this through theta phase precession and theta sequences. Subsequently, during periods of sleep or rest, the compressed information reactivates through sharp-wave ripple events, manifesting as memory replay. However, how these sequential neuronal activities are generated and how they store information about the external environment remain unknown. We developed a hippocampal cornu ammonis 3 (CA3) computational model based on anatomical and electrophysiological evidence from the biological CA3 circuit to address these questions. The model comprises theta rhythm inhibition, place input, and CA3-CA3 plastic recurrent connection. The model can compress the sequence of the external inputs, reproduce theta phase precession and replay, learn additional sequences, and reorganize previously learned sequences. A gradual increase in synaptic inputs, controlled by interactions between theta-paced inhibition and place inputs, explained the mechanism of sequence acquisition. This model highlights the crucial role of plasticity in the CA3 recurrent connection and theta oscillational dynamics and hypothesizes how the CA3 circuit acquires, compresses, and replays sequential information.

Coupling of Sharp Wave Events between Zebrafish Hippocampal and Amygdala Homologs.

The mammalian hippocampus exhibits spontaneous sharp wave events (1-30 Hz) with an often-present superimposed fast ripple oscillation (120-220 Hz) to form a sharp wave ripple (SWR) complex. During slow-wave sleep or quiet restfulness, SWRs result from the sequential spiking of hippocampal cell assemblies initially activated during learned or imagined experiences. Additional cortical/subcortical areas exhibit SWR events that are coupled to hippocampal SWRs, and studies in mammals suggest that coupling may be critical for the consolidation and recall of specific memories. In the present study, we have examined juvenile male and female zebrafish and show that SWR events are intrinsically generated and maintained within the telencephalon and that their hippocampal homolog, the anterodorsolateral lobe (ADL), exhibits SW events with ∼9% containing an embedded ripple (SWR). Single-cell calcium imaging coupled to local field potential recordings revealed that ∼10% of active cells in the dorsal telencephalon participate in any given SW event. Furthermore, fluctuations in cholinergic tone modulate SW events consistent with mammalian studies. Moreover, the basolateral amygdala (BLA) homolog exhibits SW events with ∼5% containing an embedded ripple. Computing the SW peak coincidence difference between the ADL and BLA showed bidirectional communication. Simultaneous coupling occurred more frequently within the same hemisphere, and in coupled events across hemispheres, the ADL more commonly preceded BLA. Together, these data suggest conserved mechanisms across species by which SW and SWR events are modulated, and memories may be transferred and consolidated through regional coupling.

Construction of ThermoMaze.

Physiological changes during awake immobility-related brain states remain one of the great unexplored behavioral states. Controlling periods of awake immobility is challenging because restraining the animal is stressful and is accompanied by altered physiological states. Here, we describe the ThermoMaze, a behavioral paradigm that allows for the collection of large amounts of physiological data while the animal rests at distinct experimenter-determined locations. We found that the paradigm generated long periods of immobility and did not alter the brain temperature. We combined the ThermoMaze with electrophysiology recordings in the CA1 region of the hippocampus and found a location-specific distribution of sharp-wave ripple events. We describe the construction of the ThermoMaze with the intention that it helps enable large-scale data recordings on immobility-related brain states. Key features • Controlling periods of awake immobility in rodents. • Electronic-friendly analog of the Morris water maze.

Disrupted hippocampal synchrony following maternal immune activation in a rat model.

Maternal immune activation (MIA) is a risk factor for schizophrenia and other neurodevelopmental disorders. MIA in rats models a number of the brain and behavioral changes that are observed in schizophrenia, including impaired memory. Recent studies in the MIA model have shown that the firing of the hippocampal place cells that are involved in memory processes appear relatively normal, but with abnormalities in the temporal ordering of firing. In this study, we re-analyzed data from prior hippocampal electrophysiological recordings of MIA and control animals to determine whether temporal dysfunction was evident. We find that there is a decreased ratio of slow to fast gamma power, resulting from an increase in fast gamma power and a tendency toward reduced slow gamma power in MIA rats. Moreover, we observe a robust reduction in spectral coherence between hippocampal theta and both fast and slow gamma rhythms, as well as changes in the phase of theta at which fast gamma occurs. We also find the phasic organization of place cell phase precession on the theta wave to be abnormal in MIA rats. Lastly, we observe that the local field potential of MIA rats contains more frequent sharp-wave ripple events, and that place cells were more likely to fire spikes during ripples in these animals than control. These findings provide further evidence of desynchrony in MIA animals and may point to circuit-level changes that underlie failures to integrate and encode information in schizophrenia.

