@phdthesis{6825,
abstract = {The solving of complex tasks requires the functions of more than one brain area and their interaction. Whilst spatial navigation and memory is dependent on the hippocampus, flexible behavior relies on the medial prefrontal cortex (mPFC). To further examine the roles of the hippocampus and mPFC, we recorded their neural activity during a task that depends on both of these brain regions.
With tetrodes, we recorded the extracellular activity of dorsal hippocampal CA1 (HPC) and mPFC neurons in Long-Evans rats performing a rule-switching task on the plus-maze. The plus-maze task had a spatial component since it required navigation along one of the two start arms and at the maze center a choice between one of the two goal arms. Which goal contained a reward depended on the rule currently in place. After an uncued rule change the animal had to abandon the old strategy and switch to the new rule, testing cognitive flexibility. Investigating the coordination of activity between the HPC and mPFC allows determination during which task stages their interaction is required. Additionally, comparing neural activity patterns in these two brain regions allows delineation of the specialized functions of the HPC and mPFC in this task. We analyzed neural activity in the HPC and mPFC in terms of oscillatory interactions, rule coding and replay.
We found that theta coherence between the HPC and mPFC is increased at the center and goals of the maze, both when the rule was stable or has changed. Similar results were found for locking of HPC and mPFC neurons to HPC theta oscillations. However, no differences in HPC-mPFC theta coordination were observed between the spatially- and cue-guided rule. Phase locking of HPC and mPFC neurons to HPC gamma oscillations was not modulated by
maze position or rule type. We found that the HPC coded for the two different rules with cofiring relationships between
cell pairs. However, we could not find conclusive evidence for rule coding in the mPFC. Spatially-selective firing in the mPFC generalized between the two start and two goal arms. With Bayesian positional decoding, we found that the mPFC reactivated non-local positions during awake immobility periods. Replay of these non-local positions could represent entire behavioral trajectories resembling trajectory replay of the HPC. Furthermore, mPFC
trajectory-replay at the goal positively correlated with rule-switching performance.
Finally, HPC and mPFC trajectory replay occurred independently of each other. These results show that the mPFC can replay ordered patterns of activity during awake immobility, possibly underlying its role in flexible behavior. },
author = {Käfer, Karola},
issn = {2663-337X},
pages = {89},
publisher = {IST Austria},
title = {{The hippocampus and medial prefrontal cortex during flexible behavior}},
doi = {10.15479/AT:ISTA:6825},
year = {2019},
}
@phdthesis{6957,
abstract = {In many shear flows like pipe flow, plane Couette flow, plane Poiseuille flow, etc. turbulence emerges subcritically. Here, when subjected to strong enough perturbations, the flow becomes turbulent in spite of the laminar base flow being linearly stable. The nature of this instability has puzzled the scientific community for decades. At onset, turbulence appears in localized patches and flows are spatio-temporally intermittent. In pipe flow the localized turbulent structures are referred to as puffs and in planar flows like plane Couette and channel flow, patches arise in the form of localized oblique bands. In this thesis, we study the onset of turbulence in channel flow in direct numerical simulations from a dynamical system theory perspective, as well as by performing experiments in a large aspect ratio channel.
The aim of the experimental work is to determine the critical Reynolds number where turbulence first becomes sustained. Recently, the onset of turbulence has been described in analogy to absorbing state phase transition (i.e. directed percolation). In particular, it has been shown that the critical point can be estimated from the competition between spreading and decay processes. Here, by performing experiments, we identify the mechanisms underlying turbulence proliferation in channel flow and find the critical Reynolds number, above which turbulence becomes sustained. Above the critical point, the continuous growth at the tip of the stripes outweighs the stochastic shedding of turbulent patches at the tail and the stripes expand. For growing stripes, the probability to decay decreases while the probability of stripe splitting increases. Consequently, and unlike for the puffs in pipe flow, neither of these two processes is time-independent i.e. memoryless. Coupling between stripe expansion and creation of new stripes via splitting leads to a significantly lower critical point ($Re_c=670+/-10$) than most earlier studies suggest.
