Empirical evidence suggests that complex cognitive processes such as decision-making can be influenced by incidental affect (i.e. emotional states unrelated to the decision), which may have importance implications for furthering our understanding and treatment of mood disorders. Following up on previous behavioral findings suggesting that sad mood leads to biases in social decision-making, the present research first investigated how such biases are implemented in the brain. Nineteen adult participants made decisions that involved accepting or rejecting monetary offers from others in an Ultimatum Game (a well known economic task), while undergoing functional magnetic resonance imaging (fMRI). Prior to each set of decisions, participants watched a short video clip aimed at inducing either sadness or a neutral emotional state. Results indicated that sad participants rejected more "unfair" offers than those in the neutral condition, thereby replicating our previous findings. Neuroimaging analyses revealed that receiving unfair offers while in a sad mood elicited activity in brain areas related to aversive emotional states and somatosensory integration (anterior insula) and to cognitive conflict (anterior cingulate cortex). Sad participants also showed a diminished sensitivity in neural regions associated with reward processing (ventral striatum). Importantly, insular activation uniquely mediated the relationship between sadness and decision bias, demonstrating how subtle mood states can be integrated at the neural level to bias decision-making.In a second study, we assessed to what extent such affect infusion in decision-making may translate to clinical depression, a mood disorder involving chronic sad affect. Fifteen depressed and twenty-three nondepressed individuals made decisions to accept or reject monetary offers from other players in the Ultimatum Game. Like transiently sad, but healthy, individuals, depressed participants reported a more negative emotional reaction to unfair offers. However, unlike sad healthy individuals, they accepted significantly more of these offers than did controls. A positive relationship was observed in the depressed group, but not in controls, between acceptance rates of unfair offers and resting cardiac vagal tone, a physiological index of emotion regulation capacity. These findings suggest distinct biasing processes in depression, which may be related to higher reliance on regulating negative emotion.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Heart failure is a prevalent health concern within the western world. It has huge economic, financial and personal implications. Despite the development of several clinically available treatments, heart failure associated mortality remains high. Heart failure patients display with dysfunction of the autonomic nervous system, including a high degree of vagal withdrawal. Consequently, the up-regulation of cardiac vagal tone, using vagal nerve stimulation (VNS) has recently gained attention as a potential new therapeutic approach to the treatment of heart failure. Clinical trials of VNS have produced mixed outcomes and very little is known about the mechanisms mediating the cardioprotective effects of VNS. This study has therefore implemented VNS in an ovine tachypaced model of heart failure, with the primary aim of quantifying its therapeutic effect in this model. Secondly, two potential underlying mechanisms of VNS have been investigated: 1) the effects of VNS on cellular calcium handling and 2) the effects of VNS on myocardial S-nitrosylation (S•NO).VNS treatment in this model of heart failure had a modest therapeutic effect. However, no differences in echocardiographic parameters, including those used as outcome measures in ongoing clinical trials, were observed between treated and untreated animals. Similarly, no differences in calcium handling parameters were observed between ventricular myocytes isolated from treated and untreated animals. Finally, VNS caused an increase in S•NO of several identified myocardial proteins when compared to untreated heart failure controls. However, this was a relatively small change compared to that observed between control and heart failure tissues. This data, as with studies before, highlights the need for a greater understanding of autonomic regulation and VNS in the heart failure setting, so that treatment strategies can be more effectively optimised. Given the limited therapeutic effect observed in this study, these potential mechanisms cannot be excluded as contributing to the cardioprotective effects of VNS observed in other studies.

African Americans are at a greater risk of developing cardiovascular disease and associated risk factors than are Whites, and recent research has suggested that the effects of racial discrimination are a significant contributor to this disparity. Thus, a preattentive bias and vigilance for threat might serve as a mechanism through which experienced racial discrimination would negatively impact cardiovascular health. A study was conducted to investigate the physiological and attentional underpinnings of vigilance for discriminatory threat via examination of phasic heart period (HP) responses to cued threat and nonthreat stimuli. Thirty African American and forty-two European American undergraduate students from a large urban university participated in the study. Phasic HP reactions of participants were recorded during an S1-S2 procedure where cued stereotype-related threatening, nonstereotype-related threatening, and nonthreatening stimuli were presented. It was hypothesized that Blacks, more than Whites, would show: smaller magnitude and impaired habituation of cardiac orienting to neutral words; acceleration of heart rate in response to threat words; and a conditioned anticipatory heart rate deceleration to threat words over repeated trials. However, results did not support hypotheses; neither Whites nor Blacks exhibited significant changes in phasic heart period in response to cued stimuli.

