京都大学 / 新制・課程博士 / 博士(理学) / 甲第23711号 / 理博第4801号 / 新制||理||1688(附属図書館) / 京都大学大学院理学研究科地球惑星科学専攻 / (主査)教授 王 功輝, 教授 釜井 俊孝, 教授 久家 慶子 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

New memories are labile, but over time some of them are stabilized. This thesis investigates the network mechanisms in the brain underlying the gradual consolidation of memory representations. Specifically, I performed a causal test of the long-standing hypothesis that the offline reactivation of new, memory-representing cell assemblies supports memory consolidation by stabilizing those assemblies and increasing the likelihood of their later reinstatement - and therefore presumably of memory recall. I performed multi-unit extracellular recordings in the dorsal CA1 region of behaving mice, from which I detected short-timescale (25 ms) co-activation patterns of principal neurons during exploration of open-field enclosures. These cell assembly patterns appeared to represent space as their expression was spatially tuned and environment specific; and these patterns were preferentially reactivated during sharp wave-ripples (SWRs) in subsequent sleep. Importantly, after exposure to a novel - but not a familiar - enclosure, the strength with which an assembly pattern was reactivated predicted its later reinstatement strength during context re-exposure. Moreover, optogenetic silencing of hippocampal pyramidal neurons during on-the-fly detected SWRs during the sleep following exposure to a novel - but again not a familiar - enclosure impaired subsequent assembly pattern reinstatement. These results are direct evidence for a causal role of SWR-associated reactivation in the stability of new hippocampal cell assemblies. Surprisingly, offline reactivation was only important for the stability of a subset of the assembly patterns expressed in a novel enclosure. Optogenetic SWR silencing only impaired the reinstatement of "gradually strengthened" patterns that had had a significant increasing trend in their expression strength throughout the initial exposure session. Consistent with this result, a positive correlation between reactivation and subsequent reinstatement was only found for these gradually strengthened patterns and not for the other, "early stabilized" patterns. An interesting interpretation is that the properties of the gradually strengthened patterns are all consistent with the Hebbian postulate of "fire together, wire together". To enable investigation of the relation between interneurons and principal cell assembly patterns from extracellular recordings, as a final contribution this thesis describes a statistical framework for the unsupervised classification of interneurons based on their firing properties alone.

Master of Science / Department of Geology / Brice LaCroix / Abdelmoneam Raef / South-central Kansas has experienced an increase in seismic activity within the Proterozoic basement over the past 10 years. In 2009, Oklahoma seismic stations recorded 50 earthquakes statewide, a 200% increase from 2008. Oklahoma Geological Survey (OGS) seismograph stations recorded 1,028 in 2010, an increase of over 2000% from 2009. Between 2000-2012, Kansas experienced only 12 earthquakes statewide. Beginning in September 2013, clusters of seismic events in south-central Kansas began to increase. In 2015 alone, Kansas seismograph stations recorded 448 earthquakes, of which 166 resulted in a magnitude 2.0 or greater. Since 2013, United States Geological Survey (USGS) seismograph stations have recorded over 12,000 earthquakes within Kansas and Oklahoma. Pore fluid pressure increases associated with recent high-rate wastewater injection into the dolomitic Arbuckle disposal zone are hypothesized as cause of reactivation of the faulted study region’s Proterozoic basement. Although the magnitude of fluid-pressure change required for reactivation of these faults is likely low given failure equilibrium conditions in the midcontinent, heterogeneities (i.e. permeability, porosity, fluid pressure) in the basement could allow for a range of fluid pressure changes associated with injection. This research aims to quantify the fluid pressure changes responsible for fault reactivation of the Proterozoic basement. To address this issue, we use 97 earthquake focal mechanisms and over 12,000 seismic events, from the USGS catalog, within an area encompassing ~ 4,000 km². Focal mechanism data was utilized to determine the regional stress field present within the study region. Nodal plane data extracted from the focal mechanisms was crucial to identifying lineaments within the underlying basement complex. A 3D seismic dataset covering the Wellington and Anson Bates Fields in north central Sumner County, Kansas was utilized for enhanced structural delineation of an interpreted faultnetwork affecting the Mississippian and Arbuckle Groups, to investigate whether it impacts the underlying granitic basement and its complex network of potentially interconnected fault planes. Smoothed similarity and spectral whitening analyses were applied to the dataset to improve depth of investigation and uncover fault lineaments masked by seismic attenuation due to increasing depth. An interpreted network of fault planes at depths of 3.5 km was uncovered beneath Wellington Field. The lineaments are well aligned with known structural features present within the Proterozoic basement, the Central Kansas Uplift and the Nemaha Ridge-Humboldt fault zone.