Activity Patterns of Individual Neurons and Ensembles Correlated with Retrieval of a Contextual Memory in the Dorsal CA1 of Mouse Hippocampus.

The hippocampus is crucial for retrieval of contextual memories. The activation of a subpopulation of neurons in the dorsal CA1 (dCA1) of the hippocampus is required for memory retrieval. Given that hippocampal neurons exhibit distinct patterns of response during memory retrieval, the activity patterns of individual neurons or ensembles may be critically involved in memory retrieval. However, this relation has been unclear. To investigate this question, we used an in vivo microendoscope calcium imaging technique to optically record neuronal activity in the dCA1 of male and female mice. We observed that a portion of dCA1 neurons increased their responses to the learned context after contextual fear conditioning (FC), resulting in overall increase in response of neuronal population compared with simple context exposure. Such increased response was specific to the conditioned context as it disappeared in neutral context. The magnitude of increase in neuronal responses by FC was proportional to memory strength during retrieval. The increases in activity preferentially occurred during the putative sharp wave ripple events and were not simply because of animal's movement and immobility. At the ensemble level, synchronous cell activity patterns were associated with memory retrieval. Accordingly, when such patterns were more similar between conditioned and neutral context, animals displayed proportionally more similar level of freezing. Together, these results indicate that increase in responses of individual neurons and synchronous cell activity patterns in the dCA1 neuronal network are critically involved in representing a contextual memory recall.SIGNIFICANCE STATEMENT Neurons in the dorsal CA1 of the hippocampus are crucial for memory retrieval. By using in vivo calcium imaging methods for recording neuronal activity, we demonstrate that dCA1 neurons increased their responses to the learned context specifically by FC and such changes correlated with memory strength during retrieval. Moreover, distinct synchronous cell activity patterns were formed by FC and involved in representing contextual memory retrieval. These findings reveal dynamic activity features of dCA1 neurons that are involved in contextual memory retrieval.

Generation of Sharp Wave-Ripple Events by Disinhibition

Sharp wave-ripple complexes (SWRs) are hippocampal network phenomena involved in memory consolidation. To date, the mechanisms underlying their occurrence remain obscure. Here, we show how the interactions between pyramidal cells, parvalbumin-positive (PV+) basket cells, and an unidentified class of anti-SWR interneurons can contribute to the initiation and termination of SWRs. Using a biophysically constrained model of a network of spiking neurons and a rate-model approximation, we demonstrate that SWRs emerge as a result of the competition between two interneuron populations and the resulting disinhibition of pyramidal cells. Our models explain how the activation of pyramidal cells or PV+ cells can trigger SWRs, as shown in vitro, and suggests that PV+ cell-mediated short-term synaptic depression influences the experimentally reported dynamics of SWR events. Furthermore, we predict that the silencing of anti-SWR interneurons can trigger SWRs. These results broaden our understanding of the microcircuits supporting the generation of memory-related network dynamics.SIGNIFICANCE STATEMENT The hippocampus is a part of the mammalian brain that is crucial for episodic memories. During periods of sleep and inactive waking, the extracellular activity of the hippocampus is dominated by sharp wave-ripple events (SWRs), which have been shown to be important for memory consolidation. The mechanisms regulating the emergence of these events are still unclear. We developed a computational model to study the emergence of SWRs and to explain the roles of different cell types in regulating them. The model accounts for several previously unexplained features of SWRs and thus advances the understanding of memory-related dynamics.

The hippocampal code for space in Mongolian gerbils.

