Search

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.

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.

Specific classes of GABAergic neurons play specific roles in regulating information processing in the brain. In the hippocampus, two major classes, parvalbumin-expressing (PV+) and somatostatin-expressing (SST+), differentially regulate endogenous firing patterns and target subcellular compartments of principal cells. How these classes regulate the flow of information throughout the hippocampus is poorly understood. We hypothesize that PV+ and SST+ interneurons in the dentate gyrus (DG) and CA3 differentially modulate CA3 patterns of output, thereby altering the influence of CA3 on CA1. We find that while suppressing either interneuron class increases DG and CA3 output, the effects on CA1 were very different. Suppressing PV+ interneurons increases local field potential signatures of coupling from CA3 to CA1 and decreases signatures of coupling from entorhinal cortex to CA1; suppressing SST+ interneurons has the opposite effect. Thus, DG and CA3 PV+ and SST+ interneurons bidirectionally modulate the flow of information through the hippocampal circuit.

Representations related to past experiences play a critical role in memory and decision-making processes. The rat hippocampus expresses these types of representations during sharp-wave ripple (SWR) events, and previous work identified a minority of SWRs that contain 'replay' of spatial trajectories at ∼20x the movement speed of the animal. Efforts to understand replay typically make multiple assumptions about which events to examine and what sorts of representations constitute replay. We therefore lack a clear understanding of both the prevalence and the range of representational dynamics associated with replay. Here, we develop a state space model that uses a combination of movement dynamics of different speeds to capture the spatial content and time evolution of replay during SWRs. Using this model, we find that the large majority of replay events contain spatially coherent, interpretable content. Furthermore, many events progress at real-world, rather than accelerated, movement speeds, consistent with actual experiences.

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. [ABSTRACT FROM AUTHOR]

Memories of positive experiences link places, events, and reward outcomes. These memories recruit interactions between the hippocampus and nucleus accumbens (NAc). Both dorsal and ventral hippocampus (dH and vH) project to the NAc, but it remains unknown whether dH and vH act in concert or separately to engage NAc representations related to space and reward. We recorded simultaneously from the dH, vH, and NAc of rats during an appetitive spatial task and focused on hippocampal sharp-wave ripples (SWRs) to identify times of memory reactivation across brain regions. Here, we show that dH and vH awake SWRs occur asynchronously and activate distinct and opposing patterns of NAc spiking. Only NAc neurons activated during dH SWRs were tuned to task- and reward-related information. These temporally and anatomically separable hippocampal-NAc interactions point to distinct channels of mnemonic processing in the NAc, with the dH-NAc channel specialized for spatial task and reward information. VIDEO ABSTRACT.

A prevalent model is that sharp-wave ripples (SWR) arise 'spontaneously' in CA3 and propagate recent memory traces outward to the neocortex to facilitate memory consolidation there. Using voltage and extracellular glutamate transient recording over widespread regions of mice dorsal neocortex in relation to CA1 multiunit activity (MUA) and SWR, we find that the largest SWR-related modulation occurs in retrosplenial cortex; however, contrary to the unidirectional hypothesis, neocortical activation exhibited a continuum of activation timings relative to SWRs, varying from leading to lagging. Thus, contrary to the model in which SWRs arise 'spontaneously' in the hippocampus, neocortical activation often precedes SWRs and may thus constitute a trigger event in which neocortical information seeds associative reactivation of hippocampal 'indices'. This timing continuum is consistent with a dynamics in which older, more consolidated memories may in fact initiate the hippocampal-neocortical dialog, whereas reactivation of newer memories may be initiated predominantly in the hippocampus.

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.

Alzheimer's disease (AD) is characterized by progressive memory loss, and there is a pressing need to identify early pathophysiological alterations that predict subsequent memory impairment. Hippocampal sharp-wave ripples (SWRs)-electrophysiological signatures of memory reactivation in the hippocampus-are a compelling candidate for this purpose. Mouse models of AD show reductions in both SWR abundance and associated slow gamma (SG) power during aging, but these alterations have yet to be directly linked to memory impairments. In aged apolipoprotein E4 knockin (apoE4-KI) mice-a model of the major genetic risk factor for AD-we find that reduced SWR abundance and associated CA3 SG power predicted spatial memory impairments measured 1-2 months later. Importantly, SWR-associated CA3 SG power reduction in young apoE4-KI mice also predicted spatial memory deficits measured 10 months later. These results establish features of SWRs as potential functional biomarkers of memory impairment in AD.