While the above approach sheds light on how turbulence first becomes sustained, it provides no insight into the origin of the stripes themselves. In the numerical part of the thesis we investigate how turbulent stripes form from invariant solutions of the Navier-Stokes equations. The origin of these turbulent stripes can be identified by applying concepts from the dynamical system theory. In doing so, we identify the exact coherent structures underlying stripes and their bifurcations and how they give rise to the turbulent attractor in phase space. We first report a family of localized nonlinear traveling wave solutions of the Navier-Stokes equations in channel flow. These solutions show structural similarities with turbulent stripes in experiments like obliqueness, quasi-streamwise streaks and vortices, etc. A parametric study of these traveling wave solution is performed, with parameters like Reynolds number, stripe tilt angle and domain size, including the stability of the solutions. These solutions emerge through saddle-node bifurcations and form a phase space skeleton for the turbulent stripes observed in the experiments. The lower branches of these TW solutions at different tilt angles undergo Hopf bifurcation and new solutions branches of relative periodic orbits emerge. These RPO solutions do not belong to the same family and therefore the routes to chaos for different angles are different.
In shear flows, turbulence at onset is transient in nature. Consequently,turbulence can not be tracked to lower Reynolds numbers, where the dynamics may simplify. Before this happens, turbulence becomes short-lived and laminarizes. In the last part of the thesis, we show that using numerical simulations we can continue turbulent stripes in channel flow past the 'relaminarization barrier' all the way to their origin. Here, turbulent stripe dynamics simplifies and the fluctuations are no longer stochastic and the stripe settles down to a relative periodic orbit. This relative periodic orbit originates from the aforementioned traveling wave solutions. Starting from the relative periodic orbit, a small increase in speed i.e. Reynolds number gives rise to chaos and the attractor dimension sharply increases in contrast to the classical transition scenario where the instabilities affect the flow globally and give rise to much more gradual route to turbulence.},
author = {Paranjape, Chaitanya S},
issn = {2663-337X},
keyword = {Instabilities, Turbulence, Nonlinear dynamics},
pages = {138},
publisher = {IST Austria},
title = {{Onset of turbulence in plane Poiseuille flow}},
doi = {10.15479/AT:ISTA:6957},
year = {2019},
}
@phdthesis{6363,
abstract = {Distinguishing between similar experiences is achieved by the brain in a process called pattern separation. In the hippocampus, pattern separation reduces the interference of memories and increases the storage capacity by decorrelating similar inputs patterns of neuronal activity into non-overlapping output firing patterns. Winners-take-all (WTA) mechanism is a theoretical model for pattern separation in which a "winner" cell suppresses the activity of the neighboring neurons through feedback inhibition. However, if the network properties of the dentate gyrus support WTA as a biologically conceivable model remains unknown. Here, we showed that the connectivity rules of PV+interneurons and their synaptic properties are optimizedfor efficient pattern separation. We found using multiple whole-cell in vitrorecordings that PV+interneurons mainly connect to granule cells (GC) through lateral inhibition, a form of feedback inhibition in which a GC inhibits other GCs but not itself through the activation of PV+interneurons. Thus, lateral inhibition between GC–PV+interneurons was ~10 times more abundant than recurrent connections. Furthermore, the GC–PV+interneuron connectivity was more spatially confined but less abundant than PV+interneurons–GC connectivity, leading to an asymmetrical distribution of excitatory and inhibitory connectivity. Our network model of the dentate gyrus with incorporated real connectivity rules efficiently decorrelates neuronal activity patterns using WTA as the primary mechanism. This process relied on lateral inhibition, fast-signaling properties of PV+interneurons and the asymmetrical distribution of excitatory and inhibitory connectivity. Finally, we found that silencing the activity of PV+interneurons in vivoleads to acute deficits in discrimination between similar environments, suggesting that PV+interneuron networks are necessary for behavioral relevant computations. Our results demonstrate that PV+interneurons possess unique connectivity and fast signaling properties that confer to the dentate gyrus network properties that allow the emergence of pattern separation. Thus, our results contribute to the knowledge of how specific forms of network organization underlie sophisticated types of information processing.
