The superior mesenteric ganglion (SMG) provides sympathetic input to areas of the small intestine, colon, spleen, and mesenteric lymph nodes. Interactions between the nervous and immune systems in the SMG influence sympathetic regulation of gastrointestinal (GI) and immune function. Previous work in our laboratory has demonstrated changes in SMG neuron activity resulting from exposure to inflammatory mediators such as tumour necrosis factor α (TNFα). The current project focused on interactions between mast cells and sympathetic neurons. Mast cells within the SMG release mediators, including histamine, that can act on neurons and alter their activity. We tested the hypothesis that histamine influences signaling in SMG neurons by inhibiting calcium ion influx during cell depolarization using immunohistochemistry and calcium imaging. Immunohistochemistry revealed H3R on the majority of tyrosine hydroxylase-positive sympathetic neurons in the ganglia. Dissociated neurons were incubated in the ratiometric fluorescent calcium indicator dye Fura-2 acetoxymethyl ester, then superfused with extracellular solution containing histamine receptor agonists (histamine, HTMT, imetit) and antagonists (thioperamide) before being depolarized with a KCL solution (70 mM). Application of both histamine (10 μM) and the H3 receptor agonist imetit (100 nM) caused a decrease in depolarization-induced calcium ion influx. However, the inhibition of calcium ion influx became smaller as the concentration of histamine was increased (100 μM, 1 mM) until the inhibition was no longer statistically significant. Application of H3R antagonist thioperamine (300nM) reversed the inhibition of calcium ion influx caused by histamine (10 μM). Application of H1R & H2R agonist histamine trifluoromethyl toluidide (HTMT) (10 μM) caused an increase in calcium ion influx during depolarization. We conclude that activation of H3R decreases calcium ion influx through voltage-gated calcium ion channels, while activation of H1R / H2R increases calcium ion influx. H3R has a higher affinity for histamine, and therefore is preferentially activated at lower concentrations. Increases in histamine receptor activation may alter SMG input to the spleen, mesenteric lymph nodes, small intestine, and colon, resulting in changes in immune and gut function, such as those described in irritable bowel syndrome. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2011-08-29 11:15:09.484

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The survival of several neuron populations during development, including sympathetic neurons, is strictly regulated by neurotrophins such as nerve growth factor (NGF) released from innervation targets. NGF activates its receptor, TrkA, at axon terminals, to generate signals that are transmitted retrogradely to cell bodies to induce signaling cascades regulating survival. A general view of this process is that NGF generates retrograde survival signals that, when delivered to cell bodies, induce downstream survival signaling that prevents apoptosis. A retrograde survival signal proposed to be necessary for sympathetic neuron survival consists of endosomes containing NGF and phosphorylated TrkA. For this signal, phosphorylated TrkA arriving at cell bodies is required to initiate survival signaling. Studies have tested the necessity of TrkA phosphorylation in the cell bodies for survival: results from different studies contradict each other. Moreover, the Trk inhibitor, K252a, used in these studies, has reported non-specific effects. Using an alternate Trk inhibitor, Gö6976, data presented in this thesis demonstrates that NGF can promote survival by retrograde signaling that does not require TrkA phosphorylation in the cell bodies. These retrograde signals may be composed of signaling molecules activated downstream of TrkA in axons since pro-survival molecules downstream of TrkA, Akt and CREB, were found activated in the cell bodies/proximal axons. Data presented in this thesis also reveals a fundamentally different mechanism for how NGF promotes sympathetic neuron survival: a retrograde apoptotic signal that is suppressed by NGF. NGF withdrawal from axons induced the “axon apoptotic signal” that was retrogradely transmitted to cell bodies to activate a key pro-apoptotic molecule, c-jun. The axon apoptotic signal, which was blocked by the kinase inhibitors rottlerin and chelerythrine, was necessary for apoptosis in response to NGF deprivation. Evidence GSK3 is involved in generation or transmission of the axon apoptotic signal was provided by experiments with GSK3 inhibitors and siRNA. The axon apoptotic signal discovery refutes the previous view that NGF acting on axon terminals supports survival exclusively by generating retrograde survival signals. The axon apoptotic signal has broad implications for understanding nervous system development and other conditions where neuronal apoptosis occurs, such as neurotrauma and neurodegenerative diseases.

Su amžiumi susiję struktūriniai simpatinės nervų sistemos pokyčiai sukelia įvairių organų funkcijos sutrikimus. Simpatinio kamieno viršutiniai kakliniai mazgai, pagrindiniai galvos smegenų kraujagyslių simpatinės inervacijos šaltiniai, yra svarbūs galvos smegenų kraujotakos autonominės reguliacijos centrai. Tačiau žmogaus simpatinių mazgų morfofunkciniai tyrimai yra pavieniai. Todėl šio darbo tikslas buvo ištirti trijų amžiaus grupių žmonių ir mirusiųjų dėl išeminio galvos smegenų infarkto simpatinio kamieno viršutinio kaklinio mazgo morfologinius bei neurocheminius ypatumus, ir nustatyti jų sąsajas su amžiumi ir išeminiu galvos smegenų infarktu. Tyrimo rezultatai rodo, kad amžiaus eigoje vystosi žmogaus simpatinio kamieno viršutinio kaklinio mazgo neuronų morfologinių parametrų, neurofilamentų baltymo, nervų augimo faktoriaus receptorių p75 imunoreaktyvumo pokyčiai. Skirtingose amžiaus grupėse aptinkami neuronų ir satelitinių ląstelių apoptoz����s požymiai. Pagyvenusio amžiaus žmonių, mirusių dėl išeminio galvos smegenų infarkto, simpatiniuose mazguose vystosi neuropatologinės alteracijos požymiai: padidėja neuronų afinitetas baziniams dažams, atsiranda neuronų su degeneraciniais ir hipertrofijos požymiais židiniai, satelitinių ląstelių proliferacija, limfocitų židininė infiltracija, sumažėja neuronų kūno, branduolio, citoplazmos plotai, aptinkamas didesnis neurofilamentams ir nervų augimo faktoriaus receptoriams p75 imunoreaktyvių neuronų skaičius, didesnis apoptozinis... [toliau žr. visą tekstą] / Age-related structural changes of the sympathetic nervous system cause the disturbance of the involuntary functions of various organs. The superior cervical ganglia are the main source of sympathetic innervation of the cerebral arteries and important center of autonomic regulation of the cerebral circulation. However, only single morphofunctional studies of the human sympathetic ganglia are performed. Therefore, the aim of the study was to investigate morphological and neurochemical peculiarities of the human superior cervical ganglion in three age groups and in the subjects dead of ischemic cerebral infarction and establish their relation to age and ischemic cerebral infarction. The results of the present study show that changes of neurons morphologic parameters and immunoreactivity to neurofilament and nerve growth factor receptor p75 in the human superior cervical ganglion are developed in the course of aging. Morphological features of apoptosis in the sympathetic neurons and satellite cells in different age groups are detected. The signs of neuropathological alteration of the sympathetic ganglion of subjects with ischemic cerebral infarction were the following: increased tinctorial affinity of neurons, foci of neurons with features of neuron death and hypertrophy, proliferation of satellite cells, focal lymphocyte infiltration, decrease of neuron body, nucleus, cytoplasm area, increase of neurofilament and nerve growth factor receptor p75 immunoreactive neurons... [to full text]