Emotion is thought to modulate the long-term fate of memories. Experiences that elicit an emotional response tend to be better remembered than comparatively unemotional events, while the emotional charge associated with these memories diminishes over time. Sleep – in particular rapid-eye movement (REM) and slow-wave sleep (SWS) - has been implicated in both the selective strengthening and affective uncharging of emotional memories. According to the sleep to forget, sleep to remember (SFSR) hypothesis, both processes occur in parallel during REM sleep. Although evidence strongly supports a role of REM sleep in the selective consolidation of emotional memories, it is far less clear to what extent sleep is involved in the development of emotional charge. While some studies support a primary role of REM in habituation (i.e. the decrease of emotional charge), others suggest a more central role of SWS. Further, existing literature indicates that the physiological (bottom-up) and cognitive (top-down) components of emotional responses may be differentially processed across sleep. Chapter 2 proposes complementary functions of REM and SWS in emotional memory processes based on a combination of evidence from rodent and human research. The experiments presented in this thesis employed polysomnography (PSG), subjective arousal testing, pupillometry, targeted memory reactivation (TMR), and transcranial alternating current stimulation (tACs) to investigate the respective roles of REM and SWS in the overnight development of subjective and autonomic arousal in response to negative emotional and neutral stimuli. In Chapter 3 I assessed how subjective and autonomic responses to neutral and negative stimuli develop across 12 hours containing either nocturnal sleep or daytime wakefulness. I found that autonomic reactivity – indexed by pupil dilation – decreased across sleep but not wake, while subjective arousal did not change across either interval. In a further experiment, I investigated whether the placement of sleep within a 24 hour interval would affect habituation. Once again, autonomic arousal decreased significantly. Subjective arousal towards negative stimuli was found to decrease more if sleep followed rather than preceded daytime wakefulness within the 24 hour interval. In Chapter 4 I explored the role of REM sleep in emotional habituation by applying 5 Hz tACs in an attempt to entrain endogenous cortical theta (4-7 Hz) activity, which has previously been associated with emotional memory consolidation in humans. Surprisingly, I found that stimulation was associated with a reduction in theta power and no change in subjective or autonomic habituation compared to the sham control night. In Chapters 5 and 6, I addressed the contribution of memory reactivations during SWS and REM sleep, respectively, in emotional habituation using TMR. In Chapter 5, I found that TMR was associated with a decrease and simultaneous increase in autonomic habituation towards negative and neutral stimuli, respectively, without affecting overnight changes in subjective arousal. In contrast, in Chapter 6, TMR during REM sleep was associated with an increase in subjective habituation towards both neutral and negative stimuli without affecting autonomic responses. In conclusion, my results provide new insights to the role of sleep in emotional habituation. I have provided evidence that targeted memory reactivation during REM sleep can modulate the development of cognitive evaluations of emotion, while TMR during SWS may interfere with autonomic habituation. This suggests distinct emotional processing during REM and SWS, as well as a dissociation between subjective and autonomic habituation across sleep. These results are discussed in the light of previous research and the model of sleep-dependent emotional memory processing proposed in Chapter 2.

[pt] Visando aumentar a produção de hidrocarbonetos, a indústria do petróleo desenvolveu métodos de recuperação cujo objetivo é obter uma maior produção. Assim, diversos problemas podem ser encontrados quando se faz uso destas técnicas, principalmente a convencional, em reservatórios geologicamente complexos. Por outro lado, a consideração de estruturas geológicas na engenharia de reservatórios, como as falhas, tem caráter fundamental para a determinação de respostas realísticas quanto à produção de hidrocarboneto. No caso específico da falha, a sua consideração no modelo apresenta importância significativa no âmbito atual, principalmente no que diz respeito à possibilidade de reativação, relacionada com o surgimento de um caminho preferencial para o hidrocarboneto, implicando, nos casos mais críticos, no escape de fluido e na possível perda da estanqueidade do reservatório. Neste contexto, foram idealizados quatro modelos de reservatório com inclinações de falha e zona de falha de 80 graus e 60 graus. Aliado às simulações hidromecânicas, foram estudadas duas abordagens numéricas para tratar o plano/zona de falha. A primeira metodologia empregada faz uso de interações de contato e a falha foi tratada como um plano. A segunda metodologia considera uma zona de falha cujo comportamento é dado pelo critério de plastificação de Mohr-Coulomb. Pela análise dos resultados foi observado que o emprego de interações de contato requer a utilização de um modelo de atrito que leve em consideração a queda das tensões normais efetivas no critério de ruptura. O modelo de plasticidade apresentou resultados consistentes em relação ao processo de reativação da zona de falha para os modelos construídos. Como conclusão geral do trabalho, afirma-se que a consideração de planos de falha ou zonas de falha em reservatórios devem ser definidas cautelosamente no modelo geomorfológico, uma vez que a modelagem destes tipos de estruturas geológicas requer a utilização de diferentes técnicas numéricas para determinar seu comportamento hidromecânico. / [en] Aiming to increase hydrocarbon production, the oil industry has developed recovery methods whose purpose is to get more production. Thus, several problems may be encountered when making use of these techniques, mainly the conventional, in geologically complex reservoirs. In addition, consideration of geological structures in reservoir engineering, such as faults, has fundamental character for determining realistic response for the production of hydrocarbons. In the specific case of faults, its consideration in the model has significant importance currently, especially with regard to the possibility of reactivation associated with the emergence of a preferential path for the hydrocarbon, implying, in the most critical cases, in the leakage of fluid and possible loss of tightness of the reservoir. In this context, four reservoir models were developed with slope of 80 degrees and 60 degrees for the cases of fault plane and fault zone. Using coupled hydro-mechanical simulations we studied two numerical approaches to treat the plan/fault zone. The first methodology makes use of contact interactions and the fault was treated as a plan. The second methodology considers a fault zone whose behavior is given by the criterion of Mohr-Coulomb yielding. In the analysis of the results was observed that the use of contact interactions requires the use of a friction model that takes into account the drop of the effective normal stress in the failure criterion. The plasticity model showed consistent results in relation to the process of reactivation of the fault zone for the models built. As a general conclusion of the study, it is stated that the consideration of fault planes or fault zones in reservoirs must be carefully defined in the geomorphological model, since the modeling of these types of geological structures requires the use of different numerical techniques to determine their hydromechanical behavior.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22359号 / 医博第4600号 / 新制||医||1042(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 長尾 美紀, 教授 滝田 順子, 教授 河本 宏 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

