掲載種別：研究論文（学術雑誌）   共著区分：単著  

掲載種別：研究論文（学術雑誌）   共著区分：共著   国際・国内誌：国際誌  

New memories are believed to be consolidated over several hours of post-task sleep. The reactivation or “replay” of hippocampal cell assemblies has been proposed to provide a key mechanism for this process. However, previous studies have indicated that such replay is restricted to the first 10–30 min of post-task sleep, suggesting that it has a limited role in memory consolidation. We performed long-duration recordings in sleeping and behaving male rats and applied methods for evaluating the reactivation of neurons in pairs as well as in larger ensembles while controlling for the continued activation of ensembles already present during pre-task sleep (“preplay”). We found that cell assemblies reactivate for up to 10 h, with a half-maximum timescale of ∼6 h, in sleep following novel experience, even when corrected for preplay. We further confirmed similarly prolonged reactivation in post-task sleep of rats in other datasets that used behavior in novel environments. In contrast, we saw limited reactivation in sleep following behavior in familiar environments. Overall, our findings reconcile the duration of replay with the timescale attributed to cellular memory consolidation and provide strong support for an integral role of replay in memory.

DOI： 10.1523/JNEUROSCI.1950-18.2018

PubMed

担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   共著区分：共著   国際・国内誌：国際誌  

Neurons fire at highly variable intrinsic rates and recent evidence suggests that low- and high-firing rate neurons display different plasticity and dynamics. Furthermore, recent publications imply possibly differing rate-dependent effects in hippocampus versus neocortex, but those analyses were carried out separately and with potentially important differences. To more effectively synthesize these questions, we analyzed the firing rate dynamics of populations of neurons in both hippocampal CA1 and frontal cortex under one framework that avoids the pitfalls of previous analyses and accounts for regression to the mean (RTM). We observed several consistent effects across these regions. While rapid eye movement (REM) sleep was marked by decreased hippocampal firing and increased neocortical firing, in both regions firing rate distributions widened during REM due to differential changes in high- versus low-firing rate cells in parallel with increased interneuron activity. In contrast, upon non-REM (NREM) sleep, firing rate distributions narrowed while interneuron firing decreased. Interestingly, hippocampal interneuron activity closely followed the patterns observed in neocortical principal cells rather than the hippocampal principal cells, suggestive of long-range interactions. Following these undulations in variance, the net effect of sleep was a decrease in firing rates. These decreases were greater in lower-firing hippocampal neurons but also higher-firing frontal cortical neurons, suggestive of greater plasticity in these cell groups. Our results across two different regions, and with statistical corrections, indicate that the hippocampus and neocortex show a mixture of differences and similarities as they cycle between sleep states with a unifying characteristic of homogenization of firing during NREM and diversification during REM.

DOI： 10.1038/s41598-018-36710-8

PubMed

掲載種別：研究論文（学術雑誌）   共著区分：共著   国際・国内誌：国際誌  

The synchronous activity of populations of neurons in patterns known as sharp-wave ripples (SPW-Rs), which contain fragments of time-compressed neuronal sequences that are replayed from those experienced during waking hours, is thought to mediate the transfer of newly acquired hippocampal information to distributed circuits in support of memory consolidation. Consistent with this hypothesis, it has been shown that the perturbation of neuronal activity during SPW-Rs can lead to memory impairment. Waking theta states and rapid eye movement (REM) sleep involve different kinds of temporal coordination in the hippocampal-entorhinal circuit, reflecting the distinct balance of hippocampal and entorhinal input to the CA1 area. The firing rates of individual neurons follow lognormal-like distributions in all brain states. Fast-firing minority and slow-firing majority neurons, which support system stability and mnemonic functions, are under distinct firing-rate regulation that is initiated by spindles and SPW-Rs during non-REM sleep and implemented during REM sleep.

担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   共著区分：共著   国際・国内誌：国際誌  

STUDY OBJECTIVES:
To better understand the distinct activity patterns of the brain during sleep, we observed and investigated periods of diminished oscillatory and population spiking activity lasting for seconds during non-rapid eye movement (non-REM) sleep, which we call "LOW" activity sleep.

METHODS:
We analyzed spiking and local field potential (LFP) activity of hippocampal CA1 region alongside neocortical electroencephalogram (EEG) and electromyogram (EMG) in 19 sessions from four male Long-Evans rats (260-360 g) during natural wake/sleep across the 24-hr cycle as well as data from other brain regions obtained from http://crcns.org.1,2.

