Of Movement and Mice: A Study of Movement Variability Using Marker-based 3D Motion Capture and Mathematical Representations of Locomotion on a Treadmill

Okinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyLocomotion is an important output of the central nervous system (CNS) and an essential component of many behaviours. The inherent variability of animal locomotory movements is the key to understanding how living things move so well. Most studies asses mouse locomotion using central metrics such as step-length, speed, angular excursions, and phase differences of limbs. The limitation of such approaches is that by describing variability as just the degree of spread around some measure of centrality we lose the ability to look at the dynamics. Additionally, there is mounting evidence that variability encodes dynamic signatures that are key to understanding both the function and dysfunction of the CNS. Few studies examine the whole body of the animal as it moves, particularly in tasks that involve more natural movements. Fewer still, that do this in all three spatial dimensions (3D). However, locomotion is a whole bodied movement, and most organisms move in 3D. Therefore, there is a need to study whole bodied movements in 3D, with sufficient spatio-temporal resolution to analyse their inherent variability. This entails using observational methods capable of capturing natural movements alongside analytical methods to interpret the data. In this thesis, I present my work on obtaining mathematical representations of voluntary treadmill locomotion of mice. I use a novel marker assisted 3D motion capture system, adapted for mice, to obtain a 30 dimensional trajectory of the whole body as they run unrestrained on a treadmill set at different speeds. I use principal component analysis to get a basis set of vectors that represent the changes in the body configuration of the mice during treadmill locomotion. Additionally, I use delay embedding techniques to untangle non-stationarities in the data to uncover the different classes of body movement cycles. This approach enables the characterisation of the whole body of the mouse as it locomotes on a treadmill and sets the stage for systematically studying the effect of pharmacological perturbations and different neurological conditions on movement.doctoral thesi

The Diversification of Brain Structure in Ants

Okinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyAnts, as an example of complex social cooperation and ecological dominance, represent one of the most successful groups among animals. Their complex eusociality, cooperative behaviors, and adaptability to diverse environments is inextricably linked to the evolution of their organ systems. The brain, as a pivotal organ mediating organism-environment interactions, plays a critical role in these adaptive strategies. While the basic neuroanatomical scheme is conserved, natural selection has shaped relative sizes of neuropils and the overall brain size to generate diversity across the ants. While a rich body of literature has advanced our understanding of the vertebrate brain size evolution, broad scaled comparative neuroanatomy for insects has only gained more traction in recent decades. Here, I take the comparative neuroanatomical approach to unravel the general principles and processes driving the macroevolution of the ant brain. To do so, in the first chapter I take a broader phylogenetic view and explore the evolution of odorant receptor (OR) repertoires across a broad range of hymenopteran species, revealing that in contrast to a widely held hypothesis, eusociality did not drive an expansion in the OR repertoire. Instead, my results suggested that factors such as the loss of flight may have played a role in shaping some of this variation. Subsequently, in the second chapter I examined brain and neuropil size variation of 9 distinct neuropils from 75 ant species, uncovering divergent body size scaling patterns of different brain regions. While visual neuropils displayed hyper-allometric scaling, olfactory regions showed more constrained isometry. Additionally, I showed that the evolution of miniaturized sterile workers was associated with dramatic reductions in brain regions forming a “visual module”, leading to the reduction in the overall brain size, contributing to an energy-efficient "cheaper worker" phenotype. Together, these findings elucidate the intricate interplay between sensory, social, and ecological factors that make the brain of an ant “the most marvellous atoms of matter in the world…” (Darwin, “The descent of man”; 1871, p.145)doctoral thesi

