Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.509485
Title: Vasoactive intestinal peptide (VIP) : control of hippocampal neurogenesis
Author: Zaben, Malik J.
ISNI:       0000 0004 2677 2607
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2007
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Abstract:
Neurogenesis; the generation of new neurons, is persistent in the brain throughout life of mammals, including humans. The two well-defined neurogenic areas in the adult brain are: the subventricular zone of the lateral ventricle and the subgranular zone of the dentate gyrus in the hippocampus. Hippocampal neurogenesis is involved in learning and memory, and is influenced by many pathological states, such as epilepsy, stress, and mood disorders. The response of stem cells to different stimuli is organised by the surrounding microenvironment (niche), which extends to include endothelial cells, astrocytes and neurons. Neurogenesis is neuronally driven by projection input into the dentate gyrus and modulated by local circuit activity via GABAergic intemeurons. Hippocampal intemeurons respond to specific patterns of input activity by secreting neuropeptides; principal among them is the vasoactive intestinal polypeptide (VIP). A considerable amount of research has focused on factors which control the proliferation of neuronal precursor cells. However, it has been recently emphasised that cell survival rather than proliferation is the key determinant of net hippocampal neurogenesis and thus learning and memory acquisition. VIP is a 28 amino acid neuropeptide that has potent trophic and proliferative effects on neuronal precursor cells during neurodevelopment. VIP and its binding sites are expressed at high levels in the adult dentate gyrus of the hippocampus. While reduction in VIP level is associated with learning and memory impairments, it peaks on PI 0 in the rat hippocampus; the critical period during which the granule cell layer of the DG is largely formed. Therefore, and in an attempt to understand the mechanisms underlying trophic control of hippocampal neurogenesis, we are investigating the hypothesis that VIP modulates the survival, proliferation and differentiation of postnatal hippocampal stem cells and their progeny. We have shown that VIP at nanomolar concentrations is generally trophic to hippocampal cells in vitro with a prominent trophic and self-renewal effect on nestin cells, particularly the amplifying cell population, through enhanced symmetrical cell division. This effect is specific for dentate gyrus progenitor cells. Using immunohistochemistry and PCR techniques, we demonstrated the expression of VPACI and VPAC2 receptors and their mRNAs in hippocampal progenitor cell cultures. Pharmacologically, we have shown that VIP survival and self-renewal effects in vitro are VPAC2 mediated. We confirm that VPAC2 knockout adult mice have a reduction in the area of and the number of newly born cells in the granule cell layer of the dentate gyrus. We have also found that VIP interacts with FGF-2 and NPY to enhance neurogenesis and nestin cell survival, respectively. We conclude that VIP is a trophic and self-renewal factor that may playa key role in the process of hippocampal neurogenesis. The importance of this work is our demonstration of a putative mechanism by which neuronal activity can influence trophism and symmetric/asymmetric division of precursor cells in the postnatal dentate gyrus.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.509485  DOI: Not available
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