Biology Theses and Dissertations
Permanent URI for this collectionhttp://hdl.handle.net/1903/2749
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Item Development of the translaminar circuits in the mouse cortex(2020) Deng, Rongkang; Kanold, Patrick O; Biology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The elaborated connections among cortical neurons form the cortical circuits, which are essential mechanisms underlying various cortical functions such as sensory perception, motor control, and other cognitive functions. The cortical circuits are composed of excitatory neurons and GABAergic interneurons. Excitatory neurons send excitatory connections to cortical neurons, while inhibitory neurons send inhibitory connections. Building the neural circuits is no easy task involving complex genetic programs and the influence of the environment through sensation. Malformation of the cortical circuits during development is implicated in causing neurological disorders, but our knowledge about the developmental process is scarce. The work in this dissertation uses in vitro electrophysiology in brain slices from transgenic mice to investigate how the excitatory connections onto GABAergic interneurons in the primary auditory cortex develop during the first two postnatal weeks. Furthermore, this dissertation explores the mechanisms that could regulate the early development of the cortical circuits by testing the requirement of sensory epithelium and N-methyl-D-aspartate receptors (NMDARs) in the early postnatal development of the neural circuits in the primary sensory cortex and temporal association cortex (TeA), respectively. Results from these studies fill crucial gaps in our understanding of how GABAergic interneurons are integrated into the cortical circuits and highlight the importance of sensory epithelium in the normal development of excitatory connections onto cortical GABAergic interneurons. My results also showed impaired development of GABAergic connections onto excitatory neurons lacking functional NMDARs in the TeA, suggesting an essential role of NMDARs for the early development of inhibitory circuits in the cortex.Item DISTINCT MOLECULAR AND MORPHOLOGICAL SUBCIRCUITS OF THE SUBPLATE NEURONS(2014) Viswanathan, Sarada; Kanold, Patrick o; Looger, Loren L; Biology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Subplate neurons (SPNs) are a population of neurons in the mammalian cerebral cortex that exist predominantly in the prenatal and early postnatal period. Loss of SPNs prevents the functional maturation of the cerebral cortex. SPNs receive subcortical input from the thalamus and relay this information to the developing cortical plate and thereby can influence cortical activity in a feed-forward manner. Little is known about potential feedback projections from the cortical plate to SPN. SPNs are also a heterogeneous population in terms of molecular and morphological identity. And the functional role of the different subpopulation of SPN remains poorly defined. This is mainly due to the lack of tools- i.e. transgenic lines and reporters to target and manipulate the SPNs at different stages of development. Hence the functional significance of the molecular diversity remains unexplored. In this study, we used a combination of genetic, molecular, anatomical and physiological approaches to address these questions and also to identify and characterize transgenic `tools' to manipulate the SPN. We identified and characterized a set of reporters and transgenic lines expressing Cre recombinase or green fluorescent protein with different levels of specificity in the subplate (SP). Using these transgenic driver lines and specific antibodies, we find that defined SPNs project to the main thalamo-recipient layers - L4 and L1 - and the spatial pattern of SPN projections to layer 4 is related to the spatial pattern of thalamo-cortical projections. However different subclasses have distinct patterns of projections with respect to the thalamic afferents. While certain subclasses have been shown to project locally, we observe that certain cell types of SPN also extend long-range projections to different thalamic nuclei. Thus molecularly defined SPN cell types are differentially integrated into the thalamo-cortical and intra-cortical connectivity. We also find a laminar difference in intra-cortical connectivity of the SPN. The first class of SPNs receives inputs from only deep cortical layers, while the second class of SPNs receives inputs from deep as well as superficial layers including layer 4 and are located more superficially. These superficial cortical inputs to SPNs emerge in the second postnatal week. Taken together, we demonstrate the presence of distinct laminar and molecular circuits in the developing subplate and characterize yet another level of heterogeneity of this population.Item A COMPARATIVE STUDY OF FGFR3 SIGNALING DURING THE DEVELOPMENT OF THE ORGAN OF CORTI AND BASILAR PAPILLA(2008-12-11) Jacques, Bonnie E; Jeffery, William R; Kelley, Matthew W; Biology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Most age-related hearing loss is the result of the accumulated death of inner ear hair cells over a life span. Human hair cells lack the ability to be regenerated once they die and thus there is a need to understand the processes which regulate hair cell formation. Unlike the mammalian ear, the avian cochlea has the ability to regenerate lost hair cells and thus there exists an ongoing race to find the key to regeneration in the mammalian ear. Human