Role of Statistics as a Thermodynamic Resource in Quantum Engines

Okinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyUltracold atomic gases serve as ideal platforms for studying complex quantum effects, offering precise control over many degrees of freedom. They are therefore an excellent testbed for exploring fundamental ideas and concepts in quantum thermodynamics, where the principles of quantum mechanics and thermodynamics are linked from first principles. One of the most prominent areas of interest in this field is the study of quantum heat engines—systems in which a quantum working medium undergoes cyclic interactions with hot and cold reservoirs to convert heat into work. In this thesis I explore heat engines that utilize quantum many-body systems as their working medium. At ultracold temperatures, quantum statistical effects play a crucial role, with the fermionic or bosonic nature of the quantum gas directly influencing its energetic behavior. It is therefore an interesting question to ask what an engine that operates based on a quantum statistical energy difference would look like? To address this, I investigate two experimentally realizable settings where quantum statistics can be manipulated: the BEC-BCS crossover in three-dimensional quantum gases and the Lieb-Liniger model in one dimension. In the first part of this thesis, I introduce the concept of the Pauli engine, a purely quantum engine that operates within the BEC-BCS crossover region. Here, the change in particle statistics effectively replaces conventional heat reservoirs, offering a novel mechanism for work production. I compare the performance of the Pauli engine to both a statistics-based thermal engine and a solely interaction-driven engine. The findings demonstrate that the Pauli engine outperforms both alternatives, establishing quantum statistics as a valuable thermodynamic resource for work extraction. Additionally, I compare my theoretical predictions to experimental data from the realization of the Pauli engine conducted by the group at Kaiserslautern University. The second part of the thesis focuses on implementing a quantum heat engine using a one-dimensional repulsively interacting Bose gas as the working medium. This system is described by the Lieb-Liniger model, an integrable framework that can be exactly solved using the Bethe ansatz. Within this model, the many-body interactions can be continuously tuned from the non-interacting limit to the strongly interacting Tonks-Girardeau regime, where bosonic atoms exhibit fermionic statistical behavior. Leveraging this statistical transition, I introduce and theoretically analyze two statistically enhanced engine cycles: the A-cycle and the T-cycle. For both cycles, I examine their efficiency at maximum work by optimizing the performance with respect to system length. The results demonstrate that tailoring quantum statistics can significantly enhance engine performance, reinforcing the potential of statistical effects as a thermodynamic resource.doctoral thesi

Chaos, Correlations and Entanglement in Strongly-correlated 1D Mixtures of Ultra-cold Bosons

Okinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyIn this thesis I focus on strongly-correlated multi-species systems of interacting bosons harmonically trapped in one-dimensional space from first principles. More specifically, in the first project, I study the emergence of quantum chaos in a binary mixture of few ultracold bosons in terms of the intra- and inter-species interactions. In particular, I answer an elementary question that is ‘What is the minimum number of interacting particles required to create chaos in a quantum system in the continuum?’. In the second project, I propose a robust scheme for engineering of correlated quantum states as ground states of systems of two distinguishable impurities immersed in a few-boson host medium. Particularly, by scrutinizing the ground-state properties of such system, I demonstrate that the two impurities exhibits non-classical correlations and form Bell states. Importantly, the proposed scheme can be implemented with current ultra-cold atomic settings, where particle numbers and interaction strengths are fully experimentally controllable. In the third project, I employ an ab initio approach to unveil quantum correlations, coherence, and spatial localization in threespecies mixtures of a few repulsively interacting bosons confined harmonically. The goal is to comprehensively explore the ground-state properties and hence illustrate the complete ground-state phase diagram of the three-species correlated system in terms of the intra- and inter-species interactions.doctoral thesi

An Investigation into Inter-brain Synchrony using Simulation and Experimental Approaches

Okinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyOver the past two decades, advancements in neuroimaging technologies have enabled the simultaneous imaging of two brains with increasing spatial and temporal resolution, revealing that interacting participants can synchronise their brain signals, a phenomenon known as inter-brain synchrony (IBS). This thesis deepens research into how IBS can occur, investigating along several dimensions: the minimal requirements for IBS, the role of the body, and the brain-behaviour relationship. I rely on two research paradigms to carry out this investigation: computer simulations, which examine IBS through an evolutionary framework, and human subject experiments, which include a minimalistic perceptual crossing task in a simple virtual environment and a rhythmic video game experiment. These inquiries lead to several important findings and implications for the study of IBS and social cognition more broadly: 1) the body manifests dynamics at slower behavioural timescales that regulate faster neural signals; 2) the possibility of alpha-band IBS, even in touch-based interactions in minimally shared environments, challenges the notion that IBS is merely an epiphenomenon; 3) the type of interaction (alternating or simultaneous) influences IBS; and 4) greater IBS is not inherently better. Overall, this thesis advances theoretical and empirical understanding of IBS within neuroscience and explore its broader cultural implications.doctoral thesi