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.

Hippocampal sharp-wave ripple (SWR) events occur during both behavior (awake SWRs) and slow-wave sleep (sleep SWRs). Awake and sleep SWRs both contribute to spatial learning and memory, thought to be mediated by the coordinated reactivation of behavioral experiences in hippocampal-cortical circuits seen during SWRs. Current hypotheses suggest that reactivation contributes to memory consolidation processes, but whether awake and sleep reactivation are suited to play similar or different roles remains unclear. Here we addressed that issue by examining the structure of hippocampal (area CA1) and prefrontal (PFC) activity recorded across behavior and sleep stages in male rats learning a spatial alternation task. We found a striking state difference: prefrontal modulation during awake and sleep SWRs was surprisingly distinct, with differing patterns of excitation and inhibition. CA1-PFC synchronization was stronger during awake SWRs, and spatial reactivation, measured using both pairwise and ensemble measures, was more structured for awake SWRs compared with post-task sleep SWRs. Stronger awake reactivation was observed despite the absence of coordination between network oscillations, namely hippocampal SWRs and cortical delta and spindle oscillations, which is prevalent during sleep. Finally, awake CA1-PFC reactivation was enhanced most prominently during initial learning in a novel environment, suggesting a key role in early learning. Our results demonstrate significant differences in awake and sleep reactivation in the hippocampal-prefrontal network. These findings suggest that awake SWRs support accurate memory storage and memory-guided behavior, whereas sleep SWR reactivation is better suited to support integration of memories across experiences during consolidation.SIGNIFICANCE STATEMENT Hippocampal sharp-wave ripples (SWRs) occur both in the awake state during behavior and in the sleep state after behavior. Awake and sleep SWRs are associated with memory reactivation and are important for learning, but their specific memory functions remain unclear. Here, we found profound differences in hippocampal-cortical reactivation during awake and sleep SWRs, with key implications for their roles in memory. Awake reactivation is a higher-fidelity representation of behavioral experiences, and is enhanced during early learning, without requiring coordination of network oscillations that is seen during sleep. Our findings suggest that awake reactivation is ideally suited to support initial memory formation, retrieval and planning, whereas sleep reactivation may play a broader role in integrating memories across experiences during consolidation.

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. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • CCKI silencing triggers broad disinhibitory network effects and enhances burst firing • CCKIs are involved in theta phase precession-mediated temporal coding • Disruption of theta phase precession did not prevent subsequent sleep replay • CCKI activity regulates the magnitude of contextual fear-memory recall Rangel Guerrero et al. silenced the activity of CA1 Cholecystokinin-expressing interneurons. Optogenetic silencing disrupted the theta oscillation-related temporal coding of place cells during exploration while sleep replay was enhanced. Chemogenetic silencing enhanced the recall of contextual fear memories the next day and enabled the differentiation of similar environments. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Memory neuroscientists often measure neural activity during task trials designed to recruit specific memory processes. Behavior is championed as crucial for deciphering brain–memory linkages but is impoverished in typical experiments that rely on summary judgments. We criticize this approach as being blind to the multiple cognitive, neural, and behavioral processes that occur rapidly within a trial to support memory. Instead, time-resolved behaviors such as eye movements occur at the speed of cognition and neural activity. We highlight successes using eye-movement tracking with in vivo electrophysiology to link rapid hippocampal oscillations to encoding and retrieval processes that interact over hundreds of milliseconds. This approach will improve research on the neural basis of memory because it pinpoints discrete moments of brain–behavior–cognition correspondence. Eye movements reflect specific memory-processing events and occur at the speed of cognition and neurophysiological activity. Eye movements therefore are better suited for identifying brain–behavior–cognition linkages in episodic memory than are coarse-grained behaviors. Invasive neurophysiological recordings in conjunction with eye-movement tasks have clarified the role of sharp-wave ripples and theta oscillations in episodic memory. [ABSTRACT FROM AUTHOR]