},
author = {Espinoza Martinez, Claudia M},
isbn = {978-3-99078-000-8},
issn = {2663-337X},
pages = {140},
publisher = {IST Austria},
title = {{Parvalbumin+ interneurons enable efficient pattern separation in hippocampal microcircuits}},
doi = {10.15479/AT:ISTA:6363},
year = {2019},
}
@phdthesis{6849,
abstract = {Brain function is mediated by complex dynamical interactions between excitatory and inhibitory cell types. The Cholecystokinin-expressing inhibitory cells (CCK-interneurons) are one of the least studied types, despite being suspected to play important roles in cognitive processes. We studied the network effects of optogenetic silencing of CCK-interneurons in the CA1 hippocampal area during exploration and sleep states. The cell firing pattern in response to light pulses allowed us to classify the recorded neurons in 5 classes, including disinhibited and non-responsive pyramidal cell and interneurons, and the inhibited interneurons corresponding to the CCK group. The light application, which inhibited the activity of CCK interneurons triggered wider changes in the firing dynamics of cells. We observed rate changes (i.e. remapping) of pyramidal cells during the exploration session in which the light was applied relative to the previous control session that was not restricted neither in time nor space to the light delivery. Also, the disinhibited pyramidal cells had higher increase in bursting than in single spike firing rate as a result of CCK silencing. In addition, the firing activity patterns during exploratory periods were more weakly reactivated in sleep for those periods in which CCK-interneuron were silenced than in the unaffected periods. Furthermore, light pulses during sleep disrupted the reactivation of recent waking patterns. Hence, silencing CCK neurons during exploration suppressed the reactivation of waking firing patterns in sleep and CCK interneuron activity was also required during sleep for the normal reactivation of waking patterns. These findings demonstrate the involvement of CCK cells in reactivation-related memory consolidation. An important part of our analysis was to test the relationship of the identified CCKinterneurons to brain oscillations. Our findings showed that these cells exhibited different oscillatory behaviour during anaesthesia and natural waking and sleep conditions. We showed that: 1) Contrary to the past studies performed under anaesthesia, the identified CCKinterneurons fired on the descending portion of the theta phase in waking exploration. 2) CCKinterneuron preferred phases around the trough of gamma oscillations. 3) Contrary to anaesthesia conditions, the average firing rate of the CCK-interneurons increased around the peak activity of the sharp-wave ripple (SWR) events in natural sleep, which is congruent with new reports about their functional connectivity. We also found that light driven CCK-interneuron silencing altered the dynamics on the CA1 network oscillatory activity: 1) Pyramidal cells negatively shifted their preferred theta phases when the light was applied, while interneurons responses were less consistent. 2) As a population, pyramidal cells negatively shifted their preferred activity during gamma oscillations, albeit we did not find gamma modulation differences related to the light application when pyramidal cells were subdivided into the disinhibited and unaffected groups. 3) During the peak of SWR events, all but the CCK-interneurons had a reduction in their relative firing rate change during the light application as compared to the change observed at SWR initiation. Finally, regarding to the place field activity of the recorded pyramidal neurons, we showed that the disinhibited pyramidal cells had reduced place field similarity, coherence and spatial information, but only during the light application. The mechanisms behind such observed behaviours might involve eCB signalling and plastic changes in CCK-interneuron synapses. In conclusion, the observed changes related to the light-mediated silencing of CCKinterneurons have unravelled characteristics of this interneuron subpopulation that might change the understanding not only of their particular network interactions, but also of the current theories about the emergence of certain cognitive processes such as place coding needed for navigation or hippocampus-dependent memory consolidation. },
author = {Rangel Guerrero, Dámaris K},
isbn = {9783990780039},
issn = {2663-337X},
pages = {97},
publisher = {IST Austria},
title = {{The role of CCK-interneurons in regulating hippocampal network dynamics}},
doi = {10.15479/AT:ISTA:6849},
year = {2019},
}
@phdthesis{6546,
abstract = {Invasive migration plays a crucial role not only during development and homeostasis but also in pathological states, such as tumor metastasis. Drosophila macrophage migration into the extended germband is an interesting system to study invasive migration. It carries similarities to immune cell transmigration and cancer cell invasion, therefore studying this process could also bring new understanding of invasion in higher organisms. In our work, we uncover a highly conserved member of the major facilitator family that plays a role in tissue invasion through regulation of glycosylation on a subgroup of proteins and/or by aiding the precise timing of DN-Cadherin downregulation.
