The aim of this study was to determine motor unit firing patterns during ischemic versus non-ischemic sustained submaximal isometric contractions of the tibialis anterior muscle. 10 healthy adults attended two experimental sessions approximately 48 hours apart. Both sessions were identical except that the fatigue task in one was performed with a pressure cuff placed above the knee and inflated to 180 mm Hg. Three 5s maximum voluntary contractions (MVCs) were performed prior to and after the fatigue task. Each participant held a target force of 20% MVC until endurance time (peak-to-peak tremor amplitude exceeded 5% MVC). Single motor unit firing rates (11 non ischemic, 9 ischemic) were recorded with intramuscular fine wire electrodes. Mean interspike intervals over 5s time bins were calculated at every 5% endurance time. The endurance time for the ischemic (3.7 ± 0.58 min) fatigue task was significantly (p<0.001) shorter than the non-ischemic (9.5 ± 0.57 min) task. There was no significant difference in mean motor unit firing rates between the two conditions (p=0.883). Within both tests, there was a significant decline in firing rate (ischemic initial: 12.95 ± 0.71 Hz, minimum: 11.41 ± 0.81 Hz, p=0.023; non-ischemic initial: 13.13 ± 0.87 Hz, minimum: 11.15 ± 0.48 Hz, p=0.012). The time to minimum firing rate was significantly (p<0.001) less in the ischemic (1.29 ± 0.2 min) compared to non-ischemic (3.14 ± 0.23 min) condition. Muscle ischemia significantly reduced endurance time and the time to minimum firing rate. However, there were no differences in average motor unit firing rates between the two conditions across the relative phases of endurance time. / text

No description available.

Brainstem derived serotonin (5-HT) normally facilitates spinal motoneuron excitability and inhibits sensory afferent transmission and associated spinal reflexes. Because the 5-HT innervation of the spinal cord is almost exclusively derived from brainstem neurons, spinal cord injury leads to an immediate and dramatic loss of 5-HT and this in turn leads to the simultaneous loss of motoneuron excitability and increase (disinhibition) of sensory afferent transmission. This thesis examined how spinal cord 5-HT receptors adapt over the months after SCI (chronic injury) to compensate for the loss of 5-HT. We showed that after SCI 5-HT2B and 5-HT2C receptors become constitutively active (active in the absence of 5-HT) with chronic injury, and this leads to a recovery of motoneuron excitability and contributes to the recovery of locomotor function. Unfortunately, this also contributes to the development of muscle spasms when combined with the disinhibition of sensory afferent transmission. In contrast, 5-HT1 receptors that modulate sensory afferent transmission do not become constitutively active after chronic SCI, and this contributes to the continued disinhibition of sensory afferent transmission and associated hyperreflexia and muscle spasms after chronic SCI. However, exogenous application of 5-HT1B and 5-HT1F receptor agonists can restore inhibition over sensory afferent transmission and ultimately reduce muscle spasms. In summary, 5-HT2 receptors exhibit a remarkable adaptation to the loss of 5-HT with SCI, whereas 5-HT1 receptors do not. Understanding and promoting this natural plasticity may help in the development of better therapeutic interventions for treating SCI.

In this thesis, the relationships among oesophageal motility, bolus clearance and sensory perception of oesophageal stimuli in patients with several dysphagia syndromes were investigated. The work is divided into the following major sections: 1) Current advances in the application of impedance and its utility in distinguishing clearance characteristics between primary and secondary peristalsis; 2) The advances in our understanding of peristaltic motor characteristics, oesophageal bolus clearance and symptom perception in dysphagia syndromes; 3) Peristaltic dysfunction, impaired bolus clearance and symptom perception in gastro-oesophageal reflux disease (GORD) and in patients with globus; 4) TRPV1 expression in oesophageal mucosa in patients with GORD. The main findings from this work are: 1) Secondary peristalsis is less effective as primary peristalsis regarding esophageal transit and clearance of a liquid bolus. 2) In patients with non-obstructive dysphagia (NOD), bolus clearance by both morphologically normal and aberrant secondary peristaltic sequences is impaired. 3) Although, when compared with healthy controls, patients with NOD have a higher prevalence of non-specifically abnormal motor patterns, there is a poor correlation between dysphagia and oesophageal dysmotility. 4) Whereas manometry identified motility abnormalities in one quarter of patients with GORD, impedance demonstrated that the majority of these patients, as well as some patients with normal manometry, had defective bolus clearance. 5) Although patients with erosive GORD have delayed oesophageal bolus clearance, manometric characteristics in these patients are comparable to those seen in non-erosive reflux disease (NERD). These findings are compatible with the hypothesis that abnormal oesophageal bolus clearance may reflect a continuum of dysfunction secondary to increasing oesophageal mucosal damage. 6) Patients with globus are characterized by oesophageal visceral hypersensitivity and aberrant viscerosomatic referral of mechanical and electrical stimuli to the oesophagus. These findings support the hypothesis that oesophageal hypersensitivity with associated viscerosomatic referral patterns are an important pathogenetic mechanism for globus. 7) Patients with erosive GORD exhibit greater gene expression of TRPV1 in oesophageal mucosa when compared with NERD or healthy controls. These findings support the hypothesis that chronic inflammation may lead to the release of mediators which may modulate function of primary sensory neurons.