Dravet Syndrome (DS) is a genetic, infantile-onset epilepsy with refractory seizures and severe cognitive impairment. While network level pathophysiology is poorly understood, work in genetic mouse models of DS reveals selective reduction of inhibitory interneuron excitability, a likely mechanism of seizures and comorbidities. Consistent with the critical role of interneurons in timing and recruitment of network activity, hippocampal sharp wave ripples (SPW-R)—interneuron dependent compound brain rhythms essential for spatial learning and memory—are less frequent and ripple frequency is slower in DS mice, both likely to impair cognitive performance. Febrile seizures are characteristic of DS, reflecting a temperature-dependent shift in excitation–inhibition balance. DS interneurons are sensitive to depolarization block and may fall silent with increased excitation precipitating epileptic transformation of ripples. To determine the temperature dependence of SWP-R features and relationship of SPW-R to hippocampal interictal activity, we recorded hippocampal local field potentials in a DS mouse model and wildtype littermate controls while increasing core body temperature. In both genotypes, temperature elevation speeds ripple frequency, although DS ripples remain consistently slower. The rate of SPW-R also increases in both genotypes but subsequently falls in DS mice as interictal epileptic activity simultaneously increases preceding a thermally-evoked seizure. Epileptic events occur intermixed with SPW-R, some during SPW-R burst complexes, and transiently suppress SPW-R occurrence suggesting shared network elements. Together these data demonstrate a temperature dependence of SPW-R rate and ripple frequency and suggest a pathophysiologic mechanism by which elevated temperature transforms a normal brain rhythm into epileptic event. [ABSTRACT FROM AUTHOR]

Dravet Syndrome (DS) is a genetic, infantile-onset epilepsy with refractory seizures and severe cognitive impairment. While network level pathophysiology is poorly understood, work in genetic mouse models of DS reveals selective reduction of inhibitory interneuron excitability, a likely mechanism of seizures and comorbidities. Consistent with the critical role of interneurons in timing and recruitment of network activity, hippocampal sharp wave ripples (SPW-R)—interneuron dependent compound brain rhythms essential for spatial learning and memory—are less frequent and ripple frequency is slower in DS mice, both likely to impair cognitive performance. Febrile seizures are characteristic of DS, reflecting a temperature-dependent shift in excitation–inhibition balance. DS interneurons are sensitive to depolarization block and may fall silent with increased excitation precipitating epileptic transformation of ripples. To determine the temperature dependence of SWP-R features and relationship of SPW-R to hippocampal interictal activity, we recorded hippocampal local field potentials in a DS mouse model and wildtype littermate controls while increasing core body temperature. In both genotypes, temperature elevation speeds ripple frequency, although DS ripples remain consistently slower. The rate of SPW-R also increases in both genotypes but subsequently falls in DS mice as interictal epileptic activity simultaneously increases preceding a thermally-evoked seizure. Epileptic events occur intermixed with SPW-R, some during SPW-R burst complexes, and transiently suppress SPW-R occurrence suggesting shared network elements. Together these data demonstrate a temperature dependence of SPW-R rate and ripple frequency and suggest a pathophysiologic mechanism by which elevated temperature transforms a normal brain rhythm into epileptic event.

Representations related to past experiences play a critical role in memory and decision-making processes. The rat hippocampus expresses these types of representations during sharp-wave ripple (SWR) events, and previous work identified a minority of SWRs that contain ‘replay’ of spatial trajectories at ∼20x the movement speed of the animal. Efforts to understand replay typically make multiple assumptions about which events to examine and what sorts of representations constitute replay. We therefore lack a clear understanding of both the prevalence and the range of representational dynamics associated with replay. Here, we develop a state space model that uses a combination of movement dynamics of different speeds to capture the spatial content and time evolution of replay during SWRs. Using this model, we find that the large majority of replay events contain spatially coherent, interpretable content. Furthermore, many events progress at real-world, rather than accelerated, movement speeds, consistent with actual experiences.

The prefrontal cortex and hippocampus are crucial for memory-guided decision-making. Neural activity in the hippocampus exhibits place-cell sequences at multiple timescales, including slow behavioral sequences (~seconds) and fast theta sequences (~100–200 ms) within theta oscillation cycles. How prefrontal ensembles interact with hippocampal sequences to support decision-making is unclear. Here, we examined simultaneous hippocampal and prefrontal ensemble activity in rats during learning of a spatial working-memory decision task. We found clear theta sequences in prefrontal cortex, nested within its behavioral sequences. In both regions, behavioral sequences maintained representations of current choices during navigation. In contrast, hippocampal theta sequences encoded alternatives for deliberation and were coordinated with prefrontal theta sequences that predicted upcoming choices. During error trials, these representations were preserved to guide ongoing behavior, whereas replay sequences during inter-trial periods were impaired prior to navigation. These results establish cooperative interaction between hippocampal and prefrontal sequences at multiple timescales for memory-guided decision-making.

