Compared to other structures, such as the amygdala, the lateral septum’s (LS) role in the regulation of anxiety and/or behavioural defense is relatively understudied. Thus, the overarching goal of this thesis was to further investigate its contribution to rats’ anxiety-related behaviours. In Chapter 2, we demonstrate, for the first time, that while the dorsal LS does not mediate rats’ appetitive motivation or anxiety in the novelty induced suppression of feeding (NISF) paradigm, it does modulate their defensive behaviours in the elevated plus maze (EPM) and shock probe burying tests (SPBT). In Chapter 3, we are the first to show that bilateral infusions of histamine, a neurochemical previously linked to anxiety, into the LS reduce rats’ anxiety-related behaviours in the EPM and NISF. In addition, we report a novel double dissociation between lateral septal H1 and H2, and H3 receptors in their regulation of rats’ defensive behaviours in those two paradigms. More specifically, the H1 and H2 receptors contribute to rats’ hyponeophagia in the NISF but not their open arm exploration in the EPM, while the H3 receptors modulate rats’ defensive behaviors in the EPM but not in the NISF. Finally, in Chapter 4, we report for the first time that infusions of histamine into the LS, which produce behavioural anxiolysis, increase rather than decrease the frequency of reticular-elicited hippocampal theta activity, a putative neurophysiological correlate of anxiolytic-drug action. Altogether, the data in this thesis increase our understanding of how the LS contributes to rats’ defensive behaviours and adds to the existing literature regarding the neurobiology of fear/anxiety. More importantly though, the data presented here could ultimately aid in the development of novel drugs to treat anxiety disorders in humans. / Thesis (Ph.D, Neuroscience Studies) -- Queen's University, 2013-12-17 17:27:34.014

ADAM10 is a zinc-dependent metalloprotease. ADAM10 has emerged as a key regulator of cellular processes by cleaving and shedding extracellular domains of multiple transmembrane receptors and ligands. In this study, we examined the role of ADAM10 in the immune system. Here, we show that knocking out ADAM10 on the mature B2 cell causes a defect in the development of secondary lymphoid architecture that becomes more severe post-immunization. We also show that overexpression of ADAM10 leads to a defect in hematopoiesis, which eliminates B2 lymphocyte development. This defect additionally induces accumulation of myeloid derived suppressor cells, MDSCs. ADAM10Tg MDSCs function synonymous to tumor MDSCs. Of the two subpopulations of MDSCs, granulocytic MDSCs increase parasitic clearance in a model of N. brasiliensis. Monocytic MDSCs are more immunosuppressive in regards to tumor. Both subpopulations are dependent on the presence of mast cells for activity. It is thought that this relationship is mediated through histamine and IL-13. During N. brasiliensis infection, ADAM10Tg mice, lacking B2 B cells but having intact B1 B cells, makes increased IgE over WT mice. This production of IgE is thought to be produced by the B1 cells. Of the two types of B1 cells, B1a cells make the majority of the IgE. This IgE production is enhanced by MDSC accumulation and can be induced by MDSC adoptive transfer in a parasite-free mouse. Lastly, ADAM10 is the key sheddase for CD23 on B2 cells. When IgE is bound to its antigen to form an immune complex, IC, it binds CD23 and is internalized. After CD23 bound to IgE ICs is internalized, it is sorted into bexosomes. These bexosomes are transferred to dendritic cells which are responsible for presenting to T cells and inducing an increased antigen-specific immune response. Overall, ADAM10 is important for many aspects of the immune response.

A dor e o prurido são sensações sensoriais que auxiliam na defesa do organismo. Apesar das ações anti-nociceptivas do novo gasotransmissor endógeno H2S, nada se sabe sobre seu efeito no prurido. Avaliou-se aqui o efeito de doadores de H2S (Na2S e reagente de Lawesson - LR) no prurido e inflamação induzidos pela injeção i.d. de histamina e composto 48/80 (C48/80) na pele de camundongos. Verificou-se a produção do H2S e a expressão de suas enzimas (CBS e CSE) na pele. A injeção i.d. de histamina ou C48/80 aumentou significativamente a frequência de coceira e induziu extravasamento plasmático e influxo de leucócitos na pele dos animais em relação ao veículo. A co-injeção do Na2S ou LR reduziu (P<0.05) o extravasamento plasmático evocado por ambos agentes, mas somente o prurido induzido por histamina foi inibido. Conclui-se que a suplementação exógena de H2S inibe o extravasamento plasmático induzido por histamina e C48/80, mas somente inibiu o prurido evocado por histamina. As enzimas CSE e CBS estão expressas constitutivamente na pele e sintetizam o H2S local. / Pain and pruritus are sensory sensations that help in defending the organism. Despite the anti-nociceptive actions of the new gasotransmitter H2S, little is known about its effect on pruritus. We evaluated the effect of H2S donors (Na2S and Lawesson\'s reagent - LR) in itching and inflammation induced by i.d. injection of histamine and compound 48/80 (C48/80) in mouse dorsal skin. We also investigated the production of H2S and expression of its enzymes (CBS and CSE) in the mouse skin. The i.d. injection of histamine or C48/80 significantly increased the frequency of itching and induced plasma leakage and leukocyte influx into the skin in relation to vehicle. Co-injection of Na2S or LR decreased (P<0.05) plasma extravasation evoked by both agents, but only the itching induced by histamine was inhibited. In conclusion, the exogenous supplementation of H2S inhibits plasma extravasation induced by histamine and C48/80, but only inhibited histamine-induced pruritus. CSE and CBS are constitutively expressed in the skin and are responsible for local H2S synthesis.

