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Investigation of the Bayesian Sensory-Motor Integration in the Cerebral Cortex
Full text linkOkinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyAnimals need to sense their environment and differentiate sensory states to optimize behavior. For example, a force too weak may fail to pull a desired object closer, while too much effort will be unnecessarily exhausting. The prior experience interacting with similar objects can help generate the required action and produce an expectation of the sensory feedback. Combining prior expectation with the actual sensory observation is formalized with Bayes' rule. The neural mechanisms for such probabilistic computations remain unclear but, in mammals, can be attributed to the specific anatomical patterns of the cerebral cortex. In particular, the pathways carrying bottom-up sensory signals mostly terminate in layer 4 and activate pyramidal neurons of the layer 2/3 of the sensory cortex, while the neurons of deeper layers 5 and 6 mostly receive projections from other cortical areas including the motor cortex. Based on this, I hypothesized that the pyramidal neurons of the superficial layers encode sensory evidence while the deeper layer neurons encode prior and posterior estimations. I conducted a series of lever-pulling experiments on mice, where the lever provided a variable tactile feedback. Calcium imaging of the S1 cortical area using a prism lens enabled me to analyze how matches or mismatches between action-dependent prediction and actual sensory inputs are encoded by neurons in superficial and deep layers.
I have identified functional asymmetry between superficial and deep cortical layers in the context of the probabilistic sensory-motor task. The deep layers were more associated with the prior information about the expected tactile stimulus in terms of the number of task coding neurons and the amount of information per given population size. In comparison with the deep layers, superficial layers were stronger associated with the sensory information about the actual tactile stimulus, but also encoded prior information. This research contributes to the study of the neural mechanisms underlying probabilistic estimation in the cerebral cortex
Investigation of the Role of Male Germ Cell-Associated Kinase in Zebrafish Photoreceptor Ciliogenesis and Cell Survival
Full text linkOkinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyPhotoreceptors are composed of highly specialized structures associated with phototransduction which takes place in the outer segments (OS), a specialized cilium of the cell. The connecting cilia play a pivotal role in mediating molecular transportation between the cell body and the OS. Defects in the ciliary structure can lead to various outcomes including cell death, however, the mechanisms regulating ciliary structure are not yet fully understood. Male germ cellassociated kinase (MAK) is a cilia-associated serine/threonine kinase, and its genetic mutation causes photoreceptor degeneration in mice and retinitis pigmentosa in humans. Here, I report that zebrafish mak mutants show rapid photoreceptor degeneration during embryonic development. In mak mutants, both rod and cone photoreceptors completely lack the OS and undergo apoptosis. Interestingly, zebrafish mak mutants fail to generate axoneme during photoreceptor ciliogenesis, whereas the basal body and the transition zone are specified. These data suggest a specific role of MAK in axoneme development in zebrafish, which is opposite to mouse mak mutants showing the elongated axoneme of photoreceptors. Furthermore, the kinase activity of MAK plays a critical role in ciliary axoneme development and photoreceptor survival. Thus, MAK is required for ciliogenesis and OS formation in zebrafish photoreceptors to ensure intracellular protein transport and photoreceptor survival
Vps37b and Ramp3 Regulate CD8+ T Cell Response by Facilitating Adaptation to Plasma Membrane Damage
Full text linkOkinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyDuring the course of an immune response, T cells are regularly exposed to various agents that can compromise the integrity of their plasma membrane, such as bacterial pore-forming toxins, reactive oxygen species, and perforin. Substantial damage to the plasma membrane has the potential to lead to cell death. Thus, the ability of T cells to endure these membrane assaults may be important for mounting an effective immune response. However, the role and mechanisms of T cell adaptation to plasma membrane damage remain largely unknown. Our study demonstrates that Vps37b and Ramp3 play a pivotal role in facilitating T cell resistance to plasma membrane injury. We found that in a membrane-damaging environment, T cells enhance the expression of Vps37b and Ramp3 in response to extracellular ATP, which is released from damaged cells. These genes then contribute to the repair of the plasma membrane. Notably, CD8+ T cells lacking either of these genes exhibit impaired clonal expansion and heightened pro-apoptotic protein expression during Listeria monocytogenes infections. These findings imply that adaptation to plasma membrane damage is vital in early CD8+ T cell responses to infection with membrane-damaging pathogens. Additionally, we observed that CD8+ T cells survived in a plasma membrane-damaging environment show heightened expression of effector proteins. Importantly, CD8+ T cells deficient for Vps37b or Ramp3 are exposed to heightened, yet sub-lethal plasma membrane damage in tumor environment, and exhibit enhanced anti-tumor effect in vivo. In summary, our research elucidates how T cells adapt to a plasma membrane-damaging environment using Vps37b and Ramp3 and the critical role of this adaptation mechanism in the regulation of CD8+ T cell response. Modulating their activity could be a novel strategy for therapeutic interventions aimed at boosting immune responses in cancer and infectious diseases
Neuronal Mechanism for Processing Complemental Information of Species Identity and Individual Variation in the Zebra Finch Higher Auditory Cortex
