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No / A neurological disorder is any disorder or abnormality in the nervous system. Among different neurological disorders, Alzheimer’s disease (AD) is recognized as the sixth leading cause of death globally. Considerable research has been conducted to find pioneer treatments for this devastating disorder among which cell therapy has attracted remarkable attentions over the last decade. Up to now, targeted differentiation into specific desirable cell types has remained a major obstacle to clinical application of cell therapy. Also, potential risks including uncontrolled growth of stem cells could be disastrous. In our novel protocol, we used basal forebrain cholinergic progenitor cells (BFCN) derived from human chorion-derived mesenchymal stem cells (hC-MSCs) which made it possible to obtain high-quality population of cholinergic neurons and in vivo in much shorter time period than previous established methods. Remarkably, the transplanted progenitors fully differentiated to cholinergic neurons which in turn integrated in higher cortical networks of host brains, resulting in significant improvement in cognitive assessments. This method may have profound implications in cell therapies for any other neurodegenerative disorders. / This work was carried outwithin the framework of a collaborative project (Project Grant No. 94-02-30-25922) by the School of Medicine, Iran University of Medical Sciences, (Project Grant No. REP209) council for stem cell sciences and technologies (Presidency of the Islamic Republic of Iran, vice-presidency for science and technology), and Iran National Science Foundation (INSF).

System dynamics can be a very useful tool to expand the boundaries of one's mental models to better understand the underlying behavior of systems. But despite its utility, there remains challenges associated with system dynamics modeling that the current research addresses by expanding the system dynamics modeling toolbox. The first challenge relates to imprecision or vagueness, for example, with respect to human perception and linguistic variables. The most common approach is to use table or graph functions to capture the inherent vagueness in these linguistic (qualitative) variables. Yet, combining two or more table functions may lead to further complexity and, moreover, increased difficulty when analyzing the resulting behavior. As part of this research, we extend the system dynamics toolbox by applying fuzzy logic. Then, we select a problem of congestion pricing in mitigating traffic congestion to verify the effectiveness of our integration of fuzzy logic into system dynamics modeling. Another challenge, in system dynamics modeling, is defining proper equations to predict variables based on numerous studies. In particular, we focus on published equations in models for energy balance and weight change of individuals. For these models there is a need to define a single robust prediction equation for Basal Metabolic Rate (BMR), which is an element of the energy expenditure of the body. In our approach, we perform an extensive literature review to explore the relationship between BMR and different factors including age, body composition, gender, and ethnicity. We find that there are many equations used to estimate BMR, especially for different demographic groups. Further, we find that these equations use different independent variables and, in a few cases, generate inconsistent conclusions. It follows then that selecting a single equation for BMI can be quite difficult for purposes of modeling in a systems dynamics context. Our approach involves conducting a meta-regression to summarize the available prediction equations and identifying the most appropriate model for predicting BMR for different sub-populations. The results of this research potentially could lead to more precise predictions of body weight and enhanced policy interventions to help mitigate serious health issues such as obesity. / Ph. D.

The focus of the current project was to establish an improved and reliable protocol for somatic embryogenesis in 1) Pinus taeda and Pinus palustris; pine species of high value for commercial applications and germplasm conservation supported through breeding programs at The Virginia Department of Forestry (Chapter III); and 2) Pinus oocarpa; an economically important pine species in the southern half of Mexico and Central America (Chapter IV). In addition, 3) the study of the gene expression analysis of developmental stages of both somatic and zygotic embryos of P. taeda was compared to assess developmental fidelity at the molecular level (Chapter V). By testing four basal media combined with different plant growth regulator combinations, we have established stable embryogenic cultures from high value families of P. taeda and P. palustris using the tissue culture medium 1218 (Pullman et al 2005) in combination with an auxin:citokinin ratio at 10:5 (molar). However, optimization of the protocols for the maturation and further conversion of somatic embryos to seedlings requires further work. For P. oocarpa, we hypothesized that somatic embryo induction may be possible by mimicking natural seed-embryo developmental conditions, and a new tissue culture medium, based on the mineral content of the seed nutritive tissue (megagametophyte), was formulated. The novel culture medium (PO) was tested in combination with different plant growth regulator concentrations for the initiation of somatic embryogenesis from fresh collections of P. oocarpa immature zygotic embryos. Additionally, the established embryogenic cultures were able to mature and germinate, to our knowledge resulting in the first report of the production of P. oocarpa plantlets through somatic embryogenesis. PO medium also has the potential to be used successfully for other tropical pine species which today suffer from suboptimal somatic embryogenesis protocols. The fundamental study of molecular regulation of embryo development showed that under the current maturation conditions, P. taeda somatic embryos were temporally similar in gene expression to zygotic embryos of the same species. However, potentially important differences were found and results could potentially explain the low germination success during somatic embryogenesis. More research is still needed to further explore the natural environment of developing seed embryos to improve the somatic embryogenesis protocols and to enable full integration of this clonal propagation method into the breeding programs for pines. / Ph. D.

