Thesis (Ph. D.)--University of Hong Kong, 2001. / Includes bibliographical references.

The central fatigue hypothesis suggests that during prolonged exercise, the increased plasma free-tryptophan (f-Trp) concentration may lead to an increased rate of synthesis of brain serotonin (5-HT). This may impair central nervous system function and cause increased perceptions of fatigue and deteriorate exercise performance. Two-fold increases in plasma concentrations of f-Trp have resulted in a 20% and 53% increase in brain Trp and forebrain Trp respectively. In addition, it has been suggested that 5-HT is involved in the stimulation of PRL release. The aim of the present thesis was to examine the relationship between the main peripheral markers of central fatigue, namely venous concentrations of f-Trp and prolactin (PRL), under three different experimental conditions. It was hypothesised that the changes in venous concentrations of f-Trp and PRL would exhibit similar patterns. Plasma f-Trp concentration increased by 110% after 2 h of cycling in normobaric hypoxia at a workload corresponding to 55% of FO2max determined in normobaric normoxia (P < 0.05). Serum PRL concentration did not differ between trials but the mean concentration increased at 30 min post exercise (P < 0.05). Following highintensity exercise for 30 s, plasma f-Trp concentration decreased by 23.5% (P < 0.05), whereas serum PRL concentration did not change (P > 0.05). Oral administration of L-Trp was followed by an increased plasma f-Trp concentration of 920%, however, plasma PRL concentrations decreased by 32.6% at the same time-point (P < 0.05). Analysis of functional magnetic resonance imaging of the brain demonstrated a different pattern of brain activation while subjects performed the interference task of the counting Stroop test following L-Trp ingestion. From these results it can be proposed that central fatigue is likely not to play any part during high-intensity exercise lasting 30s. However, the 110% and 920% increase in plasma f-Trp concentration during prolonged exercise in normobaric hypoxia and following oral administration of L-Trp respectively may have led to an increased rate of brain 5-HT synthesis, although venous concentrations of PRL were not in support of this increase. There may be many reasons for the lack of relationship between the two peripheral markers of central fatigue, including an effect of the catecholamines on inhibiting PRL secretion. During oral ingestion of L-Trp, the increased plasma f-Trp concentration may also have caused the increased brain activation in the areas known to house 5-HT neurones, and for the unique pattern of brain activation when performing a cognitive task. It remains to be established whether the increased f-Trp concentration, and unique brain activation pattern is evidence of fatigue originating within the brain.

published_or_final_version / Zoology / Doctoral / Doctor of Philosophy

Thesis (Ph. D.)--University of Texas at Austin, 2000. / Vita. Includes bibliographical references (leaves 204-231). Available also in a digital version from Dissertation Abstracts.

Thesis (Ph. D.)--Ohio State University, 2007. / Title from first page of PDF file. Includes bibliographical references (p. 111-134).

Thesis (M.S.)--Virginia Polytechnic Institute and State University, 1993. / Vita. Abstract. Includes bibliographical references (leaves 72-85). Also available via the Internet.

Walking is an essential behavior across the animal kingdom. To navigate complex environments, animals must have highly robust, yet flexible locomotor behaviors. One crucial aspect of this process is the selection of an appropriate walking speed. Speed shifts entail not only the scaling of behavioral parameters (such as faster steps) but also changes in coordination to produce different gaits, and the details of how this switch occurs are currently unknown. Modulatory substances, particularly small biogenic amine neurotransmitters, can alter the output and even the connectivity of motor circuits. This work addresses the hypothesis that one such neuromodulator – serotonin (5HT) – is a key regulator of walking speed at the level of motor circuitry. To explore this question, I use the model organism Drosophila melanogaster which, like vertebrates, displays complex coordinated locomotion at a wide range of speeds. In Chapter 2, I will describe our efforts to characterize the anatomy of the serotonergic cell populations that provide direct input to motor circuitry. I find that innervation of the neuropil of the ventral nerve cord - a structure roughly analagous to the mammalian spinal cord - is provided primarily by local modulatory interneurons. Using stochastic single cell labeling techniques, I will detail the specific anatomy of individual neuromodulatory cells, and also the distribution of synapses across their processes. In Chapter 3, I will show that optogenetic activation or tonic inhibition of VNC serotonergic neurons produces opposing shifts in walking speed. To analyze behavior, I will use two complementary approaches. On the one hand, I will use an arena assay to holistically assess walking velocity and frequency. On the other, I will use a behavioral assay developed in the lab - the Flywalker - to assess walking kinematics at high resolution. The combination of these technique will give us a broad and specific picture of how the VNC serotonergic system modulates walking. In Chapter 4, I will identify natural behavioral contexts under which serotonin is used to shift walking behavior. I will use a variety of paradigms that induce animals to shift their speed, from changes in orientation and nutrition state, to pulses of light, odor, and a vibration. I will assess the requirement for the VNC serotonergic system under all of these conditions, to build a clearer picture of its role in modulating behavioral adaptation. In Chapter 5, I will describe our efforts, in collaboration with Pavan Ramdya's lab at EPFL, to functionally image VNC serotonergic cells while the animal is walking, to understand how activity is endogenously regulated in this population. Finally, in Chapter 6 I will characterize the circuit elements which might be responsible for serotonin's effect on walking. I will use recently developed mutant lines to identify the particular serotonergic receptors responsible for enacting shifts in walking behavior. Using genetic labeling tools, I will identify potential targets of serotonergic signaling in the VNC, and formulate a model by which action on these targets could adjust locomotor output. Altogether, this work seeks to characterize the anatomy and behavioral role of the VNC serotonergic system in Drosophila. I hope that through this work, I will gain a deeper understanding of not only this particular modulatory system in this particular behavioral context, but also of how static circuits are conferred with essential flexibility in behaving animals.