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., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A prevalent model is that sharp-wave ripples (SWR) arise ‘spontaneously’ in CA3 and propagate recent memory traces outward to the neocortex to facilitate memory consolidation there. Using voltage and extracellular glutamate transient recording over widespread regions of mice dorsal neocortex in relation to CA1 multiunit activity (MUA) and SWR, we find that the largest SWR-related modulation occurs in retrosplenial cortex; however, contrary to the unidirectional hypothesis, neocortical activation exhibited a continuum of activation timings relative to SWRs, varying from leading to lagging. Thus, contrary to the model in which SWRs arise ‘spontaneously’ in the hippocampus, neocortical activation often precedes SWRs and may thus constitute a trigger event in which neocortical information seeds associative reactivation of hippocampal ‘indices’. This timing continuum is consistent with a dynamics in which older, more consolidated memories may in fact initiate the hippocampal-neocortical dialog, whereas reactivation of newer memories may be initiated predominantly in the hippocampus.

The hippocampus plays an essential role in learning. Each of the three major hippocampal subfields, dentate gyrus (DG), CA3, and CA1, has a unique function in memory formation and consolidation, and also exhibit distinct local field potential (LFP) signatures during memory consolidation processes in non-rapid eye movement (NREM) sleep. The classic LFP events of the CA1 region, sharp-wave ripples (SWRs), are induced by CA3 activity and considered to be an electrophysiological biomarker for episodic memory. In LFP recordings along the dorsal CA1-DG axis from sleeping male mice, we detected and classified two types of LFP events in the DG: high-amplitude dentate spikes (DSs), and a novel event type whose current source density (CSD) signature resembled that seen during CA1 SWR, but which, most often, occurred independently of them. Because we hypothesize that this event type is similarly induced by CA3 activity, we refer to it as dentate sharp wave (DSW). We show that both DSWs and DSs differentially modulate the electrophysiological properties of SWR and multiunit activity (MUA). Following two hippocampus-dependent memory tasks, DSW occurrence rates, ripple frequencies, and ripple and sharp wave (SW) amplitudes were increased in both, while SWR occurrence rates in dorsal CA1 increased only after the spatial task. Our results suggest that DSWs, like SWRs, are induced by CA3 activity and that DSWs complement SWRs as a hippocampal LFP biomarker of memory consolidation. [ABSTRACT FROM AUTHOR]

Patterns of neural activity that occur spontaneously during sharp-wave ripple (SWR) events in the hippocampus are thought to play an important role in memory formation, consolidation and retrieval. Typical studies examining the content of SWRs seek to determine whether the identity and/or temporal order of cell firing is different from chance. Such 'first-order' analyses are focused on a single time point and template (map), and have been used to show, for instance, the existence of preplay. The major methodological challenge in first-order analyses is the construction and interpretation of different chance distributions. By contrast, 'second-order' analyses involve a comparison of SWR content between different time points, and/or between different templates. Typical second-order questions include tests of experience- dependence (replay) that compare SWR content before and after experience, and comparisons or replay between different arms of a maze. Such questions entail additional methodological challenges that can lead to biases in results and associated interpretations. We provide an inventory of analysis challenges for second-order questions about SWR content, and suggest ways of preventing, identifying and addressing possible analysis biases. Given evolving interest in understanding SWR content in more complex experimental scenarios and across different time scales, we expect these issues to become increasingly pervasive. This article is part of the TheoMurphymeeting issue 'Memory reactivation: replaying events past, present and future'. [ABSTRACT FROM AUTHOR]

