Alzheimer�s disease (AD) is a neurodegenerative disorder, charaeterised by progressive loss of memory. It is important to understand what factors initiate the onset of AD so that effective therapeutic treatments can be developed to target the precise mechanisms that initiate this disease. Currently, synaptic dysfunction is widely believed to be the first significant alteration preceding the onset of AD, and is thought to be initiated by an intracellular accumulation of amyloid-β (Aβ), or a free radical-induced increase of oxidative stress. As Aβ levels rise during the onset of AD, a concomitant reduction of secreted amyloid precursor protein-α (sAPPα) is observed, as the two proteins exist in equilibrium. Intriguingly, the neuroprotective and neurotrophic properties of sAPPα indicate that it is intimately involved in the physiological pathways of the major hypotheses for the cause of AD, and may also be involved in the mechanisms that underlie learning and memory. Therefore, it is possible that during the onset of AD, the decrease of sAPPα may contribute to synaptic dysfunction by disrupting the mechanisms of synaptic plasticity. Long-term potentiation (LTP) is the leading experimental model for investigating the neural substrate of memory formation, and describes the molecular mechanisms that underlie an increase in the strength of synaptic transmission. The role sAPPα may play in the induction and maintenance of LTP has not previously been addressed in vivo. Therefore, the aim of this thesis was to investigate whether sAPPα affects the induction of LTP in the hippocampus of the anaesthetised rat. The present findings are the first to suggest that sAPPα may modulate the induction of LTP in vivo. Decreasing the function of endogenous sAPPα (with sAPPα-binding antibodies and a pharmacological inhibition of α-secretase) significantly reduced the magnitude of LTP induced in the dentate gyrus. Therefore, the reduction of sAPPα during AD is likely to have a detrimental impact on the mechanisms of synaptic plasticity, and by extension, learning and memory. The present investigation has also found that the application of recombinant, purified sAPPα to the rat hippocampus has an �inverted U-shaped� dose-response effect on the magnitude of LTP. Low concentrations of sAPPα significantly enhanced LTP, supporting previous findings that exogenous sAPPα can facilitate in vitro LTP and enhance memory performance in animals. On the other hand, comparatively high concentrations of sAPPα significantly decreased the magnitude of LTP. This observation is also consistent with previous findings, in which high concentrations of sAPPα have been shown to be less synaptogenic and memory enhancing than lower doses. These results are the first to suggest that sAPPα modulates in vivo synaptic plasticity, and have important implications for the development of strategies to treat AD.

Long-term potentiation (LTP) is an activity-dependent increase in the efficacy of synaptic transmission. In concert with long-term depression (LTD), this synaptic plasticity likely underlies some types of learning and memory. It has been suggested that for LTP/LTD to act as effective memory storage mechanisms, homeostatic regulation is required. This need for plasticity regulation is incorporated into the Bienenstock, Cooper and Munro (BCM) theory by a threshold determining LTD/LTP induction, which is altered by the previous history of activity (Bienenstock et al., 1982). The present work aimed to test key predictions of the BCM model. This was done using field and intracellular recordings in area CA1 of hippocampal slices from young, adult male Sprague-Dawley rats. The first prediction tested was that following a strong, high-frequency priming stimulation all synapses on primed cells will show inhibition of subsequent LTP and facilitation of LTD induction (heterosynaptic metaplasticity). This was confirmed using two independent Schaffer collateral pathways to the same CA1 pyramidal cells. Following priming stimulation to one pathway, LTP induction was heterosynaptically inhibited and LTD facilitated. To more fully investigate whether all synapses show metaplastic changes, the priming stimulation was given in a different dendritic compartment, in stratum oriens, prior to LTP induction in stratum radiatum. This experiment supported the conclusion that all synapses show inhibited LTP following priming. A second prediction of the BCM model is that metaplasticity induction is determined by the history of cell firing. To investigate this, cells were hyperpolarized during priming to completely prevent somatic action potentials. Under these conditions inhibitory priming of LTP was still observed, and thus somatic action potentials are not critical for the induction of the effect. The next aim was to determine the mechanism underlying heterosynaptic metaplasticity. One way in which plasticity induction can be altered is through changes in gamma-aminobutyric acid (GABA)-mediated inhibition of pyramidal cells. For this reason, it was tested whether blocking all GABAergic inhibition, for the duration of the experiment, would prevent priming of LTP. However, priming inhibited subsequent LTP and it was concluded that GABAergic changes do not underlie either the induction, or expression, of the metaplastic state. Proposed revisions to the BCM model predict that postsynaptic elevations in intracellular Ca�⁺ determine the induction of metaplasticity. There are many potential sources for postsynaptic Ca�⁺ elevations, including entry through N-methyl-D-asparate receptors (NMDARs) or voltage-dependent calcium channels (VDCCs), or release from intracellular stores. Results of the present work demonstrate that the inhibition of LTP is dependent on the release of Ca�⁺ from intracellular stores during priming; however this release is not triggered by Ca�⁺ entry through NMDARs or VDCCs, or via activation of metabotropic glutamate receptors. Overall, the present results show that, in accordance with the BCM model, a high level of prior activity induces a cell-wide metaplastic state, such that LTD is facilitated and LTP is inhibited. In contrast to predictions of the BCM model, this is not mediated by cell-firing during priming. Instead the release of Ca�⁺ from intracellular stores is critical for induction of the metaplastic state.