Large parts of our knowledge about the physiology of the hippocampus in the intact brain are derived from studies in rats and mice. While many of those findings fit well to the limited data available from humans and primates, there are also marked differences, for example, in hippocampal oscillation frequencies and in the persistence of theta oscillations. To test whether the distinct sensory specializations of the visual and auditory system of primates play a key role in explaining these differences, we recorded basic hippocampal physiological properties in Mongolian gerbils, a rodent species with high visual acuity, and good low-frequency hearing, similar to humans. We found that gerbils show only minor differences to rats regarding hippocampal place field activity, theta properties (frequency, persistence, phase precession, theta compression), and sharp wave ripple events. The only major difference between rats and gerbils was a considerably higher degree of head direction selectivity of gerbil place fields, which may be explained by their visual system being able to better resolve distant cues. Thus, differences in sensory specializations between rodent species only affect hippocampal circuit dynamics to a minor extent, which implies that differences to other mammalian lineages, such as bats and primates, cannot be solely explained by specialization in the auditory or visual system.

Age-associated changes in waking hippocampal sharp-wave ripples.

Hippocampal sharp-wave ripples are brief high-frequency (120-250 Hz) oscillatory events that support mnemonic processes during sleep and awake behavior. Although ripples occurring during sleep are believed to facilitate memory consolidation, waking ripples may also be involved in planning and memory retrieval. Recent work from our group determined that normal aging results in a significant reduction in the peak oscillatory frequency and rate-of-occurrence of ripples during sleep that may contribute to age-associated memory decline. It is unknown, however, how aging alters waking ripples. We investigated whether characteristics of waking ripples undergo age-dependent changes. Sharp-wave ripple events were recorded from the CA1 region of the hippocampus in old (n = 5) and young (n = 6) F344 male rats as they performed a place-dependent eyeblink conditioning task. Several novel observations emerged from this analysis. First, although aged rats expressed more waking ripples than young rats during track running and reward consumption, this effect was eliminated, and, in the case of track-running, reversed when time spent in each location was accounted for. Thus, aged rats emit more ripples, but young rats express a higher ripple rate. This likely results from reduced locomotor activity in aged animals. Furthermore, although ripple rates increased as young rats approached rewards, rates did not increase in aged rats, and rates in aged and young animals were not affected by eyeblink conditioning. Finally, although the oscillatory frequency of ripples was lower in aged animals during rest, frequencies in aged rats increased during behavior to levels indistinguishable from young rats. Given the involvement of waking ripples in memory retrieval, a possible consequence of slower movement speeds of aged animals is to provide more opportunity to replay task-relevant information and compensate for age-related declines in ripple rate during task performance.

Convergent Metabotropic Signaling Pathways Inhibit SK Channels to Promote Synaptic Plasticity in the Hippocampus.

Hebbian synaptic plasticity at hippocampal Schaffer collateral synapses is tightly regulated by postsynaptic small conductance (SK) channels that restrict NMDA receptor activity. SK channels are themselves modulated by G-protein-coupled signaling pathways, but it is not clear under what conditions these are activated to enable synaptic plasticity. Here, we show that muscarinic M1 receptor (M1R) and type 1 metabotropic glutamate receptor (mGluR1) signaling pathways, which are known to inhibit SK channels and thereby disinhibit NMDA receptors, converge to facilitate spine calcium transients during the induction of long-term potentiation (LTP) at hippocampal Schaffer collateral synapses onto CA1 pyramidal neurons of male rats. Furthermore, mGluR1 activation is required for LTP induced by reactivated place-cell firing patterns that occur in sharp-wave ripple events during rest or sleep. In contrast, M1R activation is required for LTP induced by place-cell firing patterns during exploration. Thus, we describe a common mechanism that enables synaptic plasticity during both encoding and consolidation of memories within hippocampal circuits.SIGNIFICANCE STATEMENT Memory ensembles in the hippocampus are formed during active exploration and consolidated during rest or sleep. These two distinct phases each require strengthening of synaptic connections by long-term potentiation (LTP). The neuronal activity patterns in each phase are very different, which makes it hard to map generalized rules for LTP induction onto both formation and consolidation phases. In this study, we show that inhibition of postsynaptic SK channels is a common necessary feature of LTP induction and that SK channel inhibition is achieved by separate but convergent metabotropic signaling pathways. Thus, we reveal a common mechanism for enabling LTP under distinct behavioral conditions.