RESULTS:
LOW states lasted longer than OFF/DOWN states and were distinguished by a subset of "LOW-active" cells. LOW activity sleep was preceded and followed by increased sharp-wave ripple activity. We also observed decreased slow-wave activity and sleep spindles in the hippocampal LFP and neocortical EEG upon LOW onset, with a partial rebound immediately after LOW. LOW states demonstrated activity patterns consistent with sleep but frequently transitioned into microarousals and showed EMG and LFP differences from small-amplitude irregular activity during quiet waking. Their likelihood decreased within individual non-REM epochs yet increased over the course of sleep. By analyzing data from the entorhinal cortex of rats,1 as well as the hippocampus, the medial prefrontal cortex, the postsubiculum, and the anterior thalamus of mice,2 obtained from http://crcns.org, we confirmed that LOW states corresponded to markedly diminished activity simultaneously in all of these regions.

CONCLUSIONS:
We propose that LOW states are an important microstate within non-REM sleep that provide respite from high-activity sleep and may serve a restorative function.

DOI： 10.1093/sleep/zsx066

PubMed

掲載種別：研究論文（学術雑誌）   共著区分：共著   国際・国内誌：国際誌  

According to a two-stage memory consolidation model, during waking theta states, afferent activity from the neocortex to the hippocampus induces transient synaptic modification in the hippocampus, where the information is deposited as a labile form of memory trace. During subsequent sharp-wave ripples (SPW-Rs), the newly acquired hippocampal information is transferred to the neocortex and stored as a long-lasting memory trace. Consistent with this hypothesis, waking theta states and SPW-Rs distinctly control information flow in the hippocampal–entorhinal loop. Although both waking theta states and rapid eye movement (REM) sleep are characterized by prominent hippocampal theta oscillations, the two brain states involve distinct temporal coordination and oscillatory coupling in the hippocampal–entorhinal circuit. While distinct brain states have distinct network dynamics, firing rates of individual neurons in the hippocampal–entorhinal circuitry follow lognormal-like distributions in all states. Firing rates of the same neurons are positively correlated across brain states and testing environments, suggesting that memory is allocated in preconfigured, rather than tabula rasa-type, skewed neuronal networks. The fast-firing minority and slow-firing majority neurons, which can support network stability and flexibility, are under distinct homeostatic regulations that are initiated by spindles and SPW-Rs during slow wave sleep and implemented during subsequent REM sleep.

DOI： 10.1016/j.neures.2017.04.018

PubMed

担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   共著区分：共著   国際・国内誌：国際誌  

It has been hypothesized that waking leads to higher-firing neurons, with increased energy expenditure, and that sleep serves to return activity to baseline levels. Oscillatory activity patterns during different stages of sleep may play specific roles in this process, but consensus has been missing. To evaluate these phenomena in the hippocampus, we recorded from region CA1 neurons in rats across the 24-hr cycle, and we found that their firing increased upon waking and decreased 11% per hour across sleep. Waking and sleeping also affected lower- and higher-firing neurons differently. Interestingly, the incidences of sleep spindles and sharp-wave ripples (SWRs), typically associated with cortical plasticity, were predictive of ensuing firing changes and were more robustly predictive than other oscillatory events. Spindles and SWRs were initiated during non-REM sleep, yet the changes were incorporated in the network over the following REM sleep epoch. These findings indicate an important role for spindles and SWRs and provide novel evidence of a symbiotic relationship between non-REM and REM stages of sleep in the homeostatic regulation of neuronal activity.

DOI： 10.1016/j.cub.2016.02.024

PubMed

J-GLOBAL

掲載種別：研究論文（学術雑誌）   共著区分：共著   国際・国内誌：国際誌  

The medial prefrontal cortex (mPFC) plays an important role in memory. By maintaining a working memory buffer, neurons in prelimbic (PL) mPFC may selectively contribute to learning associations between stimuli that are separated in time, as in trace fear conditioning (TFC). Until now, evidence for this bridging role was largely descriptive. Here we used optogenetics to silence neurons in the PL mPFC of rats during learning in TFC. Memory formation was prevented when mPFC was silenced specifically during the interval separating the cue and shock. Our results provide support for a working memory function for these cells and indicate that associating two noncontiguous stimuli requires bridging activity in PL mPFC.

DOI： 10.1523/JNEUROSCI.0144-13.2013

PubMed

J-GLOBAL

担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   共著区分：共著   国際・国内誌：国際誌  

Synapses in the mammalian central nervous system show substantial diversity in their physiological and morphological properties. However, the correlations among them have remained elusive. Here, we tried to clarify the correlations by establishing a method to record excitatory postsynaptic currents (EPSCs) at individual synapses and also to observe the morphology at the same time. A pair of pre‐ and postsynaptic neurons were labeled with different fluorescent dyes, and a presynaptic varicosity was selectively stimulated with a θ‐tube glass electrode under conditions in which action potential generation was suppressed. Two representative types of excitatory glutamatergic synapses, one on hippocampal pyramidal neurons and the other on cerebellar Purkinje neurons, were studied. The correlations between the properties of quantal EPSCs (qEPSCs) and those of synaptic morphology were analyzed in rat primary culture preparations. The amplitude and the decay time of qEPSC were correlated with the size of the postsynaptic spine only at hippocampal synapses. In contrast, the size of the presynaptic varicosity was correlated with the size of the postsynaptic spine and the quantal content of evoked EPSCs only at granule neuron–Purkinje neuron synapses in the cerebellum. These results suggest that the interaction between pre‐ and postsynaptic structures and the coupling of postsynaptic responsiveness and the spine morphology differ between cerebellar and hippocampal glutamatergic synapses.