Theory and research suggests a link between self-esteem and cardiac vagal tone (parasympathetic nervous system influence on the heart). A literature review suggests that vagal tone protects the body against physiological threat responding (e.g., sympathetic responding) and that vagal tone is highest when we feel secure. Terror management theory posits that humans, who live in a largely symbolic world, derive feelings of security and protection from threat by way of acquiring and maintaining self-esteem. Thus we hypothesized that if vagal tone provides physiological security, and we derive a sense of security through symbolic means by way of self-esteem, then high or increased self-esteem should lead to high or increased vagal tone. To test this hypothesis we conducted two studies in which we manipulated self-esteem by giving participants positive or negative feedback. We predicted that positive feedback would lead to higher vagal tone than negative feedback. Consistent with these predictions, in both studies we found indications that positive feedback increased vagal tone relative to negative feedback. In Study 2, to more fully test our theoretical perspective we induced threat by leading participants to believe they would receive electric shocks. We predicted that both self-esteem and vagal tone would buffer against sympathetic threat responding. Consistent with our model we found that the positive feedback eliminated the sympathetic response to threat of shock that was elicited in the negative feedback condition. Also consistent with our model, higher vagal tone predicted lower sympathetic responding to threat of shock. We discuss future directions for this research and implications for physical health.

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

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterised by impaired socialisation. The current project examines the hypothesis that ASD represents a broad range of distinct disease processes typified by environmental insult(s) during a period crucial for the development of any of the systems responsible for social integration skills, sharing simply the fundamental disruption to social functioning with various, definable systemic pathologies related to the initial insult conferring the heterogeneity of the condition. ASD will therefore have both modifiable environmental factors relating to the aetio-pathogenesis of the condition and likely, remediable disease processes. Following an examination of the relevant literature this project presents the Variable Insult Model of Autism. As part of a wider research strategy, this project goes on to explore potential modifiable environmental factors in patients with ASD.Zinc deficiency was explored as a potential environmental modifiable factor involved in the pathophysiology of autism and co-morbid disease. 72 patients with ASD were compared with 234 non-ASD controls. Mean serum zinc levels in the ASD group vs. the control group were 10.01 umol/l (SD 1.52 umol/l) vs. 11.61 umol/l (SD 2.14 umol/l, with a statistically significant difference - p < 0.0001, CI 1.2 – 2.1). The findings withstood correction for age and sex, and zinc did not correlate with diet or supplement use in the ASD group. Total lymphocyte count increased as zinc increased in the ASD group with zinc levels of 10.5 umol/l or above, suggesting zinc status is poor in patients with autism and this is affecting immune function. Urinary metabolomics, quantitative PCR stool analysis and autonomic function were also explored in ASD, as biomarkers of systemic disease processes presenting potential modifiable factors. The urinary organic acids of 49 patients were analysed versus population norms. 90% of patients with ASD had at least one abnormality. A follow-up study of 122 patients revealed succinic acid and 2-hydroxyhippuric acid were significantly raised in the ASD group versus population means (p = < 0.0001 and < 0.0001 respectively). Quantitative PCR analysis was conducted on 29 patients with autism versus 7 age-matched controls. Firmicutes to Bacteriodetes ratio was significantly elevated in the autism group versus the controls 69:41 (SD 8) vs. 54:46 (SD 8) (p < 0.003). A follow-up study of 143 patients and 12 controls showed consistent abnormalities in the composition of firmicutes and bacteriodetes (p = 0.005) and this withstood correction for age and sex (p = 0.009), suggesting an on-going abnormality in gut flora composition in the ASD-cohort. Autonomic profiles were available in 45 patients with ASD. There was marked variability in vagal tone, however in 11 patients with ASD who had both autonomic profile and qPCR stool analysis there was suggestion of a positive correlation between vagal tone and microflora composition (represented by firmicutes to bacteriodetes ratio) (p < 0.003).In summary, evidence suggests there are modifiable environmental factors associated with the aetiology, pathophysiology and disease evolution in ASD, and this is worthy of further consideration and investigation. From the preliminary results presented here, zinc status is poor in ASD and may be affecting immune function; gut flora abnormalities appear common and may be affecting neurological function in ASD.