abstract: Fusion proteins that specifically interact with biochemical marks on chromosomes represent a new class of synthetic transcriptional regulators that decode cell state information rather than deoxyribose nucleic acid (DNA) sequences. In multicellular organisms, information relevant to cell state, tissue identity, and oncogenesis is often encoded as biochemical modifications of histones, which are bound to DNA in eukaryotic nuclei and regulate gene expression states. In 2011, Haynes et al. showed that a synthetic regulator called the Polycomb chromatin Transcription Factor (PcTF), a fusion protein that binds methylated histones, reactivated an artificially-silenced luciferase reporter gene. These synthetic transcription activators are derived from the polycomb repressive complex (PRC) and associate with the epigenetic silencing mark H3K27me3 to reactivate the expression of silenced genes. It is demonstrated here that the duration of epigenetic silencing does not perturb reactivation via PcTF fusion proteins. After 96 hours PcTF shows the strongest reactivation activity. A variant called Pc2TF, which has roughly double the affinity for H3K27me3 in vitro, reactivated the silenced luciferase gene by at least 2-fold in living cells. / Dissertation/Thesis / Masters Thesis Biological Design 2019

<p>RNA-directed DNA methylation (RdDM) is a process by which epigenetic silencing is maintained at the boundary between genes and flanking transposable elements. In maize, RdDM is dependent on <i>Mediator of Paramutation 1 (Mop1</i>), a putative RNA dependent RNA polymerase. Here I show that although RdDM is essential for the maintenance of DNA methylation of a silenced <i>MuDR</i> transposon in maize, a loss of that methylation does not result in a restoration of activity of that element. Instead, heritable maintenance of silencing is maintained by histone modifications. At one terminal inverted repeat (TIR) of the element, heritable silencing is mediated via H3K9 and H3K27 dimethylation, even in the absence of DNA methylation. At the second TIR, heritable silencing is mediated by H3K27 trimethylation, a mark normally associated with somatically inherited gene silencing. I find that a brief exposure of high temperature in a <i>mop1</i> mutant rapidly reverses both of these modifications in conjunction with a loss of transcriptional silencing. These reversals are heritable, even in <i>mop1</i> wild type progeny in which methylation is restored at both TIRs. These observations suggest that DNA methylation is neither necessary to maintain silencing, nor is it sufficient to initiate silencing once it has been reversed. To leverage the specificity of our observations made at bench, I also performed a transcriptome analysis in <i>mop1</i> mutants under heat. I found that a substantial number of genes as well as a subset of TEs are reactivated in <i>mop1</i> mutants under heat, which is consistent with the effects I observed on <i>MuDR</i>. Interestingly, I found that <i>mop1</i>-specific reactivation of TEs is closely correlated with changes in expression of nearby genes, most of which are involved in metabolic transportation and sensing. This suggests that one function of <i>MOP1</i> is to prevent inappropriate expression of genes in this pathway when they are close to TEs. Taken together, my work will provide an opportunity to better understand the causes and consequences of TE silencing and reactivation, as well as the effects of TEs on gene regulation under stress conditions.</p>

The method targeted memory reactivation (TMR) uses specific stimulation when subjects are completing tasks and during sleep. The TMR process is known to influence the consolidation of declarative memories. The aim of this thesis is to conduct a systematic review on the effects of TMR on declarative memory consolidation during slow-wave sleep (SWS). The research question is to answer what effect TMR during SWS has on the consolidation of declarative memory in healthy humans when presented with associated cues of the targeted learning experiences. Eighteen studies were included in this review. Four studies found a significant effect of TMR on declarative memory consolidation, and 10 found a non-significant effect. In four studies the effect of TMR depended on different inclusions, analyses, and factors, for example between slow oscillation up-and down-states and between participants that vary in pre-sleep performance in the examined task. In contrast to previous findings, this review does not provide evidence for the effect of TMR on declarative memories during SWS. More research analysing different factors, such as different cues, age of participants, duration of SWS, and specific experimental tasks, needs to be done in the fields of TMR and auditory cues.

No description available.