This study was designed to determine the impact of glycerol hyperhydration, compared with a placebo hyperhydration, on the run performance during an Olympic distance triathlon. Ten competitive triathletes (mean peak oxygen consumption, VO2 peak = 65.5 ± 5.5 ml.kg.-1min-1) undertook two simulated Olympic Distance Triathlons in 31° C and 61% relative humidity. The trials were split into two work phases: a fixed workload phase comprising a 18-20 min swim and a 60 min cycle and, a self regulated time trial run over 10 kilometres conducted on a treadmill. One hundred and fifty min prior each trial, either a glycerol solution (1 g.kg.-1 body mass (BM) in a 4% carbohydrate – electrolyte drink) or a placebo of equal volume of the 4% carbohydrate-electrolyte solution was ingested over one hour. The total fluid intake in each trial was 23 ml.kg.-1 BM. A randomised, double blind, cross over design was used. Due to either 1) the arduous nature of the trials 2) the side effects associated with the ingestion of glycerol 3) or the combination of the two aforementioned reasons, only five of the 10 subjects completed the final 10 km self regulated time trial for both treatments. Only the data obtained from these five subjects were reported in this study. Glycerol ingestion expanded body water over the placebo by 154 ml (26%). At 60 and 90 min after the start of drinking, urine output was significantly higher with glycerol than placebo treatment (216.4, 366.4 ml vs 81.0, 242.0 ml, respectively) but significantly higher at 120 min in the placebo (421.6 ml vs 131.2 ml). There were no significant differences in heart rate and rectal temperature during the swim and cycle phases. However, there were significant increases in heart rate (at 5, 10, 15, 25 and 30 min) and rectal temperature (at 5, 20 and 30 min) during the 10 km run in the glycerol trial. The mean 10 km run time for the placebo trial was 40 min 21 sec (± 2.9 min) while the glycerol trial was 39 min 22 sec (± 2.0 min). The mean difference of 2.1% in finishing time between trials was not significant. Three of the five subjects in the glycerol trial improved their 10 km time by 7.0, 2.4 and 2.7%, respectively. The finishing time for one subject did not change for both trials while another subject had deteriorated by 2.3% in the glycerol trial. In the glycerol treatment, five subjects complained of bloating and nausea while only one subject complained of feeling unwell in the placebo treatment. Data from this study have shown that glycerol hyperhydration did not significantly improve performance while plasma volume expansion and subsequent lower rectal temperature and lower heart rates were not evident. The exact mechanisms of how glycerol hyperhydration can improve performance warrant further investigation. / Masters in Applied Science