Abstract Analysis of beat-to-beat heart rate variability (HRV) provides information of cardiac vagal outflow to the sinus node. Some methodological problems might, however, be involved in the analysis of cardiac vagal outflow from ambulatory Holter recordings, such as saturation, physical activity, and abrubt prolongations of R-R intervals unrelated to respiration. The purpose of this thesis was to assess the physiological basis of beat-to-beat HRV and to develop and assess new methods for the quantification of cardiac autonomic modulation from ambulatory Holter recordings. The study population consisted of 89 healthy volunteers (age 24 ± 4 years) and 590 patients with a recent acute myocardial infarction (AMI, age 61 ± 10 years). The relationship between R-R interval length and the high-frequency (HF) spectral power of the R-R intervals was assessed in 76 healthy subjects and 82 post-AMI patients. The effects of aerobic exercise training on the dynamics between R-R interval and HF power were evaluated by means of a controlled 8-week training intervention (n = 17). The effects of sympathetic activation and concomitant sympathetic and vagal outflow on beat-to-beat HR dynamics were studied in laboratory conditions (n = 13). A new method for quantifying beat-to-beat HRV from the R-R interval lengths where the relationship between HF power and R-R interval is most linear was developed to avoid the confounding effects of possible saturation, physical activity, and random R-R interval dynamics. The clinical significance of the new method was assessed in a series of 590 post-AMI patients. Saturated HF R-R interval dynamics, expressed as a lack of increase in HF power despite an increased R-R interval, was observed in 35 healthy subjects and 9 post-AMI patients. In the training study, 7 subjects out of a total of 17 had saturated HF power before the intervention. After the training period, 5 new cases of saturated HF power were observed. In laboratory conditions, co-activation of sympathetic and vagal outflow resulted in random R-R interval dynamics. In post-AMI patients, HF power analyzed exclusively from the R-R intervals where the relationship between the R-R interval and HF power was most linear (Vindex) predicted independently the occurrence of SCD among post-AMI patients, while traditionally analyzed HF power did not. In conclusion, the saturation of beat-to-beat HRV in ambulatory conditions is a common phenomenon. The prevalence of saturated HF power increases due to enhanced cardiac vagal outflow induced by aerobic training. Finally, the novel analysis of vagally mediated HRV (Vindex) provides unique information that cannot be obtained by traditional analysis of HF R-R interval dynamics.

The acetylcholinesterase (AChE) content of rat vagal efferent neurons was studied. Retrograde transport of horseradish peroxidase (HRP) by cut vagal axons provided a means for localizing efferent cell bodies; tissue sections were then processed for the simultaneous visualization of HRP and AChE. A dorsal vagal efferent column contained the dorsal motor nucleus of the vagus, as a primary component, and extended caudally into the upper cervical spinal cord. A ventral column contained neurons in the nucleus ambiguus and the surrounding reticular formation. Although most of the vagal efferent neurons stained with moderate to heave intensity for AChE there were some HRP-labeled cells that contained little AChE and a small percentage in which AChE was absent. In spite of the fact that AChE has been demonstrated in certain non-cholinergic neurons, it has also been found in all cholinergic neurons. Therefore, the presence of AChE has been regarded as a necessary (but not sufficient) component for identifying cholinergic neurons. The absence of AChE in a small percentage of the vagal efferent neurons indicates that some preganglionic parasympathetic fibers in the vagus nerve are not cholinergic.