• Extra-hippocampal regions might participate in the expression of sharp-wave ripples (SPW-Rs). • We found two neuronal populations in the lSuM: SPW-R-active (increased firing during SPW-Rs), and SPW-R-unchanged neurons. • lSuM SPW-R-active neurons increased their firing prior to SPW-Rs peak power and hippocampal excitatory neurons. • lSuM SPW-R-active neurons showed a higher firing during theta and slow oscillations compared to SPW-R-unchanged neurons. • These results provide new insight on the interaction between a lSuM neuronal population and hippocampus during SPW-Rs. The extent of the networks that control the genesis and modulation of hippocampal sharp-wave ripples (SPW-Rs), which are involved in memory consolidation, remains incompletely understood. Here, we performed a detailed in vivo analysis of single cell firing in the lateral supramammillary nucleus (lSuM) during theta and slow oscillations, including SPW-Rs, in anesthetized rats. We classified neurons as SPW-R-active and SPW-R-unchanged according to whether or not they increased their firing during SPW-Rs. We show that lSuM SPW-R-active neurons increase their firing prior to SPW-Rs peak power and prior to hippocampal excitatory cell activation. Moreover, lSuM SPW-R-active neurons show increased firing activity during theta and slow oscillations as compared to unchanged neurons. These results suggest that a sub-population of lSuM neurons can interact with the hippocampus during SPW-Rs, raising the possibility that the lSuM may modulate memory consolidation. [ABSTRACT FROM AUTHOR]

Hippocampus forms neural representations of real-life events including multimodal information of spatial and temporal context. These representations, i.e., organized sequences of neuronal firing, are repeated during following rest and sleep, especially when so-called sharp-wave ripples (SPW-Rs) characterize hippocampal local field potentials. This SPW-R -related replay is thought to underlie memory consolidation. Here, we set out to explore how hippocampal CA1 pyramidal cells respond to the conditioned stimulus during trace eyeblink conditioning and how these responses manifest during SPW-Rs in awake adult female New Zealand White rabbits. Based on reports in rodents, we expected SPW-Rs to take place in bursts, possibly according to a slow endogenous rhythm. In awake rabbits, half of all SPW-Rs took place in bursts, but no endogenous slow rhythm appeared. Conditioning trials suppressed SPW-Rs while increasing theta for a period of several seconds. As expected based on previous findings, only a quarter of the putative CA1 pyramidal cells increased firing in response to the conditioned stimulus. Compared with other cells, rateincreasing cells were more active during spontaneous epochs of hippocampal theta while response profile during conditioning did not affect firing during SPW-Rs. Taken together, CA1 pyramidal cell firing during SPW-Rs is not limited to cells that fired during the preceding experience. Furthermore, the importance of possible reactivations taking place during theta epochs on memory consolidation warrants further investigation. [ABSTRACT FROM AUTHOR]

Dravet syndrome (DS) is a severe early-onset epilepsy associated with heterozygous loss-of-function mutations in SCN1A. Animal models of DS with global Scn1a haploinsufficiency recapitulate the DS phenotype, including seizures, premature death, and impaired spatial memory performance. Spatial memory requires hippocampal sharp-wave ripples (SPW-Rs), which consist of high-frequency field potential oscillations (ripples, 100–260 Hz) superimposed on a slower SPW. Published in vitro electrophysiologic recordings in DS mice demonstrate reduced firing of GABAergic inhibitory neurons, which are essential for the formation of SPW-R complexes. Here, in vivo electrophysiologic recordings of hippocampal local field potential in both male and female mice demonstrate that Scn1a haploinsufficiency slows intrinsic ripple frequency and reduces the rate of SPW-R occurrence. In DS mice, peak ripple-band power is shifted to lower frequencies, average intertrough intervals of individually detected ripples are slower, and the rate of SPW-R generation is reduced, while SPW amplitude remains unaffected. These alterations in SPW-R properties, in combination with published reductions in interneuron function in DS, suggest a direct link between reduced inhibitory neuron excitability and impaired SPW-R function. A simple interconnected, conductance-based in silico interneuron network model was used to determine whether reduced sodium conductance is sufficient to slow ripple frequency, and stimulation with a modeled SPW demonstrates that reduced sodium conductance alone is sufficient to slow oscillatory frequencies. These findings forge a potential mechanistic link between impaired SPW-R generation and Scn1a mutation in DS mice, expanding the set of disorders in which SPW-R dysfunction contributes to impaired memory. [ABSTRACT FROM AUTHOR]