Tetrode Recording from the Hippocampus of Behaving Mice Coupled with Four-Point-Irradiation Closed-Loop Optogenetics: A Technique to Study the Contribution of Hippocampal SWR Events to Learning.

With the advent of optogenetics, it became possible to change the activity of a targeted population of neurons in a temporally controlled manner. To combine the advantages of 60-channel in vivo tetrode recording and laser-based optogenetics, we have developed a closed-loop recording system that allows for the actual electrophysiological signal to be used as a trigger for the laser light mediating the optogenetic intervention. We have optimized the weight, size, and shape of the corresponding implant to make it compatible with the size, force, and movements of a behaving mouse, and we have shown that the system can efficiently block sharp wave ripple (SWR) events using those events themselves as a trigger. To demonstrate the full potential of the optogenetic recording system we present a pilot study addressing the contribution of SWR events to learning in a complex behavioral task.

2459 Hippocampal network disruption in early amyloid pathology

OBJECTIVES/SPECIFIC AIMS: We aim to show that amyloid accumulation in an animal model of Alzheimer’s disease leads to a preferential disruption of inhibitory parvalbumin-expressing interneurons, and the peri-neuronal nets that surround them, resulting in downstream network alterations to potentially explain early mechanisms of memory impairment in the disease. METHODS/STUDY POPULATION: We employ the 5xFAD mouse model of familial Alzheimer’s disease crossed with transgenic mouse lines which fluoresce red or green in specific neuronal populations. We conducted immunostaining and immunoblotting in amyloid accumulating animals compared with healthy littermate control. Future experiments will be performed in human postmortem tissue to translate these results from mouse model to the human population. Electrophysiological recordings from acute mouse brain slices were conducted as a functional assay. RESULTS/ANTICIPATED RESULTS: Preliminary results indicate that PNNs are disrupted and that activity-associated levels of PV are reduced. Both inhibitory PV and excitatory pyramidal cell populations exhibit altered spiking and synaptic activity during sharp wave ripple events. DISCUSSION/SIGNIFICANCE OF IMPACT: By elucidating the specific neuronal sub-type that is responsible for hippocampal network disruption, future studies could attempt a targeted optogenetic or pharmacological intervention to restore network activity important for memory consolidation.

Abnormal Sleep Architecture and Hippocampal Circuit Dysfunction in a Mouse Model of Fragile X Syndrome

Fragile X syndrome (FXS) is the most common heritable cause of intellectual disability and single-gene cause of autism spectrum disorder. The Fmr1 null mouse models much of the human disease including hyperarousal, sensory hypersensitivity, seizure activity, and hippocampus-dependent cognitive impairment. Sleep architecture is disorganized in FXS patients, but has not been examined in Fmr1 knockout (Fmr1-KO) mice. Hippocampal neural activity during sleep, which is implicated in memory processing, also remains uninvestigated in Fmr1-KO mice. We performed in vivo electrophysiological studies of freely behaving Fmr1-KO mice to assess neural activity, in the form of single-unit spiking and local field potential (LFP), within the hippocampal CA1 region during multiple differentiated sleep and wake states. Here, we demonstrate that Fmr1-KO mice exhibited a deficit in rapid eye movement sleep (REM) due to a reduction in the frequency of bouts of REM, consistent with sleep architecture abnormalities of FXS patients. Fmr1-KO CA1 pyramidal cells (CA1-PCs) were hyperactive in all sleep and wake states. Increased low gamma power in CA1 suggests that this hyperactivity was related to increased input to CA1 from CA3. By contrast, slower sharp-wave ripple events (SWRs) in Fmr1-KO mice exhibited longer event duration, slower oscillation frequency, with reduced CA1-PC firing rates during SWRs, yet the incidence rate of SWRs remained intact. These results suggest abnormal neuronal activity in the Fmr1-KO mouse during SWRs, and hyperactivity during other wake and sleep states, with likely adverse consequences for memory processes.

