Thesis (Ph.D.). / Written for the Dept. of Psychology. Title from title page of PDF (viewed 2008/03/12). Includes bibliographical references.

Thesis (M.S.)--West Virginia University, 2008. / Title from document title page. Document formatted into pages; contains vi, 94 p. Includes abstract. Includes bibliographical references.

The sympathetic nervous system plays an important role in maintaining cardiovascular regulation. Elevated cardiovascular-related sympathetic activity can lead to neurogenic hypertension and a host of other serious cardiac related abnormalities. The paraventricular nucleus (PVN) of the hypothalamus plays an important role in sympathetic cardiovascular regulation. Neurons from the PVN project to the rostral ventrolateral medulla (RVLM), which is the main brain stem sympathetic cardiovascular control center. While RVLM-projecting PVN neurons have been well characterized, the topographical organization within the PVN subnuclei are still not fully known. The goal of this neuroanatomical study was to map the topographical distribution of RVLM-projecting PVN neurons. To do this we microinjected four different carboxylate FluoSphere retrograde tracers (blue, 365/415; green, 505/515; red, 565/580; and far red, 660/680) at different rostro-caudal coordinates within the RVLM. The vast majority of RVLM-projecting PVN neurons were ipsilateral and located in the medial parvocellular subnucleus. Whereas most neurons were ipsilateral, there is a small fraction of neurons that crossed the midline. Neurons were also identified within the dorsal, ventral, and posterior parvocellular subnuclei of the PVN and no labeling in the anterior parvocellular or magnocellular subnuclei. We unexpectantly observed different efficiencies of the retrograde tracers with blue (365/415) being the least efficient and red (565/580) being the best. These neuroanatomical data will serve as important preliminary functional and histochemical data for future research studies.

No description available.

Although parasympathetic activity (PNS) is the primary driver and sympathetic activity (SNS) is a significant inhibitor of colonic propulsive activity, they are rarely measured, and hence, they almost play no role in diagnosing dysfunction or standard treatments for chronic conditions such as refractory constipation. We aimed to develop methodologies for the assessment of autonomic nervous system (ANS) activity, establish criteria for autonomic dysfunction, and study if stimulation of lumbar and sacral autonomic nerves using low-level laser therapy (LLLT) could affect the ANS and explore it as a potential treatment of autonomic dysfunction to restore colonic motility. By studying the active standing test and the table tilt test as a method to evoke activity in the ANS, we rejected LF power, SD1 and SD2 of Poincare plot, Pre-ejection-period (PEP), complex-correlation-measure (CCM) and detrended fluctuation analysis (DFA). Respiratory-Sinus-Arrhythmia (RSA), Root-Mean-Square-of-Successive-Differences (RMSSD) were selected for PNS activity, the Baevsky’s-Stress-Index (SI) was chosen for SNS activity, and SI/RSA and SI/RMSSD were introduced as a measure of autonomic balance. We explored high-resolution-colonic-manometry with concurrent electrocardiography to observe whether these parameters could be associated with ANS changes during colonic motor patterns. High-amplitude-propagating-pressure-waves were associated with a strong parasympathetic activity and decreased sympathetic activity. Comparing ANS reactivity of patients with severe motility disorders to controls in response to postural changes, we observed that most patients have low PNS and elevated SNS baseline activity and reactivity. This established a way to evaluate autonomic dysfunction in patients with colon motor disorders. A single session of LLLT using LED and laser light on the lumbar and sacral spine in 41 patients with chronic gastrointestinal motor dysfunction indicated that treatments with LED light followed by laser light significantly increased parasympathetic activity and decreased sympathetic nervous system activities. These results initiated a study into the effects of LLLT on restoring autonomic dysfunction in chronic refractory colonic motility disorders. / Thesis / Doctor of Philosophy (PhD)

The pathological consequences of even mild increases in blood pressure warrant treatment for hypertension in its early stages. However, chronic drug treatment programmes are generally not advantageous during the early stages of hypertension. Augmented sympathetic outflow to the heart plays a role in the early stages of hypertension, and perhaps the development of hypertension. Environmental factors are often responsible for increases in sympathetic outflow to the heart. Therefore, an alternative hypertensive treatment involves behavioural control over increases in sympathetic activity. This treatment includes biofeedback training. The literature indicates that the R-wave to ear pulse wave interval (RPI) is the most appropriate index of sympathetic influences for biofeedback training. An experiment is reported in which unconstrained normotensive subjects were asked to produce changes in RPI with and without the aid of analog feedback. Five subjects learned to produce bidirectional changes in RPI. These subjects generally showed more RPI shortening than lengthening. The data indicate that moderately heavy levels of exercise were employed to shorten RPI. This is consistent with increased sympathetic activity. Some subjects were consistently able to lengthen RPI. However, this study produced converging evidence indicating that RPI lengthening was often a product of reduced left ventricular preload. Preload influences on RPI appear to have led subjects to adopt behavioural strategies which were inconsistent with reduced sympathetic activity during attempts to lengthen RPI. Therefore, caution must be employed when using RPI to index and teach control over sympathetic activity. It is suggested that incorporating information about left ventricular ejection time or cardiac interbeat interval will improve RPI as a measure of sympathetic influences on the human heart. / Thesis / Master of Arts (MA)

No description available.

