Traveling wave solutions of integro-differential equations for modeling one-dimensional neuronal networks, are studied. Under moderate continuity assumptions, necessary and sufficient conditions for the existence and uniqueness of monotone increasing (decreasing) traveling wave solutions are established. Some faults in previous studies are corrected.

The present work investigates the applicability of Genetic Algorithms (GA) to the problem of signal propagation in Native Neuronal Networks (NNNs). These networks are comprised of neurons, some of which receive input signals. The signals propagate though the network by transmission between neurons. The research focuses on the regeneration of the output signal of the network without knowing the original input signal. The computational complexity of the problem is prohibitive for the exact computation. We propose to use a heuristic approach called Genetic Algorithm. Three algorithms are developed, based on the GA technique. The developed algorithms are tested on two different networks with varying input signals. The results obtained from the testing indicate significantly better performance of the developed algorithms compared to the Uniform Random Search (URS) technique, which is used as a control group. The importance of the research is in the demonstration of the ability of GA-based algorithms to successfully solve the problem at hand.

This dissertation explores the neural coding and mechanisms associated with consciousness by analyzing electrical rhythms of the brain under altered states of consciousness, namely epilepsy and anesthesia. First, transformation of neural coding under epileptogenic conditions is examined by computing the Volterra kernels in a rodent epilepsy model, where the epileptogenic condition is induced by altering the concentrations of Mg2+ and K+ of the perfusate for different levels of excitability. Principal dynamic modes (PDMs) are further deduced from the Volterra kernels to compare the changes in neural dynamics under epileptogenic conditions. The integrating PDMs are shown to dominate at all levels of excitability in terms of their relative contributions to the overall response, whereas the dominant frequency responses of the differentiating PDMs shift to higher ranges under epileptogenic conditions, from ripple activities (75 - 200 Hz) to fast ripple activities (200 - 500 Hz). Second, markers of anesthetic states are explored by analyzing amplitude and phase of brain rhythms as well as their interaction and modulation, utilizing electroencephalogram (EEG) recorded from patients undergoing anesthesia. Anesthesia shifts the power to low frequency rhythms, especially alpha rhythms. Additionally anesthesia increases the coupling between alpha rhythms and gamma rhythms while disrupting the coupling between alpha rhythms and ripples (70 - 200 Hz). The results also indicate that the dose responses (i.e. depth of anesthesia) are not necessarily monophasic or linear. The commonality and differences of the changes in brain rhythms associated with these conditions are discussed to elucidate on the possible underlying mechanisms involved in producing consciousness.

This dissertation explores the neural coding and mechanisms associated with consciousness by analyzing electrical rhythms of the brain under altered states of consciousness, namely epilepsy and anesthesia. First, transformation of neural coding under epileptogenic conditions is examined by computing the Volterra kernels in a rodent epilepsy model, where the epileptogenic condition is induced by altering the concentrations of Mg2+ and K+ of the perfusate for different levels of excitability. Principal dynamic modes (PDMs) are further deduced from the Volterra kernels to compare the changes in neural dynamics under epileptogenic conditions. The integrating PDMs are shown to dominate at all levels of excitability in terms of their relative contributions to the overall response, whereas the dominant frequency responses of the differentiating PDMs shift to higher ranges under epileptogenic conditions, from ripple activities (75 - 200 Hz) to fast ripple activities (200 - 500 Hz). Second, markers of anesthetic states are explored by analyzing amplitude and phase of brain rhythms as well as their interaction and modulation, utilizing electroencephalogram (EEG) recorded from patients undergoing anesthesia. Anesthesia shifts the power to low frequency rhythms, especially alpha rhythms. Additionally anesthesia increases the coupling between alpha rhythms and gamma rhythms while disrupting the coupling between alpha rhythms and ripples (70 - 200 Hz). The results also indicate that the dose responses (i.e. depth of anesthesia) are not necessarily monophasic or linear. The commonality and differences of the changes in brain rhythms associated with these conditions are discussed to elucidate on the possible underlying mechanisms involved in producing consciousness.

The molecular mechanisms that coordinate postnatal brain enlargement, synaptic properties and cognition remain an enigma. This study demonstrates that neuronal complexity controlled by p21-activated kinases (PAKs) is a key determinant for postnatal brain enlargement and synaptic properties. Double knockout (DK) mice lacking both PAK1 and PAK3 were severely impaired in postnatal brain growth, resulting in a dramatic reduction in brain volume at maturity. Remarkably, the reduced brain was accompanied by minimal changes in total cell count, due to a significant increase in cell density. However, the DK neurons have smaller soma, markedly simplified dendritic arbors/axons and reduced synapse density. Surprisingly, the DK mice were elevated in basal synaptic responses due to enhanced individual synaptic potency, but severely impaired in bi-directional synaptic plasticity. The PAK1/3 action is likely mediated by cofilin-dependent actin regulation because the activity of cofilin and the properties of actin filaments were specifically altered in the DK mice.

