Physiology - Theses
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ItemMathematical and computer modelling of the enteric nervous system( 2001)The enteric nervous system (ENS) runs within the intestinal wall and is responsible for initiating and enacting several reflexes and motor patterns, including peristalsis and the complex interdigestive motor programs, known as migrating motor complexes (MMCs). The ENS consists of several neuron types including intrinsic sensory neurons, interneurons and motor neurons. A great deal is known about the anatomy, pharmacology and electrophysiology of the ENS, yet there is almost no understanding of how enteric neural circuits perform the functions that they do and how they switch from one function to another. The ENS contains intrinsic sensory neurons (ISNs) that connect to every neuron type in the ENS, including making recurrent connections amongst themselves. Thus, they are likely to play a key role, not just in sensory transduction, but in coordination of reflexes and motor patterns. This thesis has explored how these functions are performed by developing and analysing mathematical and computer models of the network of ISNs. (For complete abstract open document)
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ItemEnteric serotonin interneurons: connections and role in intestinal movement( 2008)5-HT powerfully affects gastrointestinal function. However, the study of these effects is complicated because 5-HT from both mucosa and a subset of enteric neurons acts on multiple receptor subtypes in enteric tissues. The role of neural 5-HT has been difficult to isolate with current techniques. This thesis aimed to elucidate the role of 5-HT neurons in motility using anatomical and functional methods. In Chapter 2, confocal microscopy was used to examine over 95% of myenteric neurons in guinea pig jejunum, categorized neurochemically, to identify neurons that received anatomically-defined input from 5-HT interneurons. The data showed that cholinergic secretomotor neurons were strongly targeted by 5-HT interneurons. In another key finding, excitatory motor neurons were surrounded by 5-HT terminals; this could provide an anatomical substrate for the descending excitation reflex. Subgroups of ascending interneurons and neurons with immunoreactivity for NOS, were also targeted by 5-HT interneurons. Thus, subtypes of these neurons might act in separate reflex pathways. Despite strong physiological evidence for 5-HT inputs to AH/Dogiel type II neurons, few contacts were identified. In Chapter 3, the confocal microscopy survey was extended to the three other interneuron classes (VIP/NOS and SOM descending interneurons; calretinin ascending interneurons) of guinea pig small intestine. A high degree of convergence between the otherwise polarized ascending and descending interneuron pathways was identified.
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ItemCloning and characterisation of gripe: a novel interacting partner of e12 during brain development( 2002-10)The mammalian cerebral cortex is a remarkable product of brain evolution, and is the structure that most distinctively delineates the human species from others (Northcutt and Kaas, 1995; Rakic, 1988). Neurons in the adult brain are organised into cytoarchitectonic areas, defined by distinct biochemical, morphological and physiological characteristics (Rakic 1988). Remarkably, this complex structure is generated from a simple neuroepithelium. What are the signalling mechanisms that direct neuron formation and subsequent functional-parcellation of the cerebral cortex? Key to the study of this process is an understanding of neuronal fate determination. Available evidence demonstrates an intrinsic programming potential by neuronal progenitors within subdomains of the developing cerebral cortex that is instructive for proper corticogenesis. These regional domains are demarcated by expression of certain transcription factors, including members of the Helix-Loop-Helix (HLH) family of proteins. The HLH family of transcription factors are key contributors to a wide array of developmental processes, including neurogenesis and haematopoiesis. These factors are thought to exert their regulatory influences by binding to cognate promoter-DNA sequences as dimers. While studies in mice have convincingly demonstrated that neurogenic HLH proteins such as NeuroD (Lee et al., 1995; Miyata et al., 1999; Liu et al., 2000) and Mash1 (Casarosa et al., 1999) are intimately involved in neuronal fate determination and terminal differentiation, the role of the ubiquitously expressed HLH protein, E12, in mammalian neurogenesis remains ambiguous. Originally discovered as an important regulator of lymphopoiesis, expression studies revealed its widespread expression in proliferative zones of multiple nascent organs of the embryo, including the developing cerebral cortex; implying a role for E12 in development of the nervous system. Since the function of E12 is, in part, coded by its capacity for protein dimerisation, a search was undertaken for binding partners in developing mouse brain, and using a yeast 2-hybrid assay. Yeast 2-hybrid prey libraries were constructed using complementary DNA (cDNA) isolated from embryonic mouse forebrain tissue at early (embryonic day e11.5) and peak (e15.5) stages of neurogenesis. Screening of these libraries for binding partners to an E12 bait resulted in cloning of HLH factors, such as Mash1, NSCL and Id2. Importantly, a novel binding partner, named GRIPE, was cloned as a novel GAP Related Interacting Protein to E12. GRIPE binds to the HLH region of E12, and may require E12 for nuclear import. Furthermore, GRIPE may negatively regulate E12-dependent target gene transcription. High levels of GRIPE and E12 mRNA were coincidently detected during embryogenesis, but only GRIPE mRNA levels remained high in adult brain, particularly in neurons of the cortex and hippocampus. These observations were reconfirmed through an in vitro model of neurogenesis. Taken together, these results indicate that GRIPE is a novel protein whose dimerisation with E12 has important consequences for cells undergoing neuronal differentiation. A model is proposed to suggest how neurogenic HLH proteins that dimerise to E12 may promote signalling cascades driving early neuroblast differentiation.