Aberrant display of the truncated core1 O-glycan T-antigen is a common feature of human cancer cells that correlates with metastasis. Here we show that T-antigen in Drosophila melanogaster macrophages is involved in their developmentally programmed tissue invasion. Higher macrophage T-antigen levels require an atypical major facilitator superfamily (MFS) member that we named Minerva which enables macrophage dissemination and invasion. We characterize for the first time the T and Tn glycoform O-glycoproteome of the Drosophila melanogaster embryo, and determine that Minerva increases the presence of T-antigen on proteins in pathways previously linked to cancer, most strongly on the sulfhydryl oxidase Qsox1 which we show is required for macrophage tissue entry. Minerva’s vertebrate ortholog, MFSD1, rescues the minerva mutant’s migration and T-antigen glycosylation defects. We thus identify
a key conserved regulator that orchestrates O-glycosylation on a protein subset to activate
a program governing migration steps important for both development and cancer metastasis.
},
author = {Valosková, Katarina},
issn = {2663-337X},
pages = {141},
publisher = {IST Austria},
title = {{The role of a highly conserved major facilitator superfamily member in Drosophila embryonic macrophage migration}},
doi = {10.15479/AT:ISTA:6546},
year = {2019},
}
@phdthesis{6894,
abstract = {Hybrid automata combine finite automata and dynamical systems, and model the interaction of digital with physical systems. Formal analysis that can guarantee the safety of all behaviors or rigorously witness failures, while unsolvable in general, has been tackled algorithmically using, e.g., abstraction, bounded model-checking, assisted theorem proving.
Nevertheless, very few methods have addressed the time-unbounded reachability analysis of hybrid automata and, for current sound and automatic tools, scalability remains critical. We develop methods for the polyhedral abstraction of hybrid automata, which construct coarse overapproximations and tightens them incrementally, in a CEGAR fashion. We use template polyhedra, i.e., polyhedra whose facets are normal to a given set of directions.
While, previously, directions were given by the user, we introduce (1) the first method
for computing template directions from spurious counterexamples, so as to generalize and
eliminate them. The method applies naturally to convex hybrid automata, i.e., hybrid
automata with (possibly non-linear) convex constraints on derivatives only, while for linear
ODE requires further abstraction. Specifically, we introduce (2) the conic abstractions,
which, partitioning the state space into appropriate (possibly non-uniform) cones, divide
curvy trajectories into relatively straight sections, suitable for polyhedral abstractions.
Finally, we introduce (3) space-time interpolation, which, combining interval arithmetic
and template refinement, computes appropriate (possibly non-uniform) time partitioning
and template directions along spurious trajectories, so as to eliminate them.
We obtain sound and automatic methods for the reachability analysis over dense
and unbounded time of convex hybrid automata and hybrid automata with linear ODE.
We build prototype tools and compare—favorably—our methods against the respective
state-of-the-art tools, on several benchmarks.},
author = {Giacobbe, Mirco},
issn = {2663-337X},
pages = {132},
publisher = {IST Austria},
title = {{Automatic time-unbounded reachability analysis of hybrid systems}},
doi = {10.15479/AT:ISTA:6894},
year = {2019},
}
@phdthesis{6179,
abstract = {In the first part of this thesis we consider large random matrices with arbitrary expectation and a general slowly decaying correlation among its entries. We prove universality of the local eigenvalue statistics and optimal local laws for the resolvent in the bulk and edge regime. The main novel tool is a systematic diagrammatic control of a multivariate cumulant expansion.
In the second part we consider Wigner-type matrices and show that at any cusp singularity of the limiting eigenvalue distribution the local eigenvalue statistics are uni- versal and form a Pearcey process. Since the density of states typically exhibits only square root or cubic root cusp singularities, our work complements previous results on the bulk and edge universality and it thus completes the resolution of the Wigner- Dyson-Mehta universality conjecture for the last remaining universality type. Our analysis holds not only for exact cusps, but approximate cusps as well, where an ex- tended Pearcey process emerges. As a main technical ingredient we prove an optimal local law at the cusp, and extend the fast relaxation to equilibrium of the Dyson Brow- nian motion to the cusp regime.
