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Early Sharp Waves (eSPWs) are the earliest pattern of network activity in the developing hippocampus of neonatal rodents. eSPWs were originally considered to be an immature prototype of adult SPWs, which are spontaneous top-down hippocampal events that are self-generated in the hippocampal circuitry. However, recent studies have shifted this paradigm to a bottom-up model of eSPW genesis, in which eSPWs are primarily driven by the inputs from the layers 2/3 of the medial entorhinal cortex (MEC). A hallmark of the adult SPWs is the relay of information from the CA1 hippocampus to target structures, including deep layers of the EC. Whether and how deep layers of the MEC are activated during eSPWs in the neonates remains elusive. In this study, we investigated activity in layer 5 of the MEC of neonatal rat pups during eSPWs using silicone probe recordings from the MEC and CA1 hippocampus. We found that neurons in deep and superficial layers of the MEC fire synchronously during MEC sharp potentials, and that neuronal firing in both superficial and deep layers of the MEC precedes the activation of CA1 neurons during eSPWs. Thus, the sequence of activation of CA1 hippocampal neurons and deep EC neurons during sharp waves reverses during development, from a lead of deep EC neurons during eSPWs in neonates to a lead of CA1 neurons during adult SPWs. These findings suggest another important difference in the generative mechanisms and possible functional roles of eSPWs compared to adult SPWs. [ABSTRACT FROM AUTHOR]

Reliable prognostic biomarkers are needed to support the early diagnosis of brain injury in extremely preterm infants, and to develop effective neuroprotective protocols that are tailored to the progressing phases of injury. Experimental and clinical research shows that severity of neuronal damage is correlated with changes in the electroencephalogram (EEG) after hypoxic-ischemia (HI). We have previously reported that micro-scale sharp-wave EEG waveforms have prognostic utility within the early hours of post-HI recordings in preterm fetal sheep, before injury develops. This article aims to investigate whether these subtle EEG patterns are translational in the early hours of life in clinical recordings from extremely preterm newborns. This work evaluates the existence and morphological similarity of the sharp-waves automatically identified throughout the entire duration of EEG data from a cohort of fetal sheep 6 h after HI (n = 7, at 103 ± 1 day gestation) and in recordings commencing before 6 h of life in extremely preterm neonates (n = 7, 27 ± 2.0 weeks gestation). We report that micro-scale EEG waveforms with similar morphology and characteristics (r = 0.94) to those seen in fetal sheep after HI are also present after birth in recordings started before 6 h of life in extremely preterm neonates. This work further indicates that the post-HI sharp-waves show rapid morphological evolution, influenced by age and/or severity of neuronal loss, and thus that automated algorithms should be validated against such signal variations. Finally, this article discusses the need for more focused research on the early assessment of EEG changes in preterm infants to help determine the timing of brain injury to identify biomarkers that could assist in targeting novel therapies for particular phases of injury.

Early Sharp Waves (eSPWs) are the earliest pattern of network activity in the developing hippocampus of neonatal rodents. eSPWs were originally considered to be an immature prototype of adult SPWs, which are spontaneous top-down hippocampal events that are self-generated in the hippocampal circuitry. However, recent studies have shifted this paradigm to a bottom-up model of eSPW genesis, in which eSPWs are primarily driven by the inputs from the layers 2/3 of the medial entorhinal cortex (MEC). A hallmark of the adult SPWs is the relay of information from the CA1 hippocampus to target structures, including deep layers of the EC. Whether and how deep layers of the MEC are activated during eSPWs in the neonates remains elusive. In this study, we investigated activity in layer 5 of the MEC of neonatal rat pups during eSPWs using silicone probe recordings from the MEC and CA1 hippocampus. We found that neurons in deep and superficial layers of the MEC fire synchronously during MEC sharp potentials, and that neuronal firing in both superficial and deep layers of the MEC precedes the activation of CA1 neurons during eSPWs. Thus, the sequence of activation of CA1 hippocampal neurons and deep EC neurons during sharp waves reverses during development, from a lead of deep EC neurons during eSPWs in neonates to a lead of CA1 neurons during adult SPWs. These findings suggest another important difference in the generative mechanisms and possible functional roles of eSPWs compared to adult SPWs.