The mucosa of the small intestine is clearly able to discriminate specific chemical components of ingested meals to stimulate gastrointestinal feedback pathways and reduce further food intake. Luminal carbohydrates delay gastric emptying and initiate satiation, which are mediated by reflexes via the vagus nerve upon activation of vagal afferent endings in the mucosa. Nutrients activate these nerve fibres through intermediary epithelial cells, which release neuromediators upon transduction of luminal signals through the apical membrane. 5-hydroxytryptamine (5-HT) and glucagon-like peptide-1 (GLP-1) are released from enteroendocrine cells in response to luminal carbohydrates and both slow gastric emptying and inhibit food intake via vagal afferent pathways. The molecular mechanisms for carbohydrate detection and transduction leading to 5-HT and GLP-1 release are unknown. However molecules key to transduction of taste by receptor cells in the lingual epithelium are expressed in the gastrointestinal mucosa. The studies in this thesis aimed to investigate 1) the possibility that taste molecules expressed in the intestine form part of the carbohydrate sensing pathway that leads to 5-HT and GLP-1 release, which in turn activate mucosal vagal afferents and 2) to gauge any alterations in taste molecule expression that may relate to adaptation of carbohydrate-induced gastric motility reflexes that occurs in dietary and disease states. Firstly these studies show key taste molecules, including sweet taste receptors T1R2 and T1R3, the Gprotein gustducin (alpha-subunit Gαgust), and the taste transduction channel TRPM5, are expressed in the mouse gastrointestinal mucosa shown by RT-PCR and were further localised to individual epithelial ‘taste’ cells using immunohistochemistry. Quantification of transcript levels by real time RT-PCR revealed the proximal small intestine as the preferential site of sweet taste receptor expression along the gastrointestinal tract. This finding was also confirmed in humans using gastric and intestinal mucosal biopsies obtained at enteroscopy with significantly higher transcript expression levels in the small intestine compared to stomach. In the mouse, double label immunohistochemistry with Gα[subscript]gust antibody, as a marker of intestinal taste cells, was performed using lectin UEA-1, a marker of intestinal brush cells, and 5-HT or GLP-1 to link intestinal taste transduction to 5-HT and GLP-1 release. Results show Gα[subscript]gust is expressed within a subset of all three cell types in the small intestine but predominantly within UEA-1-expressing cells. Although Gα[subscript]gust, 5-HT and GLP-1 are largely expressed in mutually exclusive cells, within the jejunum a portion Gαgust positive cells coexpressed 5-HT or GLP-1. This Indicates a subpopulation of intestinal taste cells may be dedicated to carbohydrate-evoked gastrointestinal reflexes through 5-HT and GLP-1 mediated pathways, however, taste transduction within the small intestine appears to predominantly link to alternate mediators. After nutrient detection at the luminal surface, activation of mucosal afferents by 5-HT released from enterochromaffin cells is well documented, however although vagal afferents express GLP-1 receptors direct activation has not been demonstrated. For this purpose the effects of GLP-1 on gastrointestinal vagal afferents were investigated through single fibre recordings in in vitro tissue preparations. GLP-1 had no effect on the activity of mouse gastroesophageal vagal afferents but a rat duodenal preparation proved too problematic to be able to test GLP-1 specifically on duodenal vagal afferents. Altered gastric motility in response to carbohydrate meals due to prior dietary patterns and diabetes mellitus suggest adaptation in feedback mechanisms. Towards the second aim of this thesis taste molecule expression was quantified in fed and fasted mice by real time RT-PCR and revealed taste gene transcription is altered with the changing luminal environment, specifically transcription of taste genes was significantly decreased after feeding compared to the fasted state. Studies comparing expression in the duodenum of type 2 diabetics and non-diabetic controls show no significant difference in taste transcript levels between the two groups. However taste molecule expression was correlated to blood glucose levels in diabetics suggesting transcription of these signal molecules is adapted to both luminal and systemic carbohydrate levels. Findings in both the mouse and human gastrointestinal tract in terms of intestinal chemosensing are discussed. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1363582 / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Sciences, 2009

