Year: 2009
Type: dissertation
Abstract: Thyroid hormone (TH), which is secreted by the thyroid gland, exerts significant\neffects on the central nervous system (CNS), especially during development, so\nthat delayed treatment of perinatal hypothyroidism results in severe cognitive\nretardation. Continuous postnatal neurogenesis occurs throughout adulthood in\nthe subventricular zone (SVZ) of the lateral ventricle wall and in the subgranular\nzone (SGZ) of the dentate gyrus (DG) of the hippocampal formation. The neural\nstem cells in these regions undergo proliferation, migration, differentiation into\nfunctional neurons, and integration into neural networks. These two highly\nspecialized regions are termed ‘neurogenic niches’, which mainly contain neural\nstem cells, endothelial cells, astrocytes, and microglial cells. In the SVZ, there\nare also ependymal cells. Many factors, including growth factors and hormones,\nhave been implicated in the regulation of neurogenesis.\nThe overall aim of this thesis was to investigate the effects of TH on the different\ncell types, including neural stem cells, endothelial cells and astrocytes, in two\nneurogenic niches. A postnatal hypothyroidism rat model was set up by adding\nPTU to the drinking water from Postnatal Day 1 (P1) to P21. We studied the\nacute and long-term effects of postnatal TH deficiency (PTHD) on both\nneurogenesis and angiogenesis in the SVZ and dentate gyrus.\nIn Paper I, we show region-dependent responses to PTHD. The proliferation of\nneural stem cells and the total number of granule neurons in the dentate gyrus\nwere significantly reduced in PTHD rats at P21, whereas no effects on the\nSVZ/OB system, as compared with control rats. In addition, after the withdrawal\nof PTU at P22, hippocampal neurogenesis increased as a result of increased cell\nsurvival. These changes were paralleled by alterations in the gene expression\n2\npatterns of growth factors and apoptotic factors, i.e., Fgf2, Ngf, Wnt3a, Vegfa\nand Bcl2, at both P21 and P90.\nIn Paper II, we describe a reduction in angiogenesis at P21 due to PTHD, as\nevidenced by reductions in the complexity and density of the microvessels, both\nin the neocortex and dentate gyrus. However, these defects were fully recovered\nby P90, following PTU withdrawal at P22. In the neocortex, these changes were\nparalleled by altered levels of VEGFA and FGF2. Furthermore, we report that\nthe physiologic plasma concentration of TH promotes proliferation and tubelike\nstructure formation, and inhibits the death of brain-derived endothelial\n(RBE4) cells in vitro.\nIn Paper III, we investigate the region-specific contribution of astrocytes to the\nactivities of neural stem cells after T3 (50 nM) treatment. Conditioned medium\n(CM) was collected from cultures of SVZ and hippocampal astrocytes after T3\n(50 nM) treatment, and was added to the cultures of neural stem cells (NSCs)\nfrom the corresponding brain regions. The CM from T3-treated hippocampal\nastrocyte cultures promoted hippocampal NSCs survival by increasing the\nproliferation and decreasing the cell death, whereas the CM from T3-treated SVZ\nastrocyte cultures did not have similar effects on the activities of the SVZ NSCs.\nInterestingly, the migration of neuroblast from both SVZ and hippocampus was\nsignificantly increased after culturing with CM after T3-treatment from\ncorresponding regions. Furthermore, the astrocytes after T3-treatment from these\ntwo regions displayed different expression patterns for the Bdnf, Noggin, Wnt3a,\nPedf, and Thrb genes, which are implicated in the regulation of neurogenesis.\nIn summary, this thesis demonstrates the hyper-susceptibility of hippocampal\nneurogenesis to PTHD including NSCs and astrocytes, and provides evidence of\na strong linkage between brain angiogenesis and thyroid hormone levels.
Author: Jenny Liqun Zhang
Language: English
Subfield: Developmental Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2100210477