Full text linkOkinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyAnimals transmit various information through vocal communications. Zebra finches, a songbird species extensively studied in laboratories, recognize and discriminate their own species identity as well as individual differences by hearing their songs. However, the neuronal mechanisms allowing them to detect individually unique songs in parallel with species common features have yet to be elucidated. Here, we found that zebra finch songs consist of acoustically similar common song elements overall, while they individually differ in element sequential arrangement from each other. We further revealed that each neuron in the higher auditory area, the caudal nidopallium (NCM), detected only a small subset of zebra finch songs, while NCM neuronal ensembles responded to all the zebra finch songs we presented by performing single unit electrophysiological recording in freely moving male zebra finches. The NCM neurons selectively responded to specific song elements, which were similar in acoustical features between varieties of songs, while some of them were also sensitive to element sequential arrangement, which dramatically increases the capacities of variation with a limited number of element varieties. Taken together, our results suggest a neuronal mechanism for individual detection by sparse coding of individual NCM neurons to detect a small group of songs which are unique in sequence of elements but common in acoustic features
JunB is Essential for Chromatin Regulation in Pathogenic Th17 Cells
Full text linkOkinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyEpigenetic regulation and chromatin remodeling play critical role in governing gene expression during T helper (Th) cell differentiation. JunB, a member of the AP-1 transcription factor family, is required for autoimmune pathogenic Th17 transcriptional program, but its role in the chromatin regulation remains unknown. Using the assay for transposase-accessible chromatin sequencing (ATAC-seq), I found that JunB regulates chromatin remodeling in differentiation of diverse T helper subsets in vivo and in vitro. Particularly, in pathogenic Th17 differentiation, JunB promotes chromatin accessibility at enhancer regions associated with a subset of Th17-related genes, including interleukin 17a (Il17a) and Il23 receptor (Il23r). JunB is necessary for BATF pioneering functions and/or the deposition of histone modifications, H3K4me1 and H3K27ac, through the recruitment of histone methyltransferase MLL4, and the recruitment of the BAF chromatin remodeling complex at these loci. Moreover, JunB indirectly inhibits chromatin accessibility at loci related to fate switch from Th17 to Th1 cells, such as interferon gamma (Ifng), likely through inhibiting chromatin accessibility and expression of an immediate-early transcription factors, such as NF-kB, NR4A1, Ets and Runx family members. These results indicate that JunB is essential for enhancer activation of Th17-related genes, while indirectly inhibiting chromatin accessibility in diverse regions regulated by other key transcription factors
The Role of Tails in Maintaining Balance: Neuronal and Behavioral Insights from the Mouse
Full text linkOkinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyTails are a distinguishing feature of animals and play a critical role in many aspects of their survival, such as maintaining balance. The present study aims to address the questions of whether and how laboratory mice (Mus musculus) use their tails to maintain balance and what are the neural mechanisms that control this behavior. To quantify how mice use their tails to maintain balance, I built a set-up (the ridge task) that simulates some of the challenges they may experience in nature. This task has led us to characterize a novel response from the tail in response to roll-plane perturbations and gave us insights onto how the tail is used during locomotion in challenging balancing conditions. In the anatomical part of the project, I will describe some of the neuronal circuits responsible for such behavior. Firstly, I characterized the morphology of tail motoneurons in the spinal cord and observed that these neurons (located in the sacral segment of the spinal cord) receive inputs from the vestibular system. Then I went on describing the subpopulation of vestibular neurons that project to the sacral spinal cord, revealing that they form a cluster mainly located in the Spinal Vestibular Nucleus. Finally, I used an optogenetic approach to stimulate either the entire vestibular nucleus, or selectively activate sacral-vestibulospinal neurons, to observe the effect of such manipulation on the tail. Intriguingly, given that the vestibular complex organization and functions are highly preserved across many taxa, the results from this project brings out exciting possibility for future studies on the organization of the neuronal control of tails in other chordates as well
Seasonal Variation in Glycemic Control and Lifestyle in Middle-aged Non-diabetic Individuals
Full text linkOkinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophySeasonality of glycemic control has been observed in many studies. It has been hypothesized that factors such as reduced daylight hours, lower temperatures, and seasonal changes in lifestyle habits contribute to these variations. However, there is limited research that integrates data on both glycemic control and lifestyle habits. In particular, there is a lack of knowledge regarding non-diabetic populations, and there is inconsistency among the few existing studies. Here, we investigate seasonal variations in a wide range of glycemic indicators derived from continuous glucose measurement (CGM) in non-diabetic adults. We analyzed various factors related to meteorology, anthropometrics, and lifestyle habits that could potentially contribute to fluctuations in glycemic indices. The results revealed a seasonal trend of increased mean glucose and estimated A1c levels in winter-spring, which aligned with previous studies. Furthermore, seasonal trends in several factors, including meteorological factors, physical activity, sleep patterns, dietary patterns and macronutrient intake, were associated with seasonal trends in daily glucose fluctuations. On the other hand, time in the range decreased in summer-autumn, and coefficient of variation preceded it a few month along with meteorological factors, physical activity, sleep patterns, dietary patterns and macronutrient intake. This study adds to the evidence on seasonal variations in glycemic control and emphasizes the importance of considering seasonality when interpreting glucose levels
The Interplay of Elasticity and Plasticity in Elastoviscoplastic Fluid Flows in Complex Configurations
Full text linkOkinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyIn this thesis, we delve into a class of non-Newtonian fluids called elastoviscoplastic (EVP) fluids, such as gels, pastes, mud, and foams, which exhibit both solid-like and liquid-like, behaviors depending on the stress applied. Through a combination of numerical simulations and experimental methods, this research explores the intricate interplay between elasticity and plasticity under complex flow configurations.
