Contemporary cellular models of learning and memory are articulated around the idea that synapses undergo activity-dependent weight changes. However, conventional forms of Hebbian plasticity do not adequately address certain features inherent to behavioral learning. First, associative learning driven by delayed behavioral outcomes introduces a temporal credit assignment problem, whereby one must remember which action corresponds to which outcome. Yet, current models of associative synaptic plasticity, such as spike-timing-dependent plasticity, require near coincident activation of pre- and postsynaptic neurons (i.e., within ~ 10 ms), a time delay that is orders of magnitude smaller than that required for behavioral associations. For individual neurons to associate two cues, a biological mechanism capable of potentiating synaptic weights must be able to bind events that are separated in time. Theoretical work has suggested that a synaptic eligibility trace, a time-limited process that momentarily renders synapses eligible for weight updates via delayed instructive signals, can solve this problem. However, no material substrate of eligibility traces has been identified in the brain. Second, under certain conditions, neurons need to swiftly update their weights to reflect rapid learning. Current plasticity experiments require the repetition of multiple pairings to induce long-term synaptic plasticity. In this thesis, I addressed these problems using a combination of whole-cell recordings, two-photon uncaging, calcium imaging, and mechanistic modeling. I uncovered a form of synaptic plasticity known as behavioral timescale synaptic plasticity (BTSP) in layer 5 pyramidal neurons in the prefrontal cortex of mice. BTSP induced synaptic potentiation by pairing temporally separated pre- and postsynaptic events (0.5 s - 1 s), regardless of their order. The temporal window for BTSP induction offers a line of solution to the temporal credit assignment problem by highlighting the presence of a synaptic mechanism that expands the time for the induction of activity-dependent long-term synaptic plasticity, spanning hundreds of milliseconds. We further found that BTSP can be induced following a single pairing, enabling rapid weight updates required for one-shot learning. Using two-photon calcium imaging in apical oblique dendrites, I discovered a novel short-term and associative plasticity of calcium dynamics (STAPCD) that exhibited temporal characteristics mirroring the induction rules of BTSP. I identified a core set of molecular components crucial for both STAPCD and BTSP and developed a computational simulation that models the calcium dynamics as a latent memory trace of neural activity (i.e., eligibility traces). Together, we find that calcium handling by the endoplasmic reticulum enables synaptic weight updates upon receipt of delayed instructive signals, obeys rules of burst-dependent one-shot learning, and thus provides a mechanism that satisfies the requirements anticipated of eligibility traces. Collectively, these findings offer a neural mechanism for the binding of cellular events occurring in single shot and separated by behaviorally relevant temporal delays to induce potentiation at synapses, providing a cellular model of associative learning.

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京都大学 / 新制・課程博士 / 博士(理学) / 甲第23703号 / 理博第4793号 / 新制||理||1686(附属図書館) / 京都大学大学院理学研究科物理学・宇宙物理学専攻 / (主査)教授 井岡 邦仁, 教授 萩野 浩一, 教授 田中 貴浩 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

Yes / Bridge pier is a common feature in hydraulic structure. Its impact to the river usually occurs in group form rather than single pier, so this challenging piers-group influence towards river hydraulics and turbulence needs to be explored. In this paper, the measurements were conducted using an Acoustic doppler velocimeter (ADV) to study velocities in three dimensions (longitudinal, transversal, and vertical). Based on the experimental data, we have observed reversed depth-averaged velocity vector after each pier in the group of three-pier. The analysis has been conducted on the contribution of each bursting event to Reynolds shear stress (RSS) generation, in order to identify the critical events and turbulence structures around the piers. In the upstream near-wake flow in the bed-wall layer, strong sweep and ejection events have been observed; while at downstream, sweeps were more dominant. The pattern of burst changed in the outer layer of flow, where ejections were more dominant. Furthermore, the contribution fractional ratio to RSS variation at hole size H = 0 indicates that sweeps and ejections were significantly generated at the near wake-flow in upstream.

Post-traumatic stress disorder (PTSD) is a highly debilitating mental illness that is incited by various types of trauma and causes core symptoms of re-experiencing, hyperarousal, avoidance of trauma-related stimuli, and negative cognition and mood. It is accompanied by functional, social, and occupational impairment, as well as higher risks of medical comorbidities and mortality. Estimates indicate that PTSD affects 3.9% of the global population, and 7-9% of the US population, with only 50% of those with persistent PTSD treatment-seeking. The gold standard of PTSD treatment is prolonged exposure therapy and cognitive processing theory, with the addition of antidepressants; however, dropout rates are high likely due to the adverse effects of worsening re-experiencing of trauma and exacerbating behaviors of avoidance. As a result, alternative therapies such as transcranial magnetic stimulation (TMS) represent more tolerable treatment options. Historically, literature on TMS is promising for its low risk of side effects and efficacy, but there is no general consensus on treatment-specific targets, frequency of treatment delivery, or long-term efficacy. This proposed study will evaluate the use of neuroimaging guided intermittent theta burst stimulation, a form of TMS, for core PTSD symptom reduction and its efficacy up to one year in duration to potentially reduce the morbidity and mortality sequelae of PTSD.