Molecular Crowding and Enzyme Dynamics: Unraveling the Complex Interactions in Cellular Environments

Okinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyEnzymes are ubiquitously involved in cellular processes. The enzyme environment conditions greatly affect enzyme specificity, folding and activity. These facts suggest a pivotal role of the cytosolic milieu on enzyme behavior. On the other hand, enzymes could also affect the cytosolic biophysical properties, suggesting an intricated interplay between enzyme catalysis and the cellular milieu. However, this interplay has been poorly studied due to the paramount challenges in mimicking the cellular complexity in vitro and the interdisciplinary nature of these mechanisms. Here, we utilized a liquid-liquid phase separation system to generate membraneless protein droplets, simulating cytosolic protein crowding in vitro. These droplets allow the study of enzyme kinetics in a cytosol-mimicking environment. By using an interdisciplinary approach spanning from biochemistry, rheology and fluid dynamics, we characterized the interplay between enzyme activity and a cytosolic-mimicking droplets. Specifically, we showed how enzymatic activity is affected by the cytosolic features and environmental stress in protein-crowded conditions. Moreover, we discovered that enzyme can generate emerging phenomena when localized in a protein-crowded environment such as droplets migration and viscosity modulation. This study highlights the interconnection between enzymes and the cytosolic environment and the underestimated role of enzyme activity in triggering complex cellular phenomena.doctoral thesi

The Role of the CNOT3 Subunit of the CCR4-NOT Complex in Cellular Senescence

Okinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyCellular senescence is a fundamentally irreversible cell cycle arrest associated with upregulated inflammatory responses. Cellular senescence is involved in numerous biological processes, including tumor suppression and organismal aging. Uncovering its mechanism will contribute to the development of novel therapeutic strategies for age-associated diseases as well as cancer. However, the molecular regulators involved in senescence are not fully elucidated. The CCR4- NOT complex, known for its role in gene expression and mRNA decay, is one such regulator. Despite its broad functions, the specific function of the CCR4-NOT complex, particularly the CNOT3 subunit, in cellular senescence remains unknown. In this thesis work, I studied the role of the CCR4-NOT deadenylase complex in cellular senescence, focusing on the regulatory interplay between the CNOT3 subunit and long non-coding RNA (lncRNA). LncRNAs were chosen for their emerging role in regulating gene expression and senescence. Here, I show that the downregulation of CNOT3 is sufficient for cellular senescence induction in A549 human non-small cell lung cancer cells. Knockdown of CNOT3 causes the upregulation of multiple cellular senescence hallmarks, such as CDKN1A, TP53, the senescence-associated secretory phenotype (SASP) (IL6, IL8, and STC1), and senescence-associated β-galactosidase activity. Moreover, these senescence hallmarks are more significantly upregulated when CNOT3 downregulation is combined with PLK-1 inhibitor (BI2536), which reduces the dividing cell population. These results suggest that CNOT3 downregulation could enhance the susceptibility of lung cancer cells to chemotherapy. I also explored the regulatory network involving CNOT3 and lncRNA. Previously, it has been reported that lncRNA can interact with RNA and RNAbinding proteins to regulate gene expression at the post-transcriptional level by determining the fate of target molecules. To investigate the relationship between CNOT3 and lncRNAs, I analyzed microarray RNA-seq data from CNOT3 knockdown in A549 cells and identified a subset of lncRNAs that were upregulated upon CNOT3 depletion. Among them, the lncRNA MAGI2-AS3 was found to influence the cellular senescence pathway, suggesting that CNOT3 and lncRNAs collaboratively regulate cellular senescence. This thesis highlights the multilayered regulatory roles of CNOT3 and its lncRNA partners, offering a novel perspective on enhancing chemotherapy efficacy.doctoral thesi