In the third and final part we explore the entrywise linear statistics of Wigner ma- trices and identify the fluctuations for a large class of test functions with little regularity. This enables us to study the rectangular Young diagram obtained from the interlacing eigenvalues of the random matrix and its minor, and we find that, despite having the same limit, the fluctuations differ from those of the algebraic Young tableaux equipped with the Plancharel measure.},
author = {Schröder, Dominik J},
pages = {375},
publisher = {IST Austria},
title = {{From Dyson to Pearcey: Universal statistics in random matrix theory}},
doi = {10.15479/AT:ISTA:th6179},
year = {2019},
}
@phdthesis{6371,
abstract = {Decades of studies have revealed the mechanisms of gene regulation in molecular detail. We make use of such well-described regulatory systems to explore how the molecular mechanisms of protein-protein and protein-DNA interactions shape the dynamics and evolution of gene regulation.
i) We uncover how the biophysics of protein-DNA binding determines the potential of regulatory networks to evolve and adapt, which can be captured using a simple mathematical model.
ii) The evolution of regulatory connections can lead to a significant amount of crosstalk between binding proteins. We explore the effect of crosstalk on gene expression from a target promoter, which seems to be modulated through binding competition at non-specific DNA sites.
iii) We investigate how the very same biophysical characteristics as in i) can generate significant fitness costs for cells through global crosstalk, meaning non-specific DNA binding across the genomic background.
iv) Binding competition between proteins at a target promoter is a prevailing regulatory feature due to the prevalence of co-regulation at bacterial promoters. However, the dynamics of these systems are not always straightforward to determine even if the molecular mechanisms of regulation are known. A detailed model of the biophysical interactions reveals that interference between the regulatory proteins can constitute a new, generic form of system memory that records the history of the input signals at the promoter.
We demonstrate how the biophysics of protein-DNA binding can be harnessed to investigate the principles that shape and ultimately limit cellular gene regulation. These results provide a basis for studies of higher-level functionality, which arises from the underlying regulation.
},
author = {Igler, Claudia},
issn = {2663-337X},
keyword = {gene regulation, biophysics, transcription factor binding, bacteria},
pages = {152},
publisher = {IST Austria},
title = {{On the nature of gene regulatory design - The biophysics of transcription factor binding shapes gene regulation}},
doi = {10.15479/AT:ISTA:6371},
year = {2019},
}
@phdthesis{7172,
abstract = {The development and growth of Arabidopsis thaliana is regulated by a combination of genetic programing and also by the environmental influences. An important role in these processes play the phytohormones and among them, auxin is crucial as it controls many important functions. It is transported through the whole plant body by creating local and temporal concentration maxima and minima, which have an impact on the cell status, tissue and organ identity. Auxin has the property to undergo a directional and finely regulated cell-to-cell transport, which is enabled by the transport proteins, localized on the plasma membrane. An important role in this process have the PIN auxin efflux proteins, which have an asymmetric/polar subcellular localization and determine the directionality of the auxin transport. During the last years, there were significant advances in understanding how the trafficking molecular machineries function, including studies on molecular interactions, function, subcellular localization and intracellular distribution. However, there is still a lack of detailed characterization on the steps of endocytosis, exocytosis, endocytic recycling and degradation. Due to this fact, I focused on the identification of novel trafficking factors and better characterization of the intracellular trafficking pathways. My PhD thesis consists of an introductory chapter, three experimental chapters, a chapter containing general discussion, conclusions and perspectives and also an appendix chapter with published collaborative papers.
The first chapter is separated in two different parts: I start by a general introduction to auxin biology and then I introduce the trafficking pathways in the model plant Arabidopsis thaliana. Then, I explain also the phosphorylation-signals for polar targeting and also the roles of the phytohormone strigolactone.