DOI： 10.1002/syn.20860

PubMed

J-GLOBAL

掲載種別：研究論文（学術雑誌）   共著区分：共著   国際・国内誌：国際誌  

プルキンエ細胞は小脳皮質における唯一の出力細胞であり、その機能障害は重篤な運動失調を引き起こす。本研究では、自己誘導された峡部オーガナイザーの微小環境からシグナルを捉えることにより、小脳プルキンエ細胞がマウスの胚性幹細胞（ES細胞）から安定的に形成されることを発見した。細胞表面のマーカー分子Neph3を用いることにより、成熟プルキンエ細胞と同様の樹状突起分枝パターンを有しプルキンエ細胞特異的マーカーであるグルタミン酸受容体δ２サブユニットを発現するプルキンエ細胞前駆体を前もって選択することが可能となった。これらの細胞は成熟プルキンエ細胞と同様の特徴的な自発発火パターンを示し、これらの細胞への興奮性シナプス入力は非NMDA型グルタミン酸受容体を介したものであった。蛍光フローサイトメトリーにより分離された前駆細胞を胎生移植すると、プルキンエ細胞層に同所性に組み込まれ、その軸索は小脳核に到達し樹状突起は登上線維および平行線維からの入力を受けることが見いだされた。この小脳プルキンエ細胞の分化誘導法はこの重要な神経細胞の研究に対するさらなる研究の礎となるものである。

DOI： 10.1038/nn.2638

PubMed

J-GLOBAL

掲載種別：記事・総説・解説・論説等（学術雑誌）  

DOI： 10.1016/j.neures.2009.09.112

掲載種別：記事・総説・解説・論説等（学術雑誌）  

会議種別：口頭発表（一般）  

会議種別：口頭発表（招待・特別）  

開催地：Ribeirão Preto, Brazil  

Sleep positively impacts various types of memories, including those that are hippocampal dependent. However, it is still not clear how hippocampal activity changes during sleep. To investigate this, we performed in vivo large-scale electrophysiological recordings on hippocampal CA1 region of rats in natural awake/sleep cycles. We recorded neuronal activity continuously up to 72 hours in 12-hour light and 12-hour dark cycles. In rodents, sleep consists of two distinct states. One is REM (rapid eye movement) that is characterized by an increase in power in the theta band (5-10 Hz). The other is non-REM that is characterized by transient oscillatory events - sleep spindles and sharp wave ripples (SWRs) and continuous slow (0.5 - 4Hz) oscillation. We found that non-REM firing rates decreased during long-lasting sleep, in contrast to extended wake states where firing rates increased gradually in the hippocampus. In addition, incidences of sleep spindles and SWRs and slow-wave amplitudes decreased across sleep. These changes were not correlated with circadian cycles. These results demonstrate that hippocampal activities depend on sleep/awake history. In the triplets of non-REM1/REM/non-REM2, mean firing rates in non-REM2 were significantly lower than in non-REM1. Firing rates in non-REM1 tightly coupled with changes in firing rates between non-REM1 and non-REM2. In addition, incidence of sleep spindles and SWRs were also strongly correlated with firing rates and the firing rates changes. As previously reported by Grosmark et al. (2012), we observed significant correlation between firing rate changes between non-REM epochs and power in theta during interleaved REM. However, this correlation was weaker than incidence of spindles, SWRs, or firing rates in non-REM. In addition, we found firing rates in non-REM were predictive of theta power in the following REM. These results indicate more “excitable” states induce larger decrease of firing in the hippocampus. We also investigated correlation between hippocampal firing and slow wave oscillation. In the neocortex, it is argued that slow-wave oscillations have a role to decrease neuronal firing through downscaling synaptic connectivity (Tononi & Cirelli, 2014). However, we did not find significant correlations between slow-wave oscillations in the hippocampus and firing rates or changes in firing rates, which may indicate the hippocampus operate under a different set of rules from the neocortex. We found that hippocampal activity gradually decreased across sleep, and enhanced excitability in the hippocampus induced large decrease of hippocampal firing, which may contribute to maintain homeostasis in the hippocampus.