Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/106332
Citations
Scopus Web of Science® Altmetric
?
?
Type: Theses
Title: Expression of substance P and the Tachykinin NK1 receptor in the medullary serotonergic network of the human infant during development: implications for sudden infant death syndrome (SIDS)
Author: Bright, Fiona Maree
Issue Date: 2017
School/Discipline: Adelaide Medical School
Abstract: Sudden infant death syndrome (SIDS) is a devastating and unexpected event in which a seemingly healthy infant dies in the first year of life during a sleep period, with no warning or prior indication of any adverse pathology to cause alarm (Kinney and Thach, 2009a). It is one of the most significant causes of post neonatal mortality in developed countries, profoundly affecting families and their communities. SIDS is complex, heterogenous and a diagnosis based solely on exclusion where the exact cause of death remains largely unexplained following complete post mortem examination and investigation of the circumstances of death (Krous 2004). By attempting to identify those children who may be at risk, medical professionals and scientific researchers endeavour to uncover and understand the pathogenesis of SIDS not only to prevent its occurrence, but also to provide some form of closure for families who are left to make sense of not only the death of their child but the heartache and stigma that comes with the “nonentity” of SIDS (Thach, 2008, Wender, 2012). Multiple definitions, theories, animal and human studies have been established in an attempt to decipher the pathogenesis of SIDS. Unfortunately there are no available biomarkers for SIDS; no single universally accepted definition or theory and the direct cause remains relatively unknown. However, multiple neuropathologic studies have provided evidence that a certain subset of SIDS infants are not entirely 'normal' prior to death (Filiano and Kinney, 1994, Takashima and Becker, 1985, Sridhar et al., 2003, Paterson et al., 2006b). Instead these infants possess some form of underlying vulnerability exposing them to an increased risk for sudden death (Kinney, 2009a, Kinney and Thach, 2009a, Paterson et al., 2006b). It is thought that SIDS or a certain subset of SIDS is caused by some form of underlying neural or systematic abnormality in medullary homeostatic control that impairs critical responses to life-threatening challenges such as hypoxia during a sleep period (Kinney and Thach, 2009a). This failure is thought to result from abnormalities in a multi-neurotransmitter network of neural pathways in the medulla oblongata that control respiration, chemosensitivity, autonomic function and arousal. Indeed abnormalities in various brainstem neurochemicals including catecholaminergic, nicotinic, muscarinic, cholinergic, glutamatergic and neuropeptide systems have been reported (Kinney, 2009b, Kinney et al., 2009b). Abnormalities in the medullary serotonergic (5-HT) system have been the most significantly and consistently observed in the brainstem of SIDS infants, however it remains unclear whether these abnormalities are the primary event in SIDS or an epiphenomenon, with the underlying pathogenesis of these specific abnormalities still undetermined. The neuropeptide substance P (SP) functions within key medullary nuclei to regulate cardiorespiratory and autonomic function in conjunction with 5-HT and other neurochemicals. Actions of SP are primarily mediated by tachykinin NK1 receptors (NK1R) in the CNS and SP is recognized as a primary excitatory neurotransmitter and central mediator of cardiovascular reflexes such as baroreceptor sensitivity and chemoreceptor reflex modulation in response to hypoxia. Abnormalities in SP neurotransmission may play, therefore, a role in homeostatic dysfunction in SIDS. Previous studies analyzing SP and NK1R in the brainstem in SIDS have, however, been inconsistent and inconclusive. Furthermore a potential functional relationship between the 5-HT and SP neurotransmitter systems may be of critical importance to the pathogenesis of SIDS, where deficiencies in 5-HT which is already well established in the literature, may stimulate a compensatory response by SP. Previous animal studies and post-mortem human infant tissue research have investigated both 5-HT and SP individually in relation to homeostatic control and failure underlying the pathogenesis of SIDS, however the role of SP in association with the medullary 5-HT network in SIDS has not been fully examined. In a collaborative effort combining two independent cohorts of human infant brainstem tissue and associated digital autopsy databases from Australia and the USA, the overall objective of this research was to investigate the expression of SP and its NK1R in the medullary 5-HT network during neurodevelopment, with specific investigation of the potential role of both neurotransmitter systems in contributing to a multi-transmitter medullary homeostatic network dysfunction in a subset of SIDS cases. The thesis is comprised of three core studies, each of which are closely interrelated. Collectively these studies resulted in significant outcomes that contribute immensely to the continued investigation of the underlying pathogenesis of SIDS and have provided a foundation for promising future research directions.
Advisor: Byard, Roger W.
Vink, Robert
Leonard, Anna V.
Dissertation Note: Thesis (Ph.D.) (Research by Publication) -- University of Adelaide, Adelaide Medical School, 2017.
Keywords: neuroscience
neuropathology
brainstem
sudden infant death syndrome
SIDS
serotonin
substance P
neurotransmitters
Research by Publication
Provenance: This electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at: http://www.adelaide.edu.au/legals
DOI: 10.4225/55/59559fe1a7512
Appears in Collections:Research Theses

Files in This Item:
File Description SizeFormat 
01front.pdf307.56 kBAdobe PDFView/Open
02whole.pdf7.35 MBAdobe PDFView/Open
PermissionsLibrary staff access only501.8 kBAdobe PDFView/Open
RestrictedLibrary staff access only7.35 MBAdobe PDFView/Open


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.