Spatio-temporal specialization of GABAergic septo-hippocampal neurons for rhythmic network activity

Medial septal GABAergic neurons of the basal forebrain innervate the hippocampus and related cortical areas, contributing to the coordination of network activity, such as theta oscillations and sharp wave-ripple events, via a preferential innervation of GABAergic interneurons. Individual medial septal neurons display diverse activity patterns, which may be related to their termination in different cortical areas and/or to the different types of innervated interneurons. To test these hypotheses, we extracellularly recorded and juxtacellularly labeled single medial septal neurons in anesthetized rats in vivo during hippocampal theta and ripple oscillations, traced their axons to distant cortical target areas, and analyzed their postsynaptic interneurons. Medial septal GABAergic neurons exhibiting different hippocampal theta phase preferences and/or sharp wave-ripple related activity terminated in restricted hippocampal regions, and selectively targeted a limited number of interneuron types, as established on the basis of molecular markers. We demonstrate the preferential innervation of bistratified cells in CA1 and of basket cells in CA3 by individual axons. One group of septal neurons was suppressed during sharp wave-ripples, maintained their firing rate across theta and non-theta network states and mainly fired along the descending phase of CA1 theta oscillations. In contrast, neurons that were active during sharp wave-ripples increased their firing significantly during “theta” compared to “non-theta” states, with most firing during the ascending phase of theta oscillations. These results demonstrate that specialized septal GABAergic neurons contribute to the coordination of network activity through parallel, target area- and cell type-selective projections to the hippocampus.

Disruption of perineuronal nets increases the frequency of sharp wave ripple events.

Hippocampal sharp wave ripples (SWRs) represent irregularly occurring synchronous neuronal population events that are observed during phases of rest and slow wave sleep. SWR activity that follows learning involves sequential replay of training-associated neuronal assemblies and is critical for systems level memory consolidation. SWRs are initiated by CA2 or CA3 pyramidal cells (PCs) and require initial excitation of CA1 PCs as well as participation of parvalbumin (PV) expressing fast spiking (FS) inhibitory interneurons. These interneurons are relatively unique in that they represent the major neuronal cell type known to be surrounded by perineuronal nets (PNNs), lattice like structures composed of a hyaluronin backbone that surround the cell soma and proximal dendrites. Though the function of the PNN is not completely understood, previous studies suggest it may serve to localize glutamatergic input to synaptic contacts and thus influence the activity of ensheathed cells. Noting that FS PV interneurons impact the activity of PCs thought to initiate SWRs, and that their activity is critical to ripple expression, we examine the effects of PNN integrity on SWR activity in the hippocampus. Extracellular recordings from the stratum radiatum of horizontal murine hippocampal hemisections demonstrate SWRs that occur spontaneously in CA1. As compared with vehicle, pre-treatment (120 min) of paired hemislices with hyaluronidase, which cleaves the hyaluronin backbone of the PNN, decreases PNN integrity and increases SWR frequency. Pre-treatment with chondroitinase, which cleaves PNN side chains, also increases SWR frequency. Together, these data contribute to an emerging appreciation of extracellular matrix as a regulator of neuronal plasticity and suggest that one function of mature perineuronal nets could be to modulate the frequency of SWR events.

Mechanisms for maintaining mental maps

Neuroscience When an animal runs around, some hippocampal neurons are selectively active in specific locations called their place fields. A maplike representation created from many such place fields serves as a navigation mechanism. How such hippocampal maps stabilize is still unknown. Roux et al. investigated a discrete form of high-frequency neuronal oscillations called sharp wave ripples. In a spatial learning task, they focally silenced a subpopulation of hippocampal area CA1 neurons during sharp wave ripple events. The place fields of the silenced neurons were altered, and their spatial information content failed to increase. Control place cells, however, largely kept their spatial correlates and showed increased information after learning. Sharp wave ripple–associated neuronal firing is necessary for stabilizing and refining hippocampal place fields. Nat. Neurosci. 20 , 845 (2017).