Cigarette smoking is a major risk factor in the development of age-related chronic obstructive pulmonary disease (COPD) with chronic airway inflammation as a key feature. Currently, no effective treatment can reduce the protracted inflammation in the lung of COPD. Further research on the inflammatory mechanisms would therefore be important in determining new potential therapeutic targets in COPD. Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that plays an important role in pulmonary functions and inflammatory responses. The serotoninergic system including serotonin transporter (SERT), serotonin receptors (5-HTR) and its metabolic enzyme monoamine oxidase (MAO) have been reported to associate with cigarette smoking and/or COPD. Blockade of serotonin receptor 2A (5-HTR2A) with its selective antagonist ketanserin has been shown to improve lung function in COPD patients. In this study, we hypothesize that the serotoninergic system is involved in cigarette smoke-induced oxidative stress, inflammation and COPD. Exposure to cigarette smoke medium (CSM) caused the elevation of interleukin (IL)-8 levels in primary normal human bronchial epithelial (NHBE) cells and a human bronchial epithelial cell line (BEAS-2B) in vitro via activation of p38 and extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling pathway. Besides, CSM was found to disrupt the glutathione (GSH) system, resulting in the translocation of nuclear factor-erythroid 2 related factor 2 (Nrf2) to the nucleus. Knock-down of Nrf2 by small interference RNA (siRNA) blocked CSM-induced IL-8 release. Pretreatment with ketanserin was found to attenuate CSM-induced IL-8 release by inhibiting the p38, ERK1/2, and Nrf2 signaling pathways, and by partially restoring the GSH system. On the other hand, CSM reduced MAO activity in BEAS-2B, indicating a reduced catabolism of 5-HT. Furthermore, 5-HT was found to share the common p38 and ERK1/2 signaling pathway with CSM in IL-8 release. In the cigarette smoke-exposed rat model, the GSH system in the lung was found to be disrupted compared to the sham-air control, supporting our in vitro findings. Interestingly, we found an increased MAO-A activity in the lung of cigarette smoke-exposed rats in comparison to sham air-exposed rats. The increased MAO-A activity in the lung was associated with the reduction of 5-HT levels in bronchoalveolar lavage (BAL) and lung homogenates, while the increased metabolism of 5-HT may be involved in cigarette smoke-induced superoxide anion levels. On the other hand, serum, but not plasma level of 5-HT was elevated in cigarette smoke-exposed group, which may be due to platelet activation caused by cigarette smoke. In the clinical study, the elevated plasma 5-HT levels were found to be associated with an increased odds ratio for COPD and positively correlated with age in COPD patients. Furthermore, plasma 5-HT was also demonstrated to be a significant mediator on the relation between cigarette smoking and COPD. In summary, our study supports the hypothesis that the serotoninergic system contributes to cigarette smoke-induced oxidative stress, inflammation and COPD. The serotoninergic system (e.g. 5-HTR2A) may constitute potential therapeutic targets for the treatment of COPD, which is worthy for further investigation. / published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

Both chronic psychosocial stress and chronic administration of corticosterone have been shown to alter serotonergic type 2A (5-HT2A) receptor activity. A non-invasive behavioural index of 5-HT2A receptor activity is the frequency of "wet dog shakes" (WDS) or serotonergic stereotypy. In addition to WDS, 5-HT2A receptors mediate effects on sexual behaviour in the rat, in particular, inhibition in the male and stimulation in the female. In the present series of experiments, the potential involvement of stress and corticosterone in the regulation of WDS and sexual behaviour in the male and female rat was investigated. In Experiments 1-4, chronic exposure to several different forms of psychosocial stress was found to facilitate female and inhibit male rat sexual behaviour while concurrently increasing the display of WDS in both sexes. In Experiment 5, nefazodone, an antidepressant with 5-HT2A antagonistic properties, blocked the effects of stress on WDS but not sexual behaviour in female rats. In Experiments 6-7, the corticosterone synthesis inhibitor, metyrapone, blocked the effects of stress on sexual proceptivity and WDS in female rats. Metyrapone blocked the effects of stress on WDS but not sexual behaviour in male rats. In Experiments 8-9, high doses of corticosterone administered chronically facilitated female and inhibited male rat sexual behaviour while concurrently increasing WDS in both sexes. In Experiments 10-11, the 5-HT2A antagonist ketanserin was found to completely attenuate the effects of corticosterone on sexual behaviour and WDS in both male and female rats. In Experiments 12-13, the acute administration of corticosterone was found to exert no effect on either sexual behaviour or WDS in male or female rats. The present results indicate that both chronic corticosterone treatment and exposure to chronic stress inhibit male and facilitate female sexual behaviour while concurrently increasing WDS behaviour. The stress-induced facilitation of WDS appears to be related to elevated corticosterone levels and is suggestive of increased 5-HT2A activity. Both corticosterone and stress exerted effects on sexual behaviour in the direction that would be predicted by increased 5-HT2A activity. While the effects of corticosterone on sexual behaviour appear to be mediated by 5-HT2A activity, the effects of stress on sexual behaviour do not appear to be related to either elevations in corticosterone levels or alterations in 5-HT2A activity.

Thesis (doctoral)--Lund University, 1998. / Added t.p. with thesis statement inserted.