[Truncated abstract] It is well established that fish, amphibians and reptiles recovering from physical activity of near maximal intensity can replenish completely their muscle glycogen stores in the absence of food. In contrast, the extent to which these stores are replenished under these conditions in humans has been reported in all but one study to be partial. This implies that a few consecutive bouts of intense exercise might eventually lead to the sustained depletion of the muscle glycogen stores in humans if food is unavailable, thus limiting their capacity to engage in fight or flight behaviors unless mechanisms exist to protect muscle glycogen against sustained depletion. The objective of Study 1 was to test this prediction. Eight participants performed three intense exercise bouts each separated by a recovery period of 75 minutes. Although only 53% of muscle glycogen was replenished after the first exercise bout (postexercise and post-recovery glycogen levels of 246 ± 25 and 320 ± 36 mmol.kg-1 dry mass, respectively), all the glycogen mobilised during the second and third bouts was completely replenished during the respective recovery periods, with glycogen reaching levels of 319 ± 29 mmol.kg-1 dry mass after recovery from the third bout. These findings show that humans are not different from other vertebrate species in that there are conditions where humans have the ability to completely replenish without food intake the muscle glycogen mobilised during exercise. The results of our first study raise the intriguing possibility that humans have pre-set muscle glycogen levels that are protected against sustained depletion, with the extent to which muscle glycogen stores are replenished after exercise being dependent on the amount of glycogen required to attain those protected levels. ... During recovery, glycogen levels in the NORM group increased by more than ~50% and reached levels close to those alleged to be protected (189 ± 21 mmol.kg-1 dry mass), whereas no glycogen was deposited in the HCHO group. The sustained post-exercise activation of glycogen synthase, the transient fall in whole body carbohydrate oxidation rate, the increased mobilisation of body proteins, and the prolonged elevation in NEFA levels most probably played important roles in enabling glycogen synthesis in the NORM group. In conclusion, this thesis shows for the first time that there are some conditions (e.g. low pre-exercise muscle glycogen levels) where humans recovering from intense exercise have the capacity, like other species, to replenish completely their muscle glycogen stores from endogenous carbon sources. This study also suggests that humans protect preset levels of muscle glycogen against sustained depletion and at levels high enough to support at least one maximal sprint effort to exhaustion. Evidence is also provided for the existence of a feedback mechanism whereby glycogen below their protected levels mediate the activation of glycogen synthase to restore the depleted muscle glycogen stores back to their protected levels. Our findings, however, leave us with a number of novel unanswered questions which clearly show that the regulation of glycogen metabolism is far from the simple process generally depicted in most textbooks of biochemistry.

[Truncated abstract] Iron is a trace mineral used by the body in many physiological processes that are essential to athletic performance. Commonly, the body's iron stores are compromised by exercise via several well established mechanisms. One such mechanism is the destruction of red blood cells (hemolysis), in response to the mechanical stress and circulatory strain of exercise. Although it appears that a force-dependent relationship between the heel-strike of the running gait and ground contact exists, the effects of the intensity trained at and the ground surface type trained upon have not been documented. Similarly, the effects of a cumulative training stress (i.e. multiple daily sessions) has not been examined. In addition to hemolysis, exercise also invokes an inflammatory response that results in an up-regulation of the cytokine interleukin-6 (IL-6). This cytokine is the primary mediator of hepcidin expression, a liver-produced hormone that regulates iron metabolism in the gut and in macrophages. The influence of exercise on hepcidin expression is relatively unknown, and as such it is possible that this hormone may be a mitigating factor implicated in athletic-induced iron deficiency. Therefore, the purpose of this thesis was to investigate the effect of different training frequencies, intensities and ground surfaces on the hemolytic response. In addition, the impact of exercise-induced inflammation on hepcidin expression in the 24 h post-exercise was investigated, with the aim of determining whether this hormone may be a potential new mechanism associated with athletic-induced iron deficiency. Finally, an interaction between hemolysis and hepcidin activity was examined to investigate their potential combined effect on iron status in the 24 h post-exercise. ... Venous blood and urine samples were collected pre- and immediately post-exercise, and at 3 and 24 h of recovery. Samples were analysed for circulating levels of IL-6, free Hb, Hp, serum iron, ferritin and urinary hepcidin activity. At the conclusion of both the T1 and T2 interval runs, the free Hb and serum Hp were significantly increased (p<0.05) from pre-exercise levels. Furthermore, a cumulative effect of two running sessions was shown in the T2 trial, via a further significant fall in serum Hp. The IL-6 and hepcidin activity were significantly increased after each running session (p<0.05) with no cumulative effect seen. Serum iron and ferritin were significantly increased post-exercise after each interval run (p<0.05), but were not influenced by the addition of a prior LSD run 12 h earlier. As a result, this investigation showed a cumulative effect of consecutive training sessions on RBC destruction in male athletes. Furthermore, post-exercise increases to serum iron and hepcidin, and their interaction was suggested to have potential implications for an athlete's iron status. Overall, the findings of this thesis show that hemolysis is evident at the conclusion of endurance running, and is influenced by training intensity and frequency. The results enabled a time-line for hepcidin expression post-exercise to be established, and the implications of increases to the activity of this hormone, in association with the hemolytic changes seen with endurance exercise are discussed.