A cortical-hippocampal-cortical loop of information processing during memory consolidation.

Hippocampal replay during sharp-wave ripple events (SWRs) is thought to drive memory consolidation in hippocampal and cortical circuits. Changes in neocortical activity can precede SWR events, but whether and how these changes influence the content of replay remains unknown. Here we show that during sleep there is a rapid cortical-hippocampal-cortical loop of information flow around the times of SWRs. We recorded neural activity in auditory cortex (AC) and hippocampus of rats as they learned a sound-guided task and during sleep. We found that patterned activation in AC precedes and predicts the subsequent content of hippocampal activity during SWRs, while hippocampal patterns during SWRs predict subsequent AC activity. Delivering sounds during sleep biased AC activity patterns, and sound-biased AC patterns predicted subsequent hippocampal activity. These findings suggest that activation of specific cortical representations during sleep influences the identity of the memories that are consolidated into long-term stores.

The relationship of medial temporal lobe epilepsy with the declarative memory system

SummaryIntroduction.Medial temporal lobe of epilepsy (MTLE) is considered as local/regional epilepsy. However, as was discussed in Part I of this review (Halász, 2016a) there is more evidence regarding the involvement of both temporal lobes so as to consider MTLE as one of the typical bilateral system epilepsies.Aim.To provide contemporary review of MTLE in relation to the declarative memory system and the newly recognized hippocampo-frontal memory consolidation during slow wave sleep.Methods.A review of the available literature on experimental and clinical data and also the authors own studies in MTLE patients.Review, discussion and results.New experimental and clinical neurophysiological data have shown that MTLE is closely linked to the hippocampal memory system. It is likely that hippocampal spiking is the epileptic variations of the normal sharp wave ripple events mediating the encoding and consolidation of memory engrams by a hippocampo-frontal dialogue during slow wave sleep.Conclusions.The source of memory impairment in MTLE patients is not merely the cell loss and synaptic transformation of the hippocampal structure, but the every night interference with memory consolidation due to interictal spiking.

Interplay between Hippocampal Sharp-Wave-Ripple Events and Vicarious Trial and Error Behaviors in Decision Making

Current theories posit that memories encoded during experiences are subsequently consolidated into longer-term storage. Hippocampal sharp-wave-ripple (SWR) events have been linked to this consolidation process during sleep, but SWRs also occur during awake immobility, where their role remains unclear. We report that awake SWR rates at the reward site are inversely related to the prevalence of vicarious trial and error (VTE) behaviors, thought to be involved in deliberation processes. SWR rates were diminished immediately after VTE behaviors and an increase in the rate of SWR events at the reward site predicted a decrease in subsequent VTE behaviors at the choice point. Furthermore, SWR disruptions increased VTE behaviors. These results suggest an inverse relationship between SWRs and VTE behaviors and suggest that awake SWRs and associated planning and memory consolidation mechanisms are engaged specifically in the context of higher levels of behavioral certainty.

Optogenetically Blocking Sharp Wave Ripple Events in Sleep Does Not Interfere with the Formation of Stable Spatial Representation in the CA1 Area of the Hippocampus.

During hippocampal sharp wave/ripple (SWR) events, previously occurring, sensory input-driven neuronal firing patterns are replayed. Such replay is thought to be important for plasticity-related processes and consolidation of memory traces. It has previously been shown that the electrical stimulation-induced disruption of SWR events interferes with learning in rodents in different experimental paradigms. On the other hand, the cognitive map theory posits that the plastic changes of the firing of hippocampal place cells constitute the electrophysiological counterpart of the spatial learning, observable at the behavioral level. Therefore, we tested whether intact SWR events occurring during the sleep/rest session after the first exploration of a novel environment are needed for the stabilization of the CA1 code, which process requires plasticity. We found that the newly-formed representation in the CA1 has the same level of stability with optogenetic SWR blockade as with a control manipulation that delivered the same amount of light into the brain. Therefore our results suggest that at least in the case of passive exploratory behavior, SWR-related plasticity is dispensable for the stability of CA1 ensembles.