In this work, we develop models of neural circuits and plasticity rules that underlie different forms of learning and memory, with a focus on learning processes that involve multiple brain regions. We begin by surveying the literature on synaptic plasticity rules and implementations of learning algorithms in the brain. Each subsequent chapter presents a model of how a specific aspect of learning is implemented biologically, based on experimental evidence and normative considerations. We first focus on the neural basis of reinforcement learning in the basal ganglia. We show that in order to enable effective learning when control of behavior is distributed across multiple regions (``off-policy reinforcement learning''), classic models of dopamine activity must be adapted to include an additional action-sensitive component. We also show that the known plasticity rules of direct and indirect-pathway striatal projection neurons are inconsistent with existing models of striatal codes for action. We propose and find experimental support for a new model of striatal activity driven by efferent input. This model is functionally compatible with striatal plasticity rules and enables simultaneous multiplexing of action-selection and learning signals, a necessary ingredient for off-policy reinforcement learning. We next use an off-policy reinforcement learning model to explain a new experimental finding about the conditions under which learned motor skills are consolidated to be driven by the dorsolateral striatum in rats. We then shift our focus to consider consolidation more broadly, proposing a general model of the advantages of systems in which memories and learned behaviors are consolidated from short-term to long-term learning pathways. In particular, our model proposes that such architectures enable selective filtering of the set of experiences used for learning, which can be essential in noisy environments with many extraneous stimuli. In the appendices, we explore other factors relevant to learning algorithms, including the interaction between multiple sensory modalities, and the problem of credit assignment in multi-layer neural networks. In summary, this work presents a varied set of models of different forms of learning in the brain, emphasizing the cooperative role of plasticity rules and multi-regional circuit architecture in producing functionally useful synaptic weight updates.

The esophageal epithelium is a stratified squamous tissue. Maintenance of the esophageal epithelial proliferation-differentiation gradient is critical as esophageal epithelium is the first line barrier to prevent penetration of digestive contents, while abnormal epithelial repair contributes to remodeling and disease development. Autophagy has been demonstrated to play roles in esophageal pathologies both benign and malignant, however, the role of autophagy in normal esophageal biology remains elusive. We hypothesize that autophagy may contribute to the maintenance of the proliferation/differentiation gradient under homeostasis in the esophageal epithelium. To investigate the role of autophagy in esophageal epithelium under homeostatic conditions and in response to the carcinogen 4-nitroquinoline 1-oxide (4NQO), we utilize a novel mouse model with tamoxifen-inducible, squamous epithelial-specific Atg7 (autophagy-related 7) conditional knockout. We report that genetic autophagy inhibition in squamous epithelium under homeostatic conditions resulted in enhanced proliferation of esophageal basal cells and increased thickness of epithelium, whether challenging these mice with 4NQO-induced dramatic weight loss that further displayed perturbed epithelial tissue architecture evaluated by histological and biochemical analyses. To characterize cells with high and low levels of autophagic vesicle (AV) content functionally and molecularly, we sorted esophageal basal cells based upon fluorescence of the AV-identifying dye Cyto-ID. We then used transmission electron microscopy validate increased AVs in esophageal basal cells with high AV level (Cyto-IDHigh) as compared to their counterparts with low AV level (Cyto-IDLow). Cyto-IDHigh esophageal basal cells displayed limited organoid formation capability upon initial plating but passaged more efficiently as compared to Cyto-IDLow esophageal basal cells. By RNA-Seq we identified increased autophagy in Cyto-IDHigh esophageal basal cells along with decreased cell cycle progression, the latter of which was confirmed by cell cycle analysis. scRNA-Seq of 3D organoids generated by Cyto-IDLow and Cyto-IDHigh cells identified expansion of 3 cell populations, enrichment of G2/M-associated genes in the Cyto-IDHigh group. Ki67 expression was also increased in organoids generated by Cyto-IDHigh cells, including in cells located beyond the outermost basal cell layer. Taken together, these studies provide evidence that ATG7 contributes to homeostasis of esophageal epithelium, in which esophageal basal cells with high level of AVs exhibit limited proliferation. When esophageal basal cells with high AV level are cultured in 3D organoid assays, they exhibit increased self-renewal and enhanced proliferative capacity extending beyond the outermost basal cell layer.Maintenance of the esophageal proliferation-differentiation gradient is a key to support proper functioning of the esophagus and its dysregulation can lead to the development of esophageal pathologies. Published studies provide evidence of epithelial-fibroblast crosstalk in the development of subepithelial fibrosis, a typical type of tissue remodeling found in patients with eosinophilic esophagitis (EoE). The current paradigm presents EoE as a progressive fibrostenotic disease of the esophagus in which aged patients develop fibrosis as a function of disease chronicity. We hypothesize that age of esophageal epithelium may affect EoE presentation. To directly test the impact of age upon EoE disease presentation, we treated young and aged mice with MC903/Ovalbumin to induce EoE inflammation for the same time period. We found increased thickness of lamina propria in aged mice with EoE as compared to their young counterparts, suggesting that age-associated alterations in esophageal biology contribute to EoE-associated fibrosis. To evaluate the impact of esophageal epithelial cell age on EoE-associated fibrosis, we generated primary esophageal epithelial cell lines from young and aged mice and determined the effects of these cells on fibroblast contractility in collagen plug contraction assays in vitro. These studies revealed that esophageal epithelial cells from aged mice limited fibroblast contractility less efficiently than those from their young counterparts. To identify potential signaling pathways through which aged esophageal epithelial cells may stimulate fibrotic remodeling, we conducted cytokine array analysis. We found 6 cytokines/soluble factors that have not previously been linked to EoE but may contribute to fibrotic remodeling. Taken together, this dissertation provides (1) foundation for further studies evaluating the role of autophagy and mechanisms of its regulation in the context of normal homeostasis and carcinogen-induced stress as well as (2) identification of age-associated factors that may contribute to fibrotic remodeling that may aid in the design of strategies toward early detection, prevention, and therapy of fibrostenotic EoE. / Biomedical Sciences