Firstly, we show how polymer additives can uniquely tune the extensional properties of EVP fluids without impacting their shear rheology, revealing complex dynamics such as elastic instabilities and time-dependent behavior under high extensional rates. In more complex flow configurations, particularly within wavy channels, we find that even minimal elasticity can shift the EVP fluid behavior from a steady to a time-dependent regime, significantly affecting the pressure drop and the size and shape of the unyielded regions. Additionally, we demonstrate the ability of our modified EVP fluid with enhanced elasticity to prevent the development of stagnation regions, allowing complete yielding and displacement of the material. Finally, we explore how both plasticity and elasticity can modulate the turbulence characteristics of EVP fluids, altering the classical picture predicted by Kolmogorov for Newtonian fluids and giving rise to a new scaling in energy spectra and enhanced intermittency.
The insights gained from this research hold significant implications for optimizing industrial processes, including 3D printing and enhanced oil recovery, as well as for enhancing the predictability and management of natural phenomena, such as mudslides and lava flow
Dynamics of Dominance in Interacting Zebrafish
Full text linkWhile two-body fighting behavior occurs throughout the animal kingdom to settle dominance disputes, important questions such as how the dynamics ultimately lead to a winner and loser are unresolved. Here we examine fighting behavior at high resolution in male zebrafish. We combine multiple cameras, a large volume containing a transparent interior cage to avoid reflection artifacts, with computer vision to track multiple body points across multiple organisms while maintaining individual identity in three dimensions. In the body point trajectories we find a spectrum of timescales which we use to build informative joint coordinates consisting of relative orientation and distance. We use the distribution of these coordinates to automatically identify fight epochs, and we demonstrate the postfight emergence of an abrupt asymmetry in relative orientations—a clear and quantitative signal of hierarchy formation. We identify short-time, multi-animal behaviors as clustered transitions between joint configurations, and show that fight epochs are spanned by a subset of these clusters, which we denote as maneuvers. The resulting space of maneuvers is rich but interpretable, including motifs such as “attacks” and “circling.” In the longer-time dynamics of maneuver frequencies we find differential and changing strategies, including that the eventual loser attacks more often towards the end of the contest. Our results suggest a reevaluation of relevant assessment models in zebrafish, while our approach is generally applicable to other animal systems
Free Energy Based Neural Network Model to Study Embodied Language
Full text linkOkinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyHumans learn the use of language through physical interaction with their environment and symbolic communication with other people. Our ability to compose/decompose a whole into reusable parts, widely known as compositionlity, is a prominent linguistic competency that is essential for the acquisition and development of embodied language. A fundamental question is how linguistic compositionality, grounded in sensorimotor experience, can be acquired through learning of associations involving only partial linguistic compositions and their corresponding sensorimotor patterns. In order to investigate this problem, I developed a neural network model that integrates vision, motor, and language under the framework of active inference. The model generates action plans via teleology inspired goal directed latent variable inference, using a variational recurrent neural network. The effectiveness and capabilities of the model were assessed using a vision based robot arm in various simulation experiments. The proposed model can generate visuo-proprioceptive sequences to achieve target goals represented by language. It can also infer linguistically represented goals from observation of visuo-prorioceptive sequences. The results elucidate that generalization in learning is enhanced when the number of elements for language compositions (such as verbs and object nouns) are increased. Further analyses of the results provide insights into how linguistic compositionality is encoded within the model’s latent state. Ablation studies show that visual attention and working memory are essential to accurately generate visuo-motor sequences to achieve linguistically represented goals. These insights advance our understanding of the mechanisms underlying generalization and the role of linguistic compositionality in the context of sensorimotor learning