Master of Music / Throughout the 20th Century, female operatic singers in most of the major European opera houses were given “grace days” (where they were not required to sing) in recognition of the effect of hormonal changes on the singing voice. Financial constraints in professional companies have resulted in a reduction of such considerations, but to date, there has been no systematic study of the effects of hormonal fluctuations on the quality of the female singing voice, or of its potential adverse effects on the vocal apparatus for singers who are affected by pre-menstrual syndrome. This study investigated the effects of hormonal fluctuations on young professional female classical singers. Female and male professional singers in training (students) at the Sydney Conservatorium of Music, University of Sydney, were asked to participate as volunteers in the study by keeping daily diaries. The female singers kept a diary for two separate months beginning on the first day of menstruation, in which they recorded their daily basal temperature, mood, voice state and physical well being. The male control subjects kept daily diaries for one month. Acoustic analysis of two vocal samples taken during the second month, on days 1 and 14 of the cycle, were completed on the six most severely affected female subjects, who were identified through their diary ratings of changes in vocal quality during menstruation. The selected students assessed their own vocal samples, presented in random order, to determine whether they could reliably identify which of their samples were affected by menstruation. Vocal staff at the Conservatorium (pedagogues), who were blind to the purpose of the study, also assessed recordings presented randomly. Results indicated that self-perceived vocal quality varied over the course of the menstrual cycle, particularly during the first seven days of the cycle, that negative changes in mood affected the voice, and that fatigue, effort, hoarseness, weakness & peak performance were the most frequently affected vocal states. A surprising finding was that male self-perceived voice quality also varied over the course of one month of diary keeping. There was no consistent change in direction of scores during menstrual and non-menstrual phases. Five of the six most affected singers correctly identified their performance during menstruation but pedagogues were not consistently able to do so.. These results indicate that perceived quality of the voice through changes in the menstrual cycle may not be as obvious to a highly trained observer even though they were reliably perceived by the singer. This study demonstrates that menstruation has a discernible impact on the self-perception of female singers’ vocal quality and implies that the premenstrual or menstrual female may not feel able to present her peak performance at these times of hormonal fluctuation. Further detailed research in this area may be warranted on a larger scale to elaborate a more precise clinical management of the problem.

The purpose of the present study was to examine the time-course of mechanical power output and neuromuscular activity during fatiguing repeated-sprint exercise and recovery in man. Prior to the main study, we also investigated the reproducibility of power output during a single 6-s cycling sprint. For this study, eleven healthy moderately trained males performed a 6-s standing sprint on the front-access cycle ergometer on four separate occasions. The results of the study showed that reliable power outputs can be obtained after one familiarization session in subjects unfamiliar with maximal cycling sprint exercise. However, the inclusion of an extra familiarization session ensured more stable power outputs. Therefore, two trials should allow adequate familiarization with the maximal 6-s cycling test. For the main study, eight young moderately trained adult men performed an exercise protocol that consisted of ten, 6-s sprints on a wind-braked cycle ergometer interspersed with 30 s of recovery. After 6 min of passive recovery, five, 6-s sprints were repeated, again interspersed by 30 s of recovery. Peak power output (PPO) and mean power output (MPO) were measured during each sprint and EMG data (i.e., RMS) from the vastus lateralis muscle were also recorded. A one-way ANOVA with repeated measures (i.e., sprint number) was used to allocate the significant differences in each dependent variable over time. Analysis revealed a decline in power output during the fatiguing exercise that was accompanied by a decrease in EMG amplitude of the vastus lateralis muscle. Six minutes after the fatiguing exercise, power output during sprint 11 significantly recovered with respect to values recorded in sprint 10, but remained significantly lower than that recorded in the initial sprint. Thus, 6 min was insufficient to fully recover from the fatiguing repeated sprint protocol utilised in this study. The main findings in the present study were that: 1) the partial recovery of power output in sprint 11 was not accompanied by the recovery V of EMG amplitude; 2) similar mean power outputs were recorded during sprint 4 and 11 despite a significantly lower EMG activity recorded during the latter sprint; and 3) despite comparable mean power outputs during sprint 4 and 11, the decrease in power output over the next five sprints was greater for sprints 11 to 15 than for sprints 4 to 8.