hearing is dependent on the interactions between numerous cell types yet very little is known about the pathways which regulate the development of the functionally essential support cells of the mammalian cochlear sensory epithelium. This study aims to elucidate some of the genetic pathways involved in hair cell and support cell differentiation in the developing cochlea. Specifically, the role of Fgfr3 signaling in pillar cell and hair cell differentiation will be revealed through the use of an in vivo mutant mouse model containing a null Fgf8 gene and in vitro whole organ culturing of the embryonic cochlear sensory epithelia of mice and chickens. The classic localize, activate, inhibit scheme will be employed. This study will demonstrate that Fgf8 and Fgfr3 are expressed by inner hair cells and pillar cells, respectively, and are required throughout development for normal differentiation and pattern formation of the organ of Corti. Inhibition of the receptor or ligand results in the loss of pillar cells and ectopic formation of hair cells, while activation of this pathway inhibits hair cell formation and induces pillar cells or activation of these genes and their proteins have on the formation of hair cell and support cell types. This study also takes a comparative approach by addressing the similarities and differences of the Fgfr3 signaling pathway in the mammalian organ of Corti and the avian basilar papilla. Fgfr inhibition in the developing basilar papilla causes an increase in hair cell density via the direct transdifferentiation of support cells into hair cells suggesting a role for this signaling pathway in the ability to regenerate hair cells.Item The Gonadotropin Releasing Hormone-3 System in Zebrafish: Early Development and Regulation(2008-12-15) Abraham, Eytan; Zohar, Yonathan; Marine-Estuarine-Environmental Sciences; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The objective of this study was to expand our understanding of the early development of forebrain Gonadotropin Releasing Hormone (GnRH) neurons in vertebrates in general and in fish in particular. The correct migration during early development of the hypophysiotropic GnRH neurons from the olfactory region to the hypothalamus is crucial for normal gonadal development and reproduction. We developed a Tg(GnRH3:EGFP) zebrafish line in which EGFP is specifically expressed in GnRH3 neurons. Using this line, we have studied in detail the early spatiotemporal development of the GnRH3 system in vivo. In addition, we have studied various factors, including GnRH3, Netrins and Hedgehog to better understand some of the mechanisms that mediate this complex axophilic neuron migration event. Lastly, we have conducted targeted GnRH3 neuron ablation experiments in view of determining the embryonic origin of POA-hypothalamic GnRH3 neurons and the effect of lack of GnRH3 neurons in the CNS. Our findings show that: 1) GnRH neurons first differentiate and express GnRH3 at 24-26 hours post fertilization (hpf) and immediately thereafter begin to extend fibers. 2) GnRH3 neurons project a complex network of fibers, prior the GnRH3 soma migration, to various CNS regions, and to the pituitary. 3) GnRH3 soma begin migrating towards the hypothalamus at 3 days post fertilization (dpf), passing through the terminal nerve (TN), lateral telencephalon, and reaching the hypothalamus by 12 dpf. 4) expression of GnRH3 itself is necessary for the normal early differentiation and fiber extensions of GnRH3 neurons. 5) Netrin1a is directly involved as a chemoattractant in GnRH3 fiber organization and subsequently, in GnRH3 soma migration to the hypothalamus. 6). Netrin2 is required for normal early ZF embryogenesis. 7). Sonic hedgehog a does not serve as a specific factor in the development of the GnRH3 system. 8). GnRH3 neuron regeneration capacity is temporally limited. 9). Successful ablation of olfactory GnRH3 neurons during development results in lack of GnRH3 neurons in the entire sexually mature brain as well as abnormal gonadal development and inability to reproduce. This study expands our understanding vis-à-vis the early events that occur during GnRH3 system development and that regulate this complex process. In a broader sense these findings augment current knowledge regarding the regulation of long range tangential neuron migration during development.Item ISOLATION AND CHARACTERIZATION OF CAENORHABDITIS BRIGGSAE TRA MUTANTS.(2005-12-12) Kelleher, Danielle Fay; Haag, Eric S; Biology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)In order to aid in the reconstruction of the Caenorhabditis briggsae sex determination pathway, for the purposes of studying the convergent evolution of hermaphroditism and mating system change in nematodes, Cb-tra mutants have been isolated through forward mutagenesis. Based on phenotype, genetic linkage, molecular linkage, and in some cases sequence analysis, the C. briggsae homologs of tra-1, tra-2, and possibly tra-3 have been identified. Upon further characterization, the function of the tra genes during sex determination between C. elegans and C. briggsae appears to be largely conserved. However, notable differences, with respect to the role of tra-1 and potentially the role of tra-3, have been observed between these two species. In addition, intra-species suppression of the putative tra-3 mutant (AF16 background) by genomic variants in the wild-type strain HK104 suggests that molecular interactions underlying sex determination are changing between these two C. briggsae populations.