Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.604704
Title: Interaction of serotonin and corticosterone on neurogenesis in the dentate gyrus of the hippocampus in the adult rat
Author: Huang, G.-J.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2005
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Abstract:
The work in this thesis is directed towards understanding more about the interplay between glucocorticoids and serotonin in regulating the proliferation of neural progenitor cells in the adult hippocampus. Depleting serotonin (5-HT) by ICV 5,7-DHT (a 5-HT neurotoxin) did not change the number of proliferating cells in the dentate gyrus. Treatment with PCPA (a tryptophan hydroxylase inhibitor) resulted in reduced proliferation as measured by Ki-67 after 3 days treatment, but not by BrdU uptake, and not after 14 days treatment by either method. These results argue against ‘basal’ levels of serotonin playing a role in neurogenesis. Injecting corticosterone for 8 days significantly reduced proliferation in the dentate gyrus. However, serotonin alters the sensitivity of the dentate gyrus to corticosterone. Adrenalectomized (ADX) rats given low doses of replacement corticosterone for 7 days showed reduced proliferation, but this was prevented by depleting 5-HT (ICV 5, 7-DHT). A dose-response study showed that progressive doses of corticosterone (0-40 mg/kg/day) in ADX rats resulted in corresponding reductions in proliferation in 5-HT intact but a reduced effect (shift to the right) in 5-HT depleted rats. These results strongly suggest that serotonin regulates the sensitivity of proliferating cells in the dentate gyrus to corticosterone. Next, we explored the role of 5-HT1A receptors in the regulation of cell proliferation in the dentate gyrus of the intact and ADX adult rat. Depleting 5-HT with PCPA or stimulating 5-HT­1A receptors with 8-OH-DPAT by sc injection for 14 days had no effect no cell proliferation in the dentate gyrus. However, combined treatment with PCPA followed by 8-OH-DPAT significantly increased cell proliferation compared to PCPA alone. This suggests that reducing serotonin increases the sensitivity of progenitor cells to 5-HT1A agonists. Micro-injection of 5,7-DHT in to the fimbria-fornix and the cingulate bundle depleted hippocampal 5-HT (but not other areas of the brain) but did not change cell proliferation 3 weeks after the surgery, thus reinforcing conclusions about ‘basal’ 5-HT (see above).  However, 8-OH-DPAT stimulated cell proliferation in the dentate gyrus of hippocampal 5-HT depleted rats compared with controls. These results suggest that 5-HT1A modulates cell proliferation in the hippocampus by a direct post-synaptic effect, 8-OH-DPAT delivered by subcutaneous osmotic pumps (rather than sc injection) increased proliferation in intact rats. The 5-HT1A antagonist WAY-100635 by itself did not alter cell proliferation, but blocked the effect of 8-OH-DPAT. However, WAY-100635 could not block the stimulating action of ADX cell proliferation. 5-HT1A mRNA expression was not altered in the hippocampus by ADX.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.604704  DOI: Not available
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