[Truncated abstract] This thesis concerns itself primarily with the impact of exercise training on cardiac and vascular adaptations in humans. It contains longitudinal studies of individuals at either end of the physical activity spectrum; young elite athletes and obese children and adolescents. The study of these diverse groups was intentional, as a particular interest was to investigate the possible inter-relationships between morphological adaptations in the heart, evident in both obese and athletic populations, and the possible consequences of such adaptations for cardiac function. Whilst there exists a long tradition of echocardiographic assessment of cardiac dimensions and mass in both athletic and clinical populations, investigation of the impact of each of these “conditions” on cardiac diastolic function is novel, and has been facilitated by recent advances in the technical approach to diastolic function assessment in humans. Studies presented in the following chapters utilise advanced echocardiography imaging combined with pulse wave and tissue Doppler approaches to investigate the effects of exercise training regimen on wall thickness and ventricular mass, as well as diastolic function indices. State-of-the-art vascular imaging approaches have also been used in these populations to determine whether changes in vascular wall thickness, diameter or function occur with training in the elite athletes or obese youth.

[Truncated abstract] Shoulder injuries rank among the most prevalent and debilitating sustained by professional tennis players. The loads, or magnitude, location, direction, duration, frequency, variability and rate of force application, endured by tissues of the shoulder during stroke production, and more particularly the serve, are commonly implicated in shoulder joint injury (Chandler et al., 1992; McCann and Bigliani, 1994; Kibler, 1995). Indeed, past evidence points to these loads increasing along with serve velocity, as well as with varied segment use (Elliott et al., 2003). This dissertation therefore aimed to quantify hypothesised relationships between certain serve types and techniques, and shoulder joint loading among high performance able-bodied and wheelchair players. . . Of final note is that prospective 3D biomechanical examinations of shoulder joint motion in the tennis serve should consider placement of humeral triads distal to the biceps and/or triceps muscle belly. In comparison to markers placed at the mid-point of the humerus (i.e. as used in this thesis), these more distal triad positions appear to alleviate the spurious effects of soft tissue artefact thereby enhancing the accuracy of estimated long-axis rotation of the upper arm. Although the current representation of 3D humeral motion did not confound the comparisons made between serve types or techniques, it is likely that upper arm triads located just above the epicondyles of the humerus could have offered more insightful absolute comparisons to the literature. Further, the elaboration of a joint coordinate system at the shoulder to provide for the more meaningful and functional expression and interpretation of shoulder joint kinetic and kinematic data should also be central to all future, related investigative efforts.

[Truncated abstract] Obesity is rapidly increasing in prevalence and has significant physical and mental health implications. Stress, a general term referring to factors indicative of psychological strain such as depression and anxiety, has been identified as both a cause and consequence of weight gain and obesity in some individuals. In previous research, overeating in response to stress has been investigated as either a means of mood regulation or as a response to strict dietary restraint. Cortisol, a steroid hormone that increases in response to stress, has also been linked with increased food intake in both animal and human studies. Thus, cortisol may be an additional factor contributing to overeating and weight gain in response to stress. If stress does lead to overeating and weight gain, it is also likely that stress will inhibit attempts made by obese individuals at weight loss. The first study of this thesis was a repeated measures treatment study in which the associations of stress and cortisol levels with baseline body mass index and subsequent weight loss were investigated among females participating in a cognitive behavioural weight management programme. A cross-sectional analysis prior to treatment commencement showed that the association of stress and depression with body mass index was moderated by the severity of obesity. Dichotomous thinking, a cognitive style in which events are viewed in polarised 'black and white' terms, mediated the associations of both depression and eating disorder symptomatology with BMI. ... The second study of this thesis was a controlled laboratory-based examination of food intake following an acute psychological stressor. It was hypothesised that high baseline levels of psychological stress, such as depression and anxiety, would be associated with greater increases in negative mood and cortisol levels in response to the acute stressor, both of which, in turn, would be associated with greater food intake. Contrary to the hypothesis, baseline levels of psychological stress were not associated with the extent to which negative mood and cortisol levels increased following the acute stressor. The extent to which negative mood, but not cortisol, increased following acute stress was significantly positively associated with food intake. The results do not support the hypothesis that high cortisol levels are predictive of increased food intake in human females, although the results may have been affected by the broad participant inclusion criteria. The results suggest that increases in negative mood lead to increases in food intake, although it is argued that this is unlikely to be a general effect and suggestions for future research are made. The overall aim of this research was to examine whether stress and cortisol were associated with weight status, acute changes in eating behaviour and changes in weight in the medium-term. The results are discussed in relation to this aim, wth particular focus on the differences between treatment-seeking and community samples, implications for the treatment of obesity (especially when the individual is also experiencing high levels of depression), prevention of weight gain and possible future studies of the effects of stress and depression on weight change and eating behaviour.