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

The developing entorhinal–hippocampal system is embedded within a large-scale bottom-up network, where spontaneous myoclonic movements, presumably via somatosensory feedback, trigger hippocampal early sharp waves (eSPWs). The hypothesis, that somatosensory feedback links myoclonic movements with eSPWs, implies that direct somatosensory stimulation should also be capable of evoking eSPWs. In this study, we examined hippocampal responses to electrical stimulation of the somatosensory periphery in urethane-anesthetized, immobilized neonatal rat pups using silicone probe recordings. We found that somatosensory stimulation in ~33% of the trials evoked local field potential (LFP) and multiple unit activity (MUA) responses identical to spontaneous eSPWs. The somatosensory-evoked eSPWs were delayed from the stimulus, on average, by 188 ms. Both spontaneous and somatosensory-evoked eSPWs (i) had similar amplitude of ~0.5 mV and half-duration of ~40 ms, (ii) had similar current-source density (CSD) profiles, with current sinks in CA1 strata radiatum, lacunosum-moleculare and DG molecular layer and (iii) were associated with MUA increase in CA1 and DG. Our results indicate that eSPWs can be triggered by direct somatosensory stimulations and support the hypothesis that sensory feedback from movements is involved in the association of eSPWs with myoclonic movements in neonatal rats. [ABSTRACT FROM AUTHOR]

• CA1 ripple frequency is reduced with age. • CA3 high frequency event (HFE) power and amplitude is reduced with age. • Age-related changes to CA1 ripples cannot be explained by alterations in CA3 HFEs. • CA1 ripple-CA3 HFE co-occurrence increased frequency, power, and length of events. • Sharp wave current source density amplitude was lower in aged rats. • One young and 2 aged rats were added to the sample size to have adequate statistical power to examine radiatum sharp waves. Sharp wave/ripples/high frequency events (HFEs) are transient bursts of depolarization in hippocampal subregions CA3 and CA1 that occur during rest and pauses in behavior. Previous studies have reported that CA1 ripples in aged rats have lower frequency than those detected in young animals. While CA1 ripples are thought to be driven by CA3, HFEs in CA3 have not been examined in aged animals. The current study obtained simultaneous recordings from CA1 and CA3 in young and aged rats to examine sharp wave/ripples/HFEs in relation to age. While CA1 ripple frequency was reduced with age, there were no age differences in the frequency of CA3 HFEs, although power and length were lower in old animals. While there was a proportion of CA1 ripples that co-occurred with a CA3 HFE, none of the age-related differences in CA1 ripples could be explained by alterations in CA3 HFE characteristics. These findings suggest that age differences in CA1 are not due to altered CA3 activity, but instead reflect distinct mechanisms of ripple generation with age. [ABSTRACT FROM AUTHOR]

Single units were recorded in hippocampus, lateral septum (LS), and dorsomedial striatum (DMS) while freely behaving rats (n = 3) ran trials in a T‐maze task and rested in a holding bucket between trials. In LS, 28% (64/226) of recorded neurons were excited and 14% (31/226) were inhibited during sharp wave ripples (SWRs). LS neurons that were excited during SWRs fired preferentially on the downslope of hippocampal theta rhythm and had firing rates that were positively correlated with running speed; LS neurons that were inhibited during SWRs fired preferentially on the upslope of hippocampal theta rhythm and had firing rates that were negatively correlated with running speed. In DMS, only 3.3% (12/366) of recorded neurons were excited and 5.7% (21/366) were inhibited during SWRs. As in LS, DMS neurons that were excited by SWRs tended to have firing rates that were positively modulated by running speed, whereas DMS neurons that were inhibited by SWRs tended to have firing rates that were negatively modulated by running speed. But in contrast with LS, these two DMS subpopulations did not clearly segregate their spikes to different phases of the theta cycle. Based on these results and a review of prior findings, we discuss how concurrent activation of spatial trajectories in hippocampus and motor representations in LS and DMS may contribute to neural computations that support reinforcement learning and value‐based decision making. [ABSTRACT FROM AUTHOR]