No description available.

Neuroblastoma is the most common pediatric cancer in infants, arising from the sympathoadrenal lineage of the neural crest. Despite recent advances in other pediatric cancers, long term survival in high risk cases of neuroblastoma remains below 40%. Therefore, to develop successful therapeutics targeting high risk tumors, further research into the mechanisms involved in high risk tumor formation is necessary. Prognosis in neuroblastoma is determined by a number of factors, including certain genetic and biological variables. The genetic variable correlated most with high risk disease is amplification of the MYCN gene, which is present in ~25% of tumors. Additionally, ~70% of these MYCN-amplified tumors express the neurotrophin receptor TrkB, and its ligand, brain-derived neurotrophic factor (BDNF), with concurrent expression of these proteins correlated with high risk disease independent of MYCN-amplification status. To better understand factors influencing MYCN-amplified tumor cell phenotype, and the role of TrkB signaling in high risk neuroblastoma, the experiments in this dissertation examined growth factor effects on MYCN-amplified tumor cells from the TH-MYCN mouse model of neuroblastoma, as well as the creation, and expression of a constitutively active TrkB receptor in a neural crest derived cell line. Overexpression of MYCN targeted to the sympathoadrenal lineage by the tyrosine hydroxylase (TH) promoter is sufficient to cause neuroblastoma in 100% of mice homozygous for the transgene (TH-MYCN mice). Screening growth factors, in vitro treatment of tumor cells from dissociated TH-MYCN tumors with ciliary neurotrophic factor (CNTF) was found to promote differentiation marked by increased neurite outgrowth, and withdrawal of actively dividing cells from the cell cycle. These effects were both concentration dependent, and specific to CNTF, as all other neurotrophic factors tested had no effect on differentiation. Furthermore, TH-MYCN tumor cells were found to highly express the receptor for CNTF, CNTFR both in vitro and in vivo. Testing the ability of CNTF to affect tumor growth in vivo, CNTF treatment attenuated subcutaneous tumor growth of the TH-MYCN tumor-derived cell line NHO1S in wild type 129/SvJ mice. Therefore, CNTF signaling may be a potential therapeutic target in MYCN-amplified neuroblastoma. In addition to being significantly correlated with a poor prognosis in neuroblastoma, the presence of activated TrkB signaling promotes a more aggressive phenotype in established neuroblastoma cell lines. However, whether TrkB signaling is sufficient to transform neural crest derived cells had not been established. To determine the role of TrkB signaling in malignant transformation, the two immunoglobulin-like (Ig) ligand binding domains were removed from a full length rat TrkB receptor. Expression of this receptor, termed IgTrkB, leads to elevated phosphorylated Erk levels in the absence of ligand, indicating the receptor is constitutively active. When expressed in the neural crest derived cell line NCM-1, constitutive TrkB signaling confers a highly transformed phenotype characterized by enhanced proliferation, anchorage-independent cell growth, anoikis resistance, and matrix invasion. Furthermore, IgTrkB NCM-1 cells upregulate transcripts for a number of cancer promoting genes, in addition to the poor prognosis marker MYCN. In vivo, IgTrkB NCM-1 cells form highly aggressive tumors, requiring euthanasia of mice by 15 days following injection, while wild type cells fail to grow. Thus, TrkB signaling is sufficient to transform cells derived from the neural crest.

Secreted by adipose tissue, leptin acts as a signal of energy reserve status, and acts in the brain as a negative feedback mechanism to suppress food intake and increase energy expenditure, the net effect of which is maintenance of energy homeostasis. In addition to its role as a satiety factor, leptin has widespread autonomic effects, increasing sympathetic tone to a variety of tissues, including those involved in arterial pressure regulation. Thus, leptin has been implicated as a critical link between obesity and hypertension. However, the specific mechanisms whereby leptin elicits its diverse effects are not fully understood. This is further complicated by the many sites of leptin action within the brain, as well as its diverse intracellular effects. Here, we investigate the possibility that distinct aspects of leptin function are controlled by different neuronal populations and/or molecular signaling cascades. Specifically, we identify unique roles for leptin action on POMC and AgRP neurons in differentially mediating the regional sympathetic effects of leptin. Furthermore, we show that leptin action via mTORC1 is required for the cardiovascular sympathetic but not the metabolic effects. Together, these findings point to complex neuroanatomical and molecular differences in the mechanisms underlying leptin’s effects on different physiological processes, with important implications for future research into obesity-associated hypertension.