The Topology, Geometry and Physics of Non-Hausdorff Manifolds

Okinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyIn this thesis we investigate various mathematical and physical problems surrounding the theory of non-Hausdorff manifolds. We start by introducing a topological theory of nonHausdorff manifolds from first principles. We then pass our discussion into a smooth category by defining various structures of geometric interest on non-Hausdorff manifolds, all whilst circumventing the technical issues surrounding partitions of unity. We complete our mathematical contribution by describing de Rham cohomology for non-Hausdorff manifolds, ultimately proving a generalized version of de Rham’s Theorem. For the physical contribution, we focus our attention on certain two-dimensional non-Hausdorff manifolds that may be interpreted as a type of topology-changing spacetime. We define a gravitational action for 2d non-Hausdorff spacetimes, and determine the angular conventions required to suppress their contribution within a Lorentzian-signature path integral for gravity that sums over topologies.doctoral thesi

Nonequilibrium Properties of Strongly Correlated One-dimensional Quantum Gases

Okinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyUnderstanding and controlling nonequilibrium quantum systems offers promising routes to applications unattainable in equilibrium systems. While equilibrium physics benefits from well-established approaches, such as minimizing free energy and obtaining various thermodynamic quantities, nonequilibrium systems possess less general guiding principles and approaches. Furthermore, strong correlations plays a crucial role in various quantum phenomena, such as high-temperature superconductors or superfluid helium, yet analyzing strongly correlated quantum systems remains exceedingly challenging. This is because these systems often require rigorous analysis beyond the standard perturbation theory, leading to the necessity of dealing with the large Hilbert space dimensions, which makes theoretical analysis difficult. However, in the case of a one-dimensional strongly interacting Bose gas called Tonks–Girardeau (TG) gas, an exact mapping to a noninteracting fermions is possible, providing a unique platform to study a strongly correlated many-body systems. This thesis aims to advance the theoretical understanding of nonequilibrium strongly correlated quantum systems from two distinct perspectives: integrability and Floquet physics. First, I investigate the nonequilibrium dynamics of strongly correlated TG bosons immersed in a weakly correlated Bose–Einstein condensate. I show that the TG bosons form an integrable soliton-train supported by the condensate. Moreover, since a gas of the noninteracting fermions follows the same governing equations, the quantum statistical nature of the soliton-train can be addressed, leading to the notion of a quantum soliton-trains. Next, I study the TG gas under a strong external time-periodic drive. By computing the nonequilibrium Green’s function exactly, I reveal the excitation spectrum of this Floquet-engineered material. Employing Floquet spectral function theory and the Bose–Fermi mapping theorem, I uncover the existence of nonequilibrium Lieb excitations when the underlying mapped fermions form a Floquet–Fermi sea.doctoral thesi

Biologically Plausible Synaptic Plasticity Model for Rapid Neuronal Tuning

Okinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyIn the intricate workings of the brain, neurons play a fundamental role in detecting meaningful patterns amidst a constant stream of information. However, the rapidity with which neurons accomplish this task often goes unnoticed in computational models, leading to a gap in understanding crucial mechanistic features observed in biological neurons. To bridge this gap, I introduce a class of neural models equipped with a biologically-inspired synaptic plasticity rule. The aim of this thesis research is to shed light on the brain’s ability to rapidly learn and discern statistically salient patterns. My approach leverages the dynamic interplay between neural activity and synaptic plasticity, where somatic spikes propagate back to dendrites, facilitating self-supervised detection and learning of presynaptic neuron communities impinging on dendrites. I showcase the efficacy of these models in various tasks, including pattern recognition and spatial navigation, where they establish swift associations between behavior and environmental cues. Moreover, in exploring multi-compartmental neural architectures, I extend the synaptic plasticity rule to elucidate the initiation and development of local dendritic spikes, offering insights into neural processing mechanisms. My modeling work underscores the importance of pre-existing neural assemblies in robust pattern learning within recurrent networks. By illuminating the self-supervision function of backpropagating action potentials and the role of pre-existing neural assemblies, my findings contribute to a deeper comprehension of brain cognitive function and its implications for artificial intelligence and neuroscience.doctoral thesi