The piriform cortex is rich in recurrent excitatory synaptic connections between pyramidal neurons. We asked how such connections could shape cortical responses to olfactory lateral olfactory tract (LOT) inputs. For this, we constructed a computational network model of anterior piriform cortex with 2000 multicompartment, multiconductance neurons (500 semilunar, 1000 layer 2 and 500 layer 3 pyramids; 200 superficial interneurons of two types; 500 deep interneurons of three types; 500 LOT afferents), incorporating published and unpublished data. With a given distribution of LOT firing patterns, and increasing the strength of recurrent excitation, a small number of firing patterns were observed in pyramidal cell networks: first, sparse firings; then temporally and spatially concentrated epochs of action potentials, wherein each neuron fires one or two spikes; then more synchronized events, associated with bursts of action potentials in some pyramidal neurons. We suggest that one function of anterior piriform cortex is to transform ongoing streams of input spikes into temporally focused spike patterns, called here "cell assemblies", that are salient for downstream projection areas. [ABSTRACT FROM AUTHOR]

It has been known since the time of patient H. M. and Karl Lashley’s equipotentiality studies that the hippocampus and cortex serve mnestic functions. Current memory models maintain that these two brain structures accomplish unique, but interactive, memory functions. Specifically, most modeling suggests that memories are rapidly acquired during waking experience by the hippocampus, before being later consolidated into the cortex for long-term storage. Sleep has been shown to be critical for the transfer and consolidation of memories in the cortex. Like memory consolidation, a role for sleep in adaptive forgetting has both historical precedent, as Francis Crick suggested in 1983 that sleep was for “reverse-learning,” and recent empirical support. In this article I review the evidence indicating that the same brain activity involved in sleep replay associated memory consolidation is responsible for sleep-dependent forgetting. In reviewing the literature, it became clear that both a cellular mechanism for systems consolidation and an agreed upon general, as well as cellular, mechanism for sleep-dependent forgetting is seldom discussed or is lacking. I advocate here for a candidate cellular systems consolidation mechanism wherein changes in calcium kinetics and the activation of consolidative signaling cascades arise from the triple phase locking of non-rapid eye movement sleep (NREMS) slow oscillation, sleep spindle and sharp-wave ripple rhythms. I go on to speculatively consider several sleep stage specific forgetting mechanisms and conclude by discussing a notional function of NREM-rapid eye movement sleep (REMS) cycling. The discussed model argues that the cyclical organization of sleep functions to first lay down and edit and then stabilize and integrate engrams. All things considered, it is increasingly clear that hallmark sleep stage rhythms, including several NREMS oscillations and the REMS hippocampal theta rhythm, serve the dual function of enabling simultaneous memory consolidation and adaptive forgetting. Specifically, the same sleep rhythms that consolidate new memories, in the cortex and hippocampus, simultaneously organize the adaptive forgetting of older memories in these brain regions.

It has been known since the time of patient H. M. and Karl Lashley's equipotentiality studies that the hippocampus and cortex serve mnestic functions. Current memory models maintain that these two brain structures accomplish unique, but interactive, memory functions. Specifically, most modeling suggests that memories are rapidly acquired during waking experience by the hippocampus, before being later consolidated into the cortex for long-term storage. Sleep has been shown to be critical for the transfer and consolidation of memories in the cortex. Like memory consolidation, a role for sleep in adaptive forgetting has both historical precedent, as Francis Crick suggested in 1983 that sleep was for "reverse-learning," and recent empirical support. In this article I review the evidence indicating that the same brain activity involved in sleep replay associated memory consolidation is responsible for sleep-dependent forgetting. In reviewing the literature, it became clear that both a cellular mechanism for systems consolidation and an agreed upon general, as well as cellular, mechanism for sleep-dependent forgetting is seldom discussed or is lacking. I advocate here for a candidate cellular systems consolidation mechanism wherein changes in calcium kinetics and the activation of consolidative signaling cascades arise from the triple phase locking of non-rapid eye movement sleep (NREMS) slow oscillation, sleep spindle and sharp-wave ripple rhythms. I go on to speculatively consider several sleep stage specific forgetting mechanisms and conclude by discussing a notional function of NREM-rapid eye movement sleep (REMS) cycling. The discussed model argues that the cyclical organization of sleep functions to first lay down and edit and then stabilize and integrate engrams. All things considered, it is increasingly clear that hallmark sleep stage rhythms, including several NREMS oscillations and the REMS hippocampal theta rhythm, serve the dual function of enabling simultaneous memory consolidation and adaptive forgetting. Specifically, the same sleep rhythms that consolidate new memories, in the cortex and hippocampus, simultaneously organize the adaptive forgetting of older memories in these brain regions. [ABSTRACT FROM AUTHOR]