The second chapter includes the characterization of bar1/sacsin mutant, which was identified in a forward genetic screen for novel trafficking components in Arabidopsis thaliana, where by the implementation of an EMS-treated pPIN1::PIN1-GFP marker line and by using the established inhibitor of ARF-GEFs, Brefeldin A (BFA) as a tool to study trafficking processes, we identified a novel factor, which is mediating the adaptation of the plant cell to ARF-GEF inhibition. The mutation is in a previously uncharacterized gene, encoding a very big protein that we, based on its homologies, called SACSIN with domains suggesting roles as a molecular chaperon or as a component of the ubiquitin-proteasome system. Our physiology and imaging studies revealed that SACSIN is a crucial plant cell component of the adaptation to the ARF-GEF inhibition.
The third chapter includes six subchapters, where I focus on the role of the phytohormone strigolactone, which interferes with auxin feedback on PIN internalization. Strigolactone moderates the polar auxin transport by increasing the internalization of the PIN auxin efflux carriers, which reduces the canalization related growth responses. In addition, I also studied the role of phosphorylation in the strigolactone regulation of auxin feedback on PIN internalization. In this chapter I also present my results on the MAX2-dependence of strigolactone-mediated root growth inhibition and I also share my results on the auxin metabolomics profiling after application of GR24.
In the fourth chapter I studied the effect of two small molecules ES-9 and ES9-17, which were identified from a collection of small molecules with the property to impair the clathrin-mediated endocytosis.
In the fifth chapter, I discuss all my observations and experimental findings and suggest alternative hypothesis to interpret my results.
In the appendix there are three collaborative published projects. In the first, I participated in the characterization of the role of ES9 as a small molecule, which is inhibitor of clathrin- mediated endocytosis in different model organisms. In the second paper, I contributed to the characterization of another small molecule ES9-17, which is a non-protonophoric analog of ES9 and also impairs the clathrin-mediated endocytosis not only in plant cells, but also in mammalian HeLa cells. Last but not least, I also attach another paper, where I tried to establish the grafting method as a technique in our lab to study canalization related processes.},
author = {Vasileva, Mina K},
issn = {2663-337X},
pages = {192},
publisher = {IST Austria},
title = {{Molecular mechanisms of endomembrane trafficking in Arabidopsis thaliana}},
doi = {10.15479/AT:ISTA:7172},
year = {2019},
}
@phdthesis{6681,
abstract = {The first part of the thesis considers the computational aspects of the homotopy groups πd(X) of a topological space X. It is well known that there is no algorithm to decide whether the fundamental group π1(X) of a given finite simplicial complex X is trivial. On the other hand, there are several algorithms that, given a finite simplicial complex X that is simply connected (i.e., with π1(X) trivial), compute the higher homotopy group πd(X) for any given d ≥ 2.
However, these algorithms come with a caveat: They compute the isomorphism type of πd(X), d ≥ 2 as an abstract finitely generated abelian group given by generators and relations, but they work with very implicit representations of the elements of πd(X). We present an algorithm that, given a simply connected space X, computes πd(X) and represents its elements as simplicial maps from suitable triangulations of the d-sphere Sd to X. For fixed d, the algorithm runs in time exponential in size(X), the number of simplices of X. Moreover, we prove that this is optimal: For every fixed d ≥ 2,
we construct a family of simply connected spaces X such that for any simplicial map representing a generator of πd(X), the size of the triangulation of S d on which the map is defined, is exponential in size(X).
In the second part of the thesis, we prove that the following question is algorithmically undecidable for d < ⌊3(k+1)/2⌋, k ≥ 5 and (k, d) ̸= (5, 7), which covers essentially everything outside the meta-stable range: Given a finite simplicial complex K of dimension k, decide whether there exists a piecewise-linear (i.e., linear on an arbitrarily fine subdivision of K) embedding f : K ↪→ Rd of K into a d-dimensional Euclidean space.},
author = {Zhechev, Stephan Y},
issn = {2663-337X},
pages = {104},
publisher = {IST Austria},
title = {{Algorithmic aspects of homotopy theory and embeddability}},
doi = {10.15479/AT:ISTA:6681},
year = {2019},
}