Elucidating the Interplay of Structure, Dynamics, and Function in the Brain’s Neural Networks.

Brain’s structure, dynamics, and function are deeply intertwined. To understand how the brain functions, it is crucial to uncover the links between network structure and its dynamics. Here I examine different approaches to exploring the key connecting factors between network structure, dynamics and eventually its function. I predominantly concentrate on emergence and temporal evolution of synchronization, or coincidence of neuronal spike timings, as it has been associated with many brain functions while aberrant synchrony is implicated in many neurological disorders. Specifically, in chapter II, I investigate how the interplay of cellular properties with network coupling characteristics could affect the propensity of neural networks for synchronization. Then, in chapter III, I develop a set of measures that identify hallmarks and potentially predict autonomous network transitions from asynchronous to synchronous dynamics under various conditions. The developed metrics can be calculated in real time and therefore potentially applied in clinical situations. Finally, in chapter IV, I aim to tie the correlates of neural network dynamics to the brain function. More specifically, I elucidate dynamical underpinnings of learning and memory consolidation from in vivo recordings of mice experiencing contextual fear conditioning (CFC) and show, that the introduced notion of network stability may predict future animal performance on memory retrieval. Overall, the results presented within this dissertation underscore the importance of concurrent analysis of networks’ dynamical and structural properties. The developed approaches may prove useful beyond the specific application presented within this thesis.PhDBiophysicsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/120768/1/mofakham_1.pd

Multiple Feedback Mechanisms Fine-Tune Rho Signaling To Regulate Morphogenetic Outcomes

Rho signaling is a conserved mechanism for generating forces through activation of contractile actomyosin. How this pathway is tuned to produce different morphologies of cells and tissues is poorly understood. In the Drosophila embryonic epithelium, I investigated how Rho signaling controls force asymmetries to drive morphogenesis. Specifically, I studied a distinctive morphogenetic process termed “alignment”. This process of coordinated cell shape changes results in a unique cell geometry of rectilinear cells connected by aligned cell-cell contacts. I found that this rearrangement is initialized by contractility of actomyosin cables that elevate the local tension along aligning interfaces. Curiously, I find that hours after establishing the alignment, this cell geometry is stabilized independent of actomyosin at the end of embryogenesis. This suggests that there are alternate mechanical bases for maintaining the aligned cell geometry in the steady state. My data show that polarization of two branches of Rho signaling, Rho Kinase (ROK) and Diaphanous (Dia), is responsible for the formation of these cables. Constitutive activation of these Rho effectors causes aligning cells to instead invaginate. This observation suggests that moderation of Rho signaling is essential to producing the aligned geometry. Therefore, I tested for feedback interactions in the pathway that could fine-tune Rho signaling. I discovered that F-actin exerts negative feedback on multiple nodes in the pathway. In contrast, Myo-II does not feedback to the Rho pathway. However, inhibiting ROK caused an upregulation in Rho activity. This shows that ROK has a Myo-II independent function in regulating the Rho pathway. Taken together, this work suggests that multiple feedback mechanisms factor into the regulation of Rho signaling, which may account for the versatility of Rho in diverse morphogenetic processes. Preliminarily, I also find a requirement for a regulator of Rac-Arp 2/3-mediated actin polymerization, pointing towards cooperation and crosstalk between branched actin and linear actin promoting pathways. This may allow for a balance of different mechanical forces that can generate the aligned geometry. This thesis work lays down a foundation for understanding how the activity of contractile actomyosin and small GTPase signaling be modified to suit numerous morphogenetic processes

Aerospace medicine and biology: A continuing bibliography with indexes (supplement 352)

This bibliography lists 147 reports, articles and other documents introduced into the NASA Scientific and Technical Information System during July 1991. Subject coverage includes: aerospace medicine and psychology, life support systems and controlled environments, safety equipment, exobiology and extraterrestrial life, and flight crew behavior and performance

Hydrogen Sulfide Regulation of Kir Channels

Inwardly rectifying potassium (Kir) channels establish and regulate the resting membrane potential of excitable cells in the heart, brain and other peripheral tissues. Phosphatidylinositol- 4,5-bisphosphate (PIP2) is a key direct activator of ion channels, including Kir channels. Gasotransmitters, such as carbon monoxide (CO), have been reported to regulate the activity of Kir channels by altering channel-PIP2 interactions. We tested, in a model system, the effects and mechanism of action of another important gasotransmitter, hydrogen sulfide (H2S) thought to play a key role in cellular responses under ischemic conditions. Direct administration of sodium hydrogen sulfide (NaHS), as an exogenous H2S source, and expression of cystathionine γ-lyase (CSE), a key enzyme that produces endogenous H2S in specific brain tissues, resulted in comparable current inhibition of several Kir2 and Kir3 channels. A “tag switch” assay provided biochemical evidence for sulfhydration of Kir3.2 channels. The extent of H2S regulation depended on the strength of channel-PIP2 interactions: H2S regulation was attenuated when strengthening channel-PIP2 interactions and was increased when channel-PIP2 interactions were weakened by depleting PIP2 levels via different manipulations. These H2S effects took place through specific cytoplasmic cysteine residues in Kir3.2 channels, where atomic resolution structures with PIP2 gives us insight as to how they may alter channel-PIP2 interactions. Mutation of these residues abolished H2S inhibition, and reintroduction of specific cysteine residues into the background of the mutant lacking cytoplasmic cysteine residues, rescued H2S inhibition. Molecular dynamics simulation experiments provided mechanistic insights as to how sulfhydration of specific cysteine residues could lead to changes in channel-PIP2 interactions and channel gating