Neste estudo foi verificado os efeito do α-tocoferol (AT) nas vias de sinalização celular, dependentes de proteína quinase C (PKC) e de tirosinas quinases (TK), associadas ao \"burst\" oxidativo de neutrófilos humanos. Foram realizados também estudos comparativos com o inibidor da PKC, estaurosporina, com o inibidor de tirosinas quinases, genisteína e, com o análogo solúvel da vitamina E, Trolox. Foi feita a incorporação de AT in vitro às células, e então, estas foram estimuladas ou não com acetato de forbol miristato (PMA) ou com zymosan opsonizado (Zy). AT (40 µM) inibiu a produção de espécies reativas de oxigênio (ERO) pelos neutróflos estimulados com PMA ou Zy. Estaurosporina (10 nM), genisteína (100 µM) e Trolox (40 µM) também tiveram efeitos inibitórios. A atividade da PKC foi inibida pelo AT e pela estaurosporina, entretanto, a atividade da enzima não foi afetada pela genisteína e pelo Trolox. PMA e Zy promoveram um aumento da fosforilação em resíduos de tirosina de proteínas de neutrófilos. AT e estaurosporina provocaram um aumento adicional na fosforilação PMA-dependente, enquanto a genisteína causou uma diminiução e, Trolox não produziu nenhum efeito. Por outro lado, os quatro compostos foram inibitórios na fosforilação Zy-dependente. A atividade de tirosina fosfatases (PTPs) foi medida em neutrófilos estimulados e não-estimulados. PMA e Zy causaram uma diminuição na atividade de PTPs. A pré-incubação com AT e Trolox causou uma reversão destes efeitos inibitórios. O inibidor de serina/treonina fosfatases, caliculina A, também foi utilizado. Nós mostramos que este composto foi capaz de reverter os efeitos inibitórios do AT na produção de ERO e na atividade de PKC dos neutrófilos. Os resultados deste trabalho mostram que AT modulam ambas as via de sinalização, PKC e TK-dependentes, associadas com o \"burst\" oxidativo de neutrófilos humanos e, que esta modulação pode ser devido a ativação de fosfatases pelo AT. / The effects of α-tocopherol succinate (TS) on the signaling pathways, dependent of protein kinase C (PKC) and tirosine kinases (TK), associated with the oxidative burst of human neutrophils were analysed. Comparative studies with the PKC inhibitor, staurosporine, the TK inhibitor, genistein and the soluble analogous of vitamin E, Trolox were also performed. TS was incorporated into neutrophils and cells were then, stimulated or not with phorbol myristate acetate (PMA) or with opsonized zymosan (OZ). TS (40 µmol/l) inhibited the production of reactive oxygen species (ROS) by PMA or OZ-stimulated neutrophils. Staurosporine (10 nmol/l), genistein (100 µmol/l) and Trolox (40 µmol/l) were also inhibitory. PKC activity was inhibited by TS and staurosporine, however, the enzyme activity was not affected by genistein and Trolox. PMA and OZ promoted tyrosine phosphorylation in neutrophil proteins. TS and staurosporine caused a further increase of tyrosine phosphorylation of proteins in PMA-stimulated neutrophils, whereas, genistein diminished the levels of phosphorylation, and Trolox did not alter them. On the other hand, the four compounds decreased the tyrosine phosphorylated proteins in OZ-stimulated neutrophils. Protein tyrosine phosphatases (PTP) activity was measured in both resting and stimulated cells. PMA and OZ-stimulated neutrophils showed a decrease on PTP activity. Pre-incubation with TS or with Trolox caused partial recovery of the basal activity of stimulated neutrophils. The serine/threonine phosphatase inhibitor, calyculin A, was also utilized, and we showed that this compound was capable of reversing the inhibitory effects of TS on ROS production and PKC activity by neutrophils. These results show that TS modulates both PKC- and TK-dependent signaling pathways associated with the oxidative burst in human neutrophils, and this modulation could be due the activation of phosphatases by TS.

One of the most powerful and important applications that the brain accomplishes is solving the sensory "cocktail party problem:" to adaptively suppress extraneous signals in an environment. Theoretical studies suggest that the solution to the problem involves an adaptive filter, which learns to remove the redundant noise. However, neural learning is also in its infancy and there are still many questions about the stability and application of synaptic learning rules for neural computation. In this thesis, the implementation of an adaptive filter in the brain of a weakly electric fish, A. Leptorhynchus, was studied. It was found to require a cerebellar architecture that could supply independent frequency channels of delayed feedback and multiple burst learning rules that could shape this feedback. This unifies two ideas about the function of the cerebellum that were previously separate: the cerebellum as an adaptive filter and as a generator of precise temporal inputs.

One of the most powerful and important applications that the brain accomplishes is solving the sensory "cocktail party problem:" to adaptively suppress extraneous signals in an environment. Theoretical studies suggest that the solution to the problem involves an adaptive filter, which learns to remove the redundant noise. However, neural learning is also in its infancy and there are still many questions about the stability and application of synaptic learning rules for neural computation. In this thesis, the implementation of an adaptive filter in the brain of a weakly electric fish, A. Leptorhynchus, was studied. It was found to require a cerebellar architecture that could supply independent frequency channels of delayed feedback and multiple burst learning rules that could shape this feedback. This unifies two ideas about the function of the cerebellum that were previously separate: the cerebellum as an adaptive filter and as a generator of precise temporal inputs.