Networks at various levels of the nervous system coordinate different motor patterns such as respiration, eye or hand movements and locomotion. Intrinsic rhythm-generating networks that are located in the spinal cord generate motor behaviors that underlie locomotion in vertebrates. These networks give a continuous and measurable coordinated rhythmic motor output and are referred to as locomotor central pattern generators (CPGs). Characterization of the mammalian locomotor CPG and its molecular control is depending on the identification of participating neurons and neuronal populations. In this thesis I present work where we have studied the significance of subpopulations of neurons in the formation and function of the left-right circuitry. In summary, we show that the axon guidance receptor DCC has a central role in the formation of spinal neuronal circuitry underlying left-right coordination, and that both Netrin-1 and DCC are required for normal function of the locomotor CPG. Commissural interneurons (CINs), which send their axons across the ventral midline in the spinal cord, play a critical role in left–right coordination during locomotion. A complete loss of commissural axons in the spinal cord, as seen in the Robo3 null mutant mouse, resulted in uncoordinated fictional locomotor activity. Removing CIN connections from either dorsal or ventral neuronal populations led to a shift from alternation to strict synchronous locomotor activity. Inhibitory dI6 CIN have been suggested as promising candidate neurons in coordinating bilateral alternation circuitry. We have identified that Dmrt3, expressed in inhibitory dI6 CINs, is a crucial component for the normal development of coordinated locomotor movements in both horses and mice. We have also concluded that the prominent hopping phenotype seen in hop/hop mice is a result of abnormal developmental processes including induction from the notochord and Shh signaling. Together, these findings increase our knowledge about the flexibility in neuronal circuit development and further confirm the role of dI6 neurons in locomotor circuits.

Discovery of the ability of mesenchymal stem cells (MSCs) to differentiate into cells of non-mesodermal tissues, particularly neuronal cells, have raised the possibility of utilising MSCs in regenerative/reparative therapies for neurological disorders. However, a number of hurdles remain to be resolved. This thesis aims to address some of these issues by investigating the characteristics of bone marrow-derived human MSCs (hMSCs) during long-term culture, the potential of hMSCs to differentiate in vitro toward the neuronal lineage under the influence of cytokines, and the effects of intracerebral transplantation in the hemiparkinsonian rat model. During expansion culture hMSCs were found to display the expected characteristics of MSC populations, and also constitutively expressed neural and pluripotency markers simultaneously with mesodermal markers. Analysis of hMSC long-term subcultivation revealed an optimal period for commencing neuronal differentiation (first 6-8 passages), and also showed the absence of spontaneous neural differentiation. Application of neural-inducing cytokines and culture conditions resulted in the generation of an immature neuronal-like phenotype by hMSCs. Through live cell microscopy it was demonstrated for the first time that cytokine-based hMSC neuronal differentiation occurs through active and dynamic cellular processes involving outgrowth and motility of cellular extensions. In addition, single- and multiple-stage cytokine-based strategies for inducing dopaminergic neuronal-like cells from hMSCs were investigated. These studies revealed that FGF-2 and EGF exerted the greatest benefits for hMSC neuronal differentiation. Undifferentiated and neuronal-primed hMSCs were transplanted intracerebrally into the striatum and substantia nigra of cyclosporine-treated hemiparkinsonian rats. Grafted hMSCs could be clearly identified at 1-day and 7-days post-transplantation; however, grafts were gradually lost over time, with complete absence by 21-days. Co-transplantation with olfactory ensheathing cells, neuronal-priming prior to grafting, and nigral as well as striatal grafting could not provide engraftment and differentiation advantages. Immunohistological analysis demonstrated the presence of innate inflammatory responses (microglia and astrocyte activation) at graft sites, fibronectin deposition by hMSCs, and lack of endogenous host neurogenesis. The results of my PhD work indicate that cytokine-based culture methods are capable of differentiating hMSCs to an immature neuronal-like phenotype, and host-mediated innate inflammatory responses may be a key contributing factor for the failure of in vivo hMSC engraftment.

Discovery of the ability of mesenchymal stem cells (MSCs) to differentiate into cells of non-mesodermal tissues, particularly neuronal cells, have raised the possibility of utilising MSCs in regenerative/reparative therapies for neurological disorders. However, a number of hurdles remain to be resolved. This thesis aims to address some of these issues by investigating the characteristics of bone marrow-derived human MSCs (hMSCs) during long-term culture, the potential of hMSCs to differentiate in vitro toward the neuronal lineage under the influence of cytokines, and the effects of intracerebral transplantation in the hemiparkinsonian rat model. During expansion culture hMSCs were found to display the expected characteristics of MSC populations, and also constitutively expressed neural and pluripotency markers simultaneously with mesodermal markers. Analysis of hMSC long-term subcultivation revealed an optimal period for commencing neuronal differentiation (first 6-8 passages), and also showed the absence of spontaneous neural differentiation. Application of neural-inducing cytokines and culture conditions resulted in the generation of an immature neuronal-like phenotype by hMSCs. Through live cell microscopy it was demonstrated for the first time that cytokine-based hMSC neuronal differentiation occurs through active and dynamic cellular processes involving outgrowth and motility of cellular extensions. In addition, single- and multiple-stage cytokine-based strategies for inducing dopaminergic neuronal-like cells from hMSCs were investigated. These studies revealed that FGF-2 and EGF exerted the greatest benefits for hMSC neuronal differentiation. Undifferentiated and neuronal-primed hMSCs were transplanted intracerebrally into the striatum and substantia nigra of cyclosporine-treated hemiparkinsonian rats. Grafted hMSCs could be clearly identified at 1-day and 7-days post-transplantation; however, grafts were gradually lost over time, with complete absence by 21-days. Co-transplantation with olfactory ensheathing cells, neuronal-priming prior to grafting, and nigral as well as striatal grafting could not provide engraftment and differentiation advantages. Immunohistological analysis demonstrated the presence of innate inflammatory responses (microglia and astrocyte activation) at graft sites, fibronectin deposition by hMSCs, and lack of endogenous host neurogenesis. The results of my PhD work indicate that cytokine-based culture methods are capable of differentiating hMSCs to an immature neuronal-like phenotype, and host-mediated innate inflammatory responses may be a key contributing factor for the failure of in vivo hMSC engraftment.

Dissertation Thesis (Ph.D.)--University of South Florida, 2007. / Title from PDF of title page. Document formatted into pages; contains 202 pages. Includes vita. Includes bibliographical references.

Thesis (Ph. D.)--University of Missouri-Columbia, 2007. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Vita. "August 2007" Includes bibliographical references.