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ItemCharacterization of mechanisms of myocardial remodeling in genetic models of cardiac hypertrophy( 2005-12)Cardiac hypertrophy is clinically defined as a relative increase in heart size associated with a thickening of the ventricular wall. It is a common feature of individuals suffering from different cardio-vascular or metabolic conditions and leads to heart failure. The structural, functional and molecular mechanisms which induce hypertrophy independent of hemodynamic alterations are poorly characterized. In this study, questions about whether cardiac-specific neuro-endocrine activation or metabolic imbalance are sufficient to induce hypertrophic structural and functional remodeling are addressed using genetically manipulated mouse models of primary cardiac hypertrophy. (For complete abstract open document)
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ItemMechanisms underlying changes in microvascular blood flow in a diabetic rat model: relevance to tissue repair( 2002-08)Diabetes mellitus is a chronic syndrome affecting carbohydrate, protein, and fat metabolism. It is characterized primarily by relative or absolute insufficiency of insulin secretion (type I diabetes or IDDM) or concomitant insensitivity / resistance to the metabolic action of insulin on target tissues (Type II diabetes or NIDDM), both resulting in hyperglycaemia. Diabetes mellitus is known to induce microvascular changes and alterations to neuronal functions. The neurovascular system comprising of unmyelinated primary afferent sensory neurones and the microvasculature innervated by these nerves play a major role in modulating inflammatory and tissue repair processes. Sensory nerve terminals respond to injury via the release of sensory neuropeptides which mediate inflammation and tissue repair. These processes are known to be altered in diabetes. This thesis is concerned with the role of diabetes in modulating microvascular blood flow directly and indirectly via modulating sensory nerve activity and the effect of these changes on repair processes in skin of 4 weeks streptozotocin (STZ)-induced diabetic rats. The following hypotheses were examined: 1. That factors implicated in long-term diabetic vascular damage play a role in altering skin microvascular function in early diabetes. 2. That preventing the deleterious effects of these factors could improve skin microvascular blood flow and skin repair processes in early diabetes. (For complete abstract open document)
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ItemCardiac structure and function during human pregnancy( 2006)This thesis explored, by non-invasive assessment, the cardiovascular function of volunteer participants during the menstrual cycle and pregnancy. In doing so it addresses the potential influences of hormonal variation on the heart and blood vessels. In the case of the post-ovulatory luteal phase of the menstrual cycle and early pregnancy, the predominant hormonal change is increased progesterone. This hormonal similarity raises questions about the degree to which cardiovascular changes might also qualitatively resemble one another in these 2 circumstances, possibly providing a physiological "bridge" between pre- and early pregnancy. This thesis also examines the changes in cardiovascular structure and function between early and late pregnancy, a period of growth for the fetus and a time during which the mother shows features of insulin resistance that might be influenced by pre-pregnancy maternal characteristics such as body weight. This provides an opportunity to assess the relative strength of association between these factors (fetal and maternal) and cardiovascular adaptation. Cardiovascular characteristics were measured longitudinally during the menstrual cycle both before (follicular phase) and after (luteal phase) ovulation. Careful timing of measurement ensured that estradiol levels were stable between the follicular and luteal phase and that progesterone levels increased markedly after ovulation. Nine healthy women had measurements made in two separate cycles that were averaged to minimise individual variation. Although weight did not alter between the follicular and luteal phases, hemoglobin and hematocrit decreased significantly, suggesting an increase in intravascular volume. Supine systolic and diastolic blood pressures were lower during the luteal phase. There was a borderline increase in cardiac output over this period, suggesting a reduction in total peripheral resistance to account for the fall in supine blood pressure. Evidence of homeostatic responses to this vasodilatation included the suggestion of increased sympathetic reactivity (higher blood pressure on standing) and reduced parasympathetic responses (failure to reduce blood pressure with carotid pressure), increased renin and reduced atrial natriuretic peptide. The studies in pregnancy involved 100 healthy women who were assessed in early pregnancy (average of 16 weeks gestation). Thirty two of these women had repeat cardiovascular assessments in late pregnancy (average of 37 weeks gestation). Reflecting an exaggeration of the changes observed between the follicular and luteal phases of the menstrual cycle, in early pregnancy hemoglobin, hematocrit and blood pressure were lower than observed in the women (matched for age, body weight) in the menstrual study. It was observed that the cardiovascular system in early pregnancy was characterised by tachycardia that required a period of rest to reach basal levels. These levels were lower than previously reported. Also in contrast to previous studies, although median cardiac output in early pregnancy was slightly greater than in the menstrual study, this was not statistically significant. The most significant original finding was that at term, a decrease was observed in both systolic and diastolic left ventricular function as measured using modern tissue Doppler methods. These unexpected findings, in otherwise well women, suggest that the stress of pregnancy on the maternal heart is greater than previously appreciated. The diminished functional capacity of the heart was more marked in overweight women. These findings might also provide a clue to the (rare) complication of peripartum cardiomyopathy, a condition known to occur more frequently in overweight/obese women. Findings from this thesis provide new insights into the physiological changes of the cardiovascular system during the menstrual cycle and pregnancy. The studies were undertaken after rest, but in pregnancy especially it would be of interest to examine cardiac performance during activity. Further studies in complicated pregnancies might also clarify whether cardiovascular characteristics are qualitatively or quantitatively different to normal pregnancies. Nevertheless, these studies, which provide normative data on modern cardiovascular phenotypes, might find clinical utility particularly for women during pregnancy complicated by pre-existing cardiac disease or by medical maternal complications of pregnancy. Finally, in a more general sense, the demonstration that maternal weight impacts on cardiovascular function adds strength to the current concerns about excess weight in our community.