Ripples are brief (<150 ms) high-frequency oscillatory neural activities in the brain with a range of 140 to 200 Hz in rodents and 80 to 140 Hz in humans. Ripples are regarded as playing an essential role in several aspects of memory function, mainly in the hippocampus. This type of ripple generally occurs with sharp waves and is called a sharp-wave ripple (SPW-R). Extensive research of SPW-Rs in the rodent brain while actively awake has also linked the function of these SPW-Rs to navigation and decision making. Although many studies with rodents unveiled SPW-R function, research in humans on this subject is still sparse. Therefore, unveiling SPW-R function in the human hippocampus is warranted. A certain type of ripples may also be a biomarker of epilepsy. This type of ripple is called a pathological ripple (p-ripple). p-ripples have a wider range of frequency (80-500 Hz) than SPW-Rs, and the range of frequency is especially higher in brain regions that are intrinsically linked to epilepsy onset. Brain regions producing ripples are too small for scalp electrode recording, and intracranial recording is typically needed to detect ripples. In addition, SPW-Rs in the human hippocampus have been recorded from patients with epilepsy who may have p-ripples. Differentiating SPW-Rs and p-ripples is often not easy. We need to develop more sophisticated methods to record SPW-Rs to differentiate them from p-ripples. This paper reviews the general features and roles of ripple waves., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Functions of the hippocampus are segregated along its long axis and emerging evidence shows that the local circuitry is specialized accordingly. Sharp waves (SPWs) and ripples are a basic hippocampal network activity implicated in memory processing. Using recordings from the CA1 field of both dorsal (DH) and ventral (VH) rat hippocampal slices we found that SPWs are larger, shorter and occur much more frequently in the VH than in the DH. Clusters of SPWs (i.e. multiple consecutive events grouped in sequences that depend on NMDA receptors) occur with higher probability in the VH and the frequency of occurrence of consecutive intra-cluster events is higher in the VH (∼10 Hz) than in the DH (∼5 Hz). The ripple oscillation displays higher amplitude and frequency in the VH than in DH and the associated multiunit firing peaks at a later phase of the ripple waves in the VH than in the DH. Isolated unit complex spike bursts display a significantly lower number of spikes and longer inter-spike intervals in the VH than in the DH suggesting that the synaptically driven neuronal excitability is lower in the VH. We propose that to some extent these differences result from the relatively higher network excitability of the VH compared with DH. Furthermore, they might reflect specializations that provide the local circuitries of the DH and VH with the required optimal ability for synaptic plasticity and might also suggest that the VH could be a favored site of SPW-Rs initiation. [ABSTRACT FROM AUTHOR]

Orexin is a neuromodulatory peptide produced by lateral hypothalamic orexin neurons and binds to G-protein-coupled orexin-1 receptor and orexin-2 receptors. Whether orexin modulates learning and memory is not fully understood. Orexin has biphasic effects on learning and memory: promoting learning and memory at homeostatic levels and inhibiting at supra- and sub-homeostatic levels. Hippocampal sharp wave-ripples encode memory information and are essential for memory consolidation and retrieval. The role of orexin on sharp wave-ripples in hippocampal CA1 remains unknown. Here, we used multi-electrode array recordings in acute ex vivo hippocampal slices to determine the effects of orexin receptor antagonists on sharp wave-ripples. Bath-application of either the orexin-1 receptor antagonist N-(2-Methyl-6-benzoxazolyl)-N'-1,5-naphthyridin-4-yl urea (SB-334867) or the orexin-2 receptor antagonist N-Ethyl-2-[(6-methoxy-3-pyridinyl)[(2-methylphenyl)sulfonyl]amino]-N-(3-pyridinylmethyl)-acetamide (EMPA) reduced sharp wave and ripple incidence, sharp wave amplitude, and sharp wave duration. SB-334867 and EMPA effects on sharp wave amplitude and duration were equivalent, whereas EMPA exhibited a greater reduction of sharp wave and ripple incidence. EMPA also increased ripple duration, whereas SB-334867 had no effect. Inhibition of both orexin receptors with a dual orexin receptor antagonist N-[1,1'-Biphenyl]-2-yl-1-[2-[(1-methyl-1H-benzimidazol-2-yl)thio]acetyl-2-pyrrolidinedicarboxamide (TCS-1102) had effects similar to EMPA, however, sharp wave amplitude and duration were unaffected. Region-specific expression of orexin receptors suggests orexin may regulate sharp wave generation in CA3, dentate gyrus-mediated sharp wave modification, sharp wave propagation to CA1, and local ripple emergence in CA1. Our study indicates an orexin contribution to hippocampal sharp wave-ripple complexes and suggests a mechanism by which sub-homeostatic concentrations of orexin may inhibit learning and memory function. [ABSTRACT FROM AUTHOR]