Highlights • The hippocampus generates ordered spike sequences to support memory functions. • However, not all synchronized spike sequences contain similar ensemble pattern. • Some synchronized events include non-spatial pyramidal cells. • Non-ordered spike sequences may play functional roles in enriching brain functions. Abstract The hippocampal network generates synchronized spikes of a large population of pyramidal neurons associated with sharp-wave ripples in local field potential signals. Ample evidence demonstrates that the synchronized spikes are created by sequential activation of hippocampal place cells that correspond to the animal's past or future trajectories and are hypothesized to play instrumental roles in mnemonic functions. However, not all place-cell spike sequences are precisely organized, and some sequences are composed of spikes from non-spatial cells, implying that not all hippocampal synchronized events directly replicate learned behavioral episodes. While less attention has been given to such non-ordered spike sequences, variable and dynamic selection of active neuronal assemblies may be optimal mechanisms for rapidly reorganizing functional circuits and self-developing novel representations to enable flexible decision-making processes. We recently showed that specific neurons, including both spatial and non-spatial cells, are preferentially recruited in synchronous events for particular time periods, suggesting that there are temporally fluctuating background states of the hippocampal network that determine active neuronal ensembles. Based on recent reports, this review discusses potential roles of the low-fidelity, heterogeneous repertoire of synchronized spike sequences of hippocampal neurons. [ABSTRACT FROM AUTHOR]

The hippocampus plays a central role as a hub for episodic memory and as an integrator of multimodal sensory information in time and space. Thereby, it critically determines contextual setting and specificity of episodic memories. It is also a key site for the control of innate anxiety states and involved in psychiatric diseases with heightened anxiety and generalized fear memory such as post-traumatic stress disorder (PTSD). Expression of both innate "unlearned" anxiety and "learned" fear requires contextual processing and engagement of a brain-wide network including the hippocampus together with the amygdala and medial prefrontal cortex. Strikingly, the hippocampus is also the site of emergence of oscillatory rhythms that coordinate information processing and filtering in this network. Here, we review data on how the hippocampal network oscillations and their coordination with amygdalar and prefrontal oscillations are engaged in innate threat evaluation. We further explore how such innate oscillatory communication might have an impact on contextualization and specificity of "learned" fear. We illustrate the partial overlap of fear and anxiety networks that are built by the hippocampus in conjunction with amygdala and prefrontal cortex. We further propose that (mal)-adaptive interplay via (dis)-balanced oscillatory communication between the anxiety network and the fear network may determine the strength of fear memories and their resistance to extinction. [ABSTRACT FROM AUTHOR]

Highlights • Network oscillations coordinate neural communication and plasticity. • Network oscillations provide time windows during which memory ensembles can be modified. • Network oscillations and synaptic plasticity are synergized in modulation of memory engrams. • Balanced network oscillations and plasticity are required for adaptive behavioural changes. • Network oscillations act as mediators of behavioural metaplasticity. Abstract Behavioural metaplasticity is evident in experience–dependent changes of network activity patterns in neuronal circuits that connect the hippocampus, amygdala and medial prefrontal cortex. These limbic regions are key structures of a brain-wide neural network that translates emotionally salient events into persistent and vivid memories. Communication in this network by-and-large depends on behavioural state-dependent rhythmic network activity patterns that are typically generated and/or relayed via the hippocampus. In fact, specific hippocampal network oscillations have been implicated to the acquisition, consolidation and retrieval, as well as the reconsolidation and extinction of emotional memories. The hippocampal circuits that contribute to these network activities, at the same time, are subject to both Hebbian and non-Hebbian forms of plasticity during memory formation. Further, it has become evident that adaptive changes in the hippocampus-dependent network activity patterns provide an important means of adjusting synaptic plasticity. We here summarise our current knowledge on how these processes in the hippocampus in interaction with amygdala and medial prefrontal cortex mediate the formation and persistence of emotional memories. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • Awake hippocampal ripples are necessary for post-experience neuronal reactivation • Awake synchronous spike patterns are represented in post-experience reactivation • Place cells recruited in synchronization contribute to post-experience reactivation Yagi et al. find that awake synchronous spike patterns are preferentially incorporated into post-experience neuronal reactivation in the hippocampus. This study proposes a role for awake synchronous events in the extraction of neuronal spike patterns for subsequent neuronal reactivation. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • KIBRA is necessary for experience modulation of neural activity during SWRs • SWR-associated low gamma increases after experience and is disrupted by KIBRA loss • Experience-induced coupling of hippocampal SWRs and cortical spindles requires KIBRA • KIBRA is not required to maintain basal hippocampal or cortical oscillatory dynamics Hippocampal sharp wave/ripples (SWRs) and cortical spindles are coordinated network oscillations proposed to support memory consolidation. Quigley et al. show that KIBRA, a memory-associated regulator of AMPAR trafficking, is required for experience-induced modification and temporal coupling of SWRs and spindles. They identify plasticity mechanisms that enable networks to adapt to new experience. [ABSTRACT FROM AUTHOR]