The mucosa of the small intestine is clearly able to discriminate specific chemical components of ingested meals to stimulate gastrointestinal feedback pathways and reduce further food intake. Luminal carbohydrates delay gastric emptying and initiate satiation, which are mediated by reflexes via the vagus nerve upon activation of vagal afferent endings in the mucosa. Nutrients activate these nerve fibres through intermediary epithelial cells, which release neuromediators upon transduction of luminal signals through the apical membrane. 5-hydroxytryptamine (5-HT) and glucagon-like peptide-1 (GLP-1) are released from enteroendocrine cells in response to luminal carbohydrates and both slow gastric emptying and inhibit food intake via vagal afferent pathways. The molecular mechanisms for carbohydrate detection and transduction leading to 5-HT and GLP-1 release are unknown. However molecules key to transduction of taste by receptor cells in the lingual epithelium are expressed in the gastrointestinal mucosa. The studies in this thesis aimed to investigate 1) the possibility that taste molecules expressed in the intestine form part of the carbohydrate sensing pathway that leads to 5-HT and GLP-1 release, which in turn activate mucosal vagal afferents and 2) to gauge any alterations in taste molecule expression that may relate to adaptation of carbohydrate-induced gastric motility reflexes that occurs in dietary and disease states. Firstly these studies show key taste molecules, including sweet taste receptors T1R2 and T1R3, the Gprotein gustducin (alpha-subunit Gαgust), and the taste transduction channel TRPM5, are expressed in the mouse gastrointestinal mucosa shown by RT-PCR and were further localised to individual epithelial ‘taste’ cells using immunohistochemistry. Quantification of transcript levels by real time RT-PCR revealed the proximal small intestine as the preferential site of sweet taste receptor expression along the gastrointestinal tract. This finding was also confirmed in humans using gastric and intestinal mucosal biopsies obtained at enteroscopy with significantly higher transcript expression levels in the small intestine compared to stomach. In the mouse, double label immunohistochemistry with Gα[subscript]gust antibody, as a marker of intestinal taste cells, was performed using lectin UEA-1, a marker of intestinal brush cells, and 5-HT or GLP-1 to link intestinal taste transduction to 5-HT and GLP-1 release. Results show Gα[subscript]gust is expressed within a subset of all three cell types in the small intestine but predominantly within UEA-1-expressing cells. Although Gα[subscript]gust, 5-HT and GLP-1 are largely expressed in mutually exclusive cells, within the jejunum a portion Gαgust positive cells coexpressed 5-HT or GLP-1. This Indicates a subpopulation of intestinal taste cells may be dedicated to carbohydrate-evoked gastrointestinal reflexes through 5-HT and GLP-1 mediated pathways, however, taste transduction within the small intestine appears to predominantly link to alternate mediators. After nutrient detection at the luminal surface, activation of mucosal afferents by 5-HT released from enterochromaffin cells is well documented, however although vagal afferents express GLP-1 receptors direct activation has not been demonstrated. For this purpose the effects of GLP-1 on gastrointestinal vagal afferents were investigated through single fibre recordings in in vitro tissue preparations. GLP-1 had no effect on the activity of mouse gastroesophageal vagal afferents but a rat duodenal preparation proved too problematic to be able to test GLP-1 specifically on duodenal vagal afferents. Altered gastric motility in response to carbohydrate meals due to prior dietary patterns and diabetes mellitus suggest adaptation in feedback mechanisms. Towards the second aim of this thesis taste molecule expression was quantified in fed and fasted mice by real time RT-PCR and revealed taste gene transcription is altered with the changing luminal environment, specifically transcription of taste genes was significantly decreased after feeding compared to the fasted state. Studies comparing expression in the duodenum of type 2 diabetics and non-diabetic controls show no significant difference in taste transcript levels between the two groups. However taste molecule expression was correlated to blood glucose levels in diabetics suggesting transcription of these signal molecules is adapted to both luminal and systemic carbohydrate levels. Findings in both the mouse and human gastrointestinal tract in terms of intestinal chemosensing are discussed. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1363582 / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Sciences, 2009

[Truncated abstract] One of the problems in researching tinnitus is that it has often been assumed that the physiological mechanisms underlying the tinnitus percept cannot be objectively measured. Nonetheless, it is generally accepted that the percept results from altered spontaneous neural activity at some site along the auditory pathway, although it is still debated whether it is produced by: synchronisation of activity of adjacent neurones; a change in the temporal pattern of activity of individual neurones; or an increase in the spontaneous firing rate per se. Similarly, it is possible that the recently coined “auditory neuropathy” is produced by under-firing of the primary afferent synapse, although several other mechanisms can also produce the symptoms described by this disorder (normal cochlear mechanical function but absent, or abnormal, synchronous neural firing arising from the cochlea and auditory brainstem, known as the auditory brainstem response, or ABR). Despite an absent ABR, some subjects can detect pure tones at near-normal levels, although their ability to integrate complex sounds, such as speech, is severely degraded in comparison with the pure-tone audiogram. The aim of the following study was to investigate the normal mechanisms underlying neural firing at the primary afferent synapse, and its regulation, to determine the possible mechanisms underlying over-firing (tinnitus) or under-firing (auditory neuropathy) of primary afferent neurones.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.