In human disease, channelopathies involving functional reduction of the delayed rectifier potassium channel α-subunit Kv1.1 – either by mutation or autoimmune inhibition – result in temporal lobe epilepsy. Kv1.1 is prominently expressed in the axons of the hippocampal tri-synaptic pathway, suggesting its absence will result in widespread effects on normal network oscillatory activity. Here, we performed in vitro extracellular recordings using a multielectrode array to determine the effects of loss of Kv1.1 on spontaneous sharp waves (SPWs) and high frequency oscillations (HFOs). We found that Kcna1-null hippocampi generate SPWs and ripples (80–200 Hz bandwidth) with a 50% increased rate of incidence and 50% longer duration, and that epilepsy-associated pathologic HFOs in the fast ripple bandwidth (200–600 Hz) are also present. Furthermore, Kcna1-null CA3 has enhanced coupling of excitatory inputs and population spike generation and CA3 principal cells have reduced spike timing reliability. Removing the influence of mossy fiber and perforant path inputs by micro-dissecting the Kcna1-null CA3 region mostly rescued the oscillatory behavior and improved spike timing. We found that Kcna1-null mossy fibers and medial perforant path axons are hyperexcitable and produce greater pre- and post-synaptic responses with reduced paired-pulse ratios suggesting increased neurotransmitter release at these terminals. These findings were recapitulated in wild-type slices exposed to the Kv1.1 inhibitor dendrotoxin-κ. Collectively, these data indicate that loss of Kv1.1 enhances synaptic release in the CA3 region, which reduces spike timing precision of individual neurons leading to disorganization of network oscillatory activity and promotes the emergence of fast ripples.

During slowwave sleep, interareal communications via coordinated, slow oscillatory activities occur in the large-scale networks of the mammalian neocortex. Because olfactory cortex (OC) areas, which belong to paleocortex, show characteristic sharp-wave (SPW) activity during slow-wave sleep, we examined whether OC SPWs in freely behaving rats occur in temporal coordination with up- and downstates of the orbitofrontal cortex (OFC) slow oscillation. Simultaneous recordings of local field potentials and spike activities in the OC and OFC showed that during the downstate in the OFC, the OC also exhibited downstate with greatly reduced neuronal activity and suppression of SPW generation. OC SPWs occurred during two distinct phases of the upstate of the OFC: early-phase SPWs occurred at the start of upstate shortly after the down-to-up transition in the OFC, whereas late-phase SPWs were generated at the end of upstate shortly before the up-todown transition. Such temporal coordination between neocortical upand downstates and olfactory system SPWs was observed between the prefrontal cortex areas (OFC and medial prefrontal cortex) and the OC areas (anterior piriform cortex and posterior piriform cortex). These results suggest that during slow-wave sleep, OC and OFC areas communicate preferentially in specific time windows shortly after the down-to-up transition and shortly before the up-to-down transition. [ABSTRACT FROM AUTHOR]

In current fMRI studies designed to map BOLD changes related to interictal epileptiform discharges (IED), which are recorded on simultaneous EEG, the information contained in the morphology and field extent of the EEG events is exclusively used for their classification. Usually, a BOLD predictor based on IED onset times alone is constructed, effectively treating all events as identical. We used intracranial EEG (icEEG)-fMRI data simultaneously recorded in humans to investigate the effect of including any of the features: amplitude, width (duration), slope of the rising phase, energy (area under the curve), or spatial field extent (number of contacts over which the sharp wave was observed) of the fast wave of the IED (the sharp wave), into the BOLD model, to better understand the neurophysiological origin of sharp wave-related BOLD changes, in the immediate vicinity of the recording contacts. Among the features considered, the width was the only one found to explain a significant amount of additional variance, suggesting that the amplitude of the BOLD signal depends more on the duration of the underlying field potential (reflected in the sharp wave width) than on the degree of neuronal activity synchrony (reflected in the sharp wave amplitude), and, consequently, that including inter-event variations of the sharp wave width in the BOLD signal model may increase the sensitivity of forthcoming EEG-fMRI studies of epileptic activity. [ABSTRACT FROM AUTHOR]