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 ( V m) level. Here, we recorded V m 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, V m 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 V m, formed by approximately postnatal day 30. This V m 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., Competing Interests: The authors declare no competing financial interests., (Copyright © 2023 the authors.)

Background Hippocampal sharp-wave ripples (SWRs) arising from synchronous bursting in CA3 pyramidal cells and propagating to CA1 are thought to facilitate memory consolidation. Stimulation of the CA3 axon collaterals comprising the hippocampal commissure in rats interrupts sharp-wave ripples and leads to memory impairment. In primates, however, these commissural collaterals are limited. Other hippocampal fiber pathways, like the fornix, may be potential targets for modulating ongoing hippocampal activity, with the short latencies necessary to interrupt ripples. Objective The aim of this study is to determine the efficacy of closed-loop stimulation adjacent to the fornix for interrupting hippocampal ripples. Method Stimulating electrodes were implanted bilaterally alongside the fornix in the macaque, together with microelectrodes targeting the hippocampus for recording SWRs. We first verified that fornix stimulation reliably and selectively evoked a response in the hippocampus. We then implemented online detection and stimulation as hippocampal ripples occurred. Results The closed-loop interruption method was effective in interrupting ripples as well as the associated hippocampal multi-unit activity, demonstrating the feasibility of ripple interruption using fornix stimulation in primates. Conclusion Analogous to murine research, such an approach will likely be useful in understanding the role of SWRs in memory formation in macaques and other primates sharing these pathways, such as humans. More generally, closed-loop stimulation of the fornix may prove effective in interrogating hippocampal-dependent memory processes. Finally, this rapid, contingent-DBS approach may be a means for modifying pathological high-frequency events within the hippocampus, and potentially throughout the extended hippocampal circuit. [ABSTRACT FROM AUTHOR]

Hippocampal- cortical interaction during sleep promotes transformation of memory for long-term storage in the cortex. In particular, hippocampal sharp-wave ripple-associated neural activation is important for this transformation during slow-wave sleep. The anterior cingulate cortex (ACC) has been shown to be crucial for expression and likely storage of long-term memory. However, little is known about howACCactivity is influenced by hippocampal ripple activity during sleep.Wereport here about coordinated interactions between hippocampal ripple activity and ACC neural firings. By recording from the ACC and hippocampal CA1 simultaneously in mice, we found that almost all ACC neurons showed increased activity before hippocampal ripple activity; moreover, a subpopulation (17%) displayed a further activation immediately after ripple activity. This postripple activation of ACC neurons correlated positively with ripple amplitude, and the same neurons were excited upon electrical stimulation of the CA1. Interestingly, the preripple activation of ACC neurons was present during the sleep state, but not during the awake state. These results suggest intimate interactions between hippocampal sharp-wave ripples and ACC neurons in a state-dependent manner. Importantly, sharp-wave ripples and associated activation appear to regulate activity of a small population of ACC neurons, a process that may play a critical role in memory consolidation. [ABSTRACT FROM AUTHOR]

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., Competing Interests: JK, ZR, TK, BM, MM No competing interests declared, (© 2023, Karimi Abadchi et al.)

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. [Display omitted] • TORO cells are hippocampal GABAergic neurons • TORO cells rarely spike during theta states but burst during sharp-wave ripples • TORO cells express inhibitory M2Rs • TORO cells preferentially innervate INs and project extra-hippocampally Szabo et al. identify a subset of hippocampal GABAergic cells with long-range projections and unique activity dynamics. Theta-OFF/ripple-ON (TORO) cells are virtually silent during locomotion and REM sleep theta but fire vigorously during sharp-wave ripples. TORO cells receive CA3 glutamatergic, septal GABAergic, and inhibitory cholinergic inputs and target interneurons. [ABSTRACT FROM AUTHOR]