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Title: Ultra-structural characterization of exocytotic vesicles and their neuropeptide Y content in the central noradrenergic system
Author: Kourtesis, Ioannis
ISNI:       0000 0004 5920 8631
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2014
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Dysfunction of the nor/epinephrine (N/E) system in the brain is implicated III essential hypertension. Although links between sympathetic activity, co-transmission of neuropeptides and N/E, and development or maintenance of essential hypertension have been described, the mechanisms regulating catecholamine release in the brain are not established yet. The goal of this thesis was to map and characterize the extent of co-localized neuropeptide Y (NPY) in N/E-ergic neurones in CNS, both at the level of cells and of single exocytotic NIE-ergic vesicles, based on immunolabelling. This allowed me to compare the sizes of vesicles containing N/E and NPY across dorsal and ventral brainstem - known to play a role in hypertension - and the pons, between normotensive (WR) and spontaneous hypertensive adult rats (SHR). To address this goal, N/E-ergic neurones were selectively labelled by microinjection of adenoviral vector for cell-specific expression of EGFP in nucleus tracts solitarius (NTS), rostral ventrolateral medulla (RVLM) and locus coeruleus (LC) of both WR and SHR in vivo, and appropriate sample preparation for preserving the ultrastructure and antigenicity for electron microscopy was established. Mathematical modelling was necessary to reconstruct imaged vesicle distributions to 'true' vesicle sizes. The data reveal increased expression and co-expression levels of NPY in N/E-ergic neurones of LC, and larger N/E-ergic vesicle sizes with increased co-localization in RVLM and LC, but not NTS, in SHR compared to WR. Morphological correlates of vesicle sizes above 150 nm and up to 650 nm in diameter are in line with previously quantified N/E release events in NTS and RVLM (Chiti & Teschemacher, 2007;Teschemacher et al. , 2008) and correspond to an estimated intra-vesicular NIE concentration of approximately 35 mM. Our evidence underpins the putative role for NPY -ergic and N/E-ergic co-transmission in brain stem areas and LC in hypeltension, as well as the hypothesis for a hypotensive role of A2 neurones in the NTS, and the increased central N/E volume transmission into extracellular space in pro-hypeltensive Cl neurons in the RVLM. In conclusion, the functional significance of neuropeptide co-localization and cotransmission in central N/E-ergic neurones enables us to further understand the cellular physiology and mechanisms of N/E signaling in order to develop future potential therapeutic strategies against hypertension
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available