On the development of slime mould morphological, intracellular and heterotic computing devices

The use of live biological substrates in the fabrication of unconventional computing (UC) devices is steadily transcending the barriers between science fiction and reality, but efforts in this direction are impeded by ethical considerations, the field’s restrictively broad multidisciplinarity and our incomplete knowledge of fundamental biological processes. As such, very few functional prototypes of biological UC devices have been produced to date. This thesis aims to demonstrate the computational polymorphism and polyfunctionality of a chosen biological substrate — slime mould Physarum polycephalum, an arguably ‘simple’ single-celled organism — and how these properties can be harnessed to create laboratory experimental prototypes of functionally-useful biological UC prototypes. Computing devices utilising live slime mould as their key constituent element can be developed into a) heterotic, or hybrid devices, which are based on electrical recognition of slime mould behaviour via machine-organism interfaces, b) whole-organism-scale morphological processors, whose output is the organism’s morphological adaptation to environmental stimuli (input) and c) intracellular processors wherein data are represented by energetic signalling events mediated by the cytoskeleton, a nano-scale protein network. It is demonstrated that each category of device is capable of implementing logic and furthermore, specific applications for each class may be engineered, such as image processing applications for morphological processors and biosensors in the case of heterotic devices. The results presented are supported by a range of computer modelling experiments using cellular automata and multi-agent modelling. We conclude that P. polycephalum is a polymorphic UC substrate insofar as it can process multimodal sensory input and polyfunctional in its demonstrable ability to undertake a variety of computing problems. Furthermore, our results are highly applicable to the study of other living UC substrates and will inform future work in UC, biosensing, and biomedicine

Perspectives on adaptive dynamical systems

Adaptivity is a dynamical feature that is omnipresent in nature, socio-economics, and technology. For example, adaptive couplings appear in various real-world systems like the power grid, social, and neural networks, and they form the backbone of closed-loop control strategies and machine learning algorithms. In this article, we provide an interdisciplinary perspective on adaptive systems. We reflect on the notion and terminology of adaptivity in different disciplines and discuss which role adaptivity plays for various fields. We highlight common open challenges, and give perspectives on future research directions, looking to inspire interdisciplinary approaches.Comment: 46 pages, 9 figure

The role of T-type calcium channels in human pancreatic β cell maturity

This PhD work has optimized a series of in vivo, ex vivo and in vitro approaches to recapitulate, intervene and appraise in vivo maturation of naïve β cells within human induced pluripotent stem cell-derived islets (hiPSC-islets). These approaches have also been applied to characterize hyperglycemia-induced dedifferentiation of mature β cells within native human islets grafted into the anterior chamber of the eye (ACE) of immunodeficient mice. It has verified the critical role of exaggerated T-type Ca2+ channels in these adverse events. The immunodeficient mouse ACE serves as a remarkable transplantation site for human islets including hiPSC-islets and native human islets. They are placed apart from each other on the iris and undergo satisfactory survival, engraftment and vascularization. This allows in vivo recapitulation and microscopy of hiPSC-islet insulin-expressing cell maturation and mature human islet β cell dedifferentiation. This also enables intact retrieval of intracameral human islet grafts for ex vivo measurements of cytosolic free Ca2+ concentration ([Ca2+]i) and patch clamp analysis as well as in vitro confocal microscopy/immunofluorescence labeling. In addition, intravitreally-infused drugs enter the ACE and act on intracameral human islets with special, beneficial pharmacokinetic, pharmacodynamic and toxicological properties. The feasibility and merits of these approaches bring about the following main results. Intracameral hiPSC-islets display heterogeneity in their survival, engraftment, vascularization, growth and fates during post-transplantation. They gradually mature at least in their insulin-secretory capacity and glucoseactivated [Ca2+]i dynamics. Intriguingly, naïve hiPSC-islet insulin-expressing cells mistakenly retain excessive T-type Ca2+ channels and in vivo inhibition of these channels significantly promotes development of glucose-dependent [Ca2+]i dynamics in intracameral hiPSC-islets. Furthermore, hyperglycemia induces mature β cell dedifferentiation in intracameral native human islets by activating Ttype Ca2+ channel-calcineurin signaling resulting in β cell HSF1 dislocation, VAMP- 2 reduction and exocytosis deterioration. This pathway is inactivated by inhibition of β cell T-type Ca2+ channels, calcineurin or both. These findings demonstrate that upregulated β cell T-type Ca2+ channels impede naïve human β cell maturation and promote mature human β cell dedifferentiation. This points out that T-type Ca2+ channel inhibition has a great potential counteracting these two detrimental events for generation of clinically transplantable hiPSC-islets and for effective treatment for diabetes