Wong Lai Lok. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (leaves 162-173). / Abstracts in English and Chinese. / Abstract --- p.ii / Acknowledgements --- p.vi / Publications --- p.vii / Abbreviations --- p.viii / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1. --- Historical Background --- p.2 / Chapter 1.2. --- Heterogeneity of mast cells --- p.3 / Chapter 1.3. --- Mast cell mediators --- p.5 / Chapter 1.3.1. --- Performed and granule associated mediators --- p.5 / Chapter 1.3.2. --- Newly synthesized mediators --- p.8 / Chapter 1.3.3. --- Cytokines --- p.10 / Chapter 1.4. --- Mast cell activation --- p.10 / Chapter 1.4.1. --- Aggregation of IgE Receptors (FcεRI) --- p.10 / Chapter 1.4.2. --- Activation of Phospholipase C --- p.11 / Chapter 1.4.3. --- Activation of Adenylate cyclase --- p.13 / Chapter 1.5. --- Adenosine --- p.14 / Chapter 1.5.1. --- Adenosine receptors --- p.14 / Chapter 1.5.2. --- Selective agonists and antagonists --- p.17 / Chapter 1.5.3. --- Physiological and pathological roles of adenosine --- p.20 / Chapter 1.6. --- Role of adenosine receptors in mast cell activation --- p.21 / Chapter 1.7. --- Aims of the study --- p.23 / Chapter Chapter 2 --- Materials and Methods --- p.30 / Chapter 2.1. --- Materials --- p.31 / Chapter 2.1.1. --- Mast cells secretagogues --- p.31 / Chapter 2.1.2. --- Anti-allergic compounds --- p.31 / Chapter 2.1.3. --- Adenosine receptor agonists and antagonists --- p.31 / Chapter 2.1.4. --- Materials for buffers --- p.32 / Chapter 2.1.5. --- Materials for rat sensitization --- p.32 / Chapter 2.1.6. --- Materials for histamine assay --- p.33 / Chapter 2.1.7. --- Miscellaneous --- p.33 / Chapter 2.2. --- Buffers and stock solutions --- p.34 / Chapter 2.2.1 --- Buffer ingredients --- p.34 / Chapter 2.2.2 --- Stock solutions --- p.34 / Chapter 2.3. --- Source of mast cells --- p.35 / Chapter 2.3.1. --- Animals --- p.35 / Chapter 2.3.2. --- Sensitization of animals --- p.35 / Chapter 2.3.3. --- Isolation of rat peritoneal mast cells --- p.35 / Chapter 2.3.4. --- Mast cells purification --- p.36 / Chapter 2.3.5. --- Cell counting --- p.36 / Chapter 2.4. --- General protocol for histamine release --- p.37 / Chapter 2.4.1. --- Histamine assay --- p.37 / Chapter 2.4.2. --- Antagonist studies --- p.38 / Chapter 2.4.3. --- Determination of histamine contents --- p.38 / Chapter 2.4.4. --- Calculation of histamine levels --- p.39 / Chapter 2.5. --- Statistical analysis --- p.40 / Chapter Chapter 3 --- "Effects of adenosine, adenosine deaminase and adenosine receptor agonists on mast cell activation" --- p.42 / Chapter 3.1. --- Introduction --- p.43 / Chapter 3.2. --- Materials and methods --- p.44 / Chapter 3.3. --- Results --- p.45 / Chapter 3.3.1. --- Effects of adenosine on anti-IgE induced histamine release in HEPES buffer --- p.45 / Chapter 3.3.2. --- Effects of NECA on anti-IgE induced histamine release in HEPES buffer --- p.46 / Chapter 3.3.3. --- Effects of CCPA on anti-IgE induced histamine release in HEPES buffer --- p.47 / Chapter 3.3.4. --- Effects of CPA on anti-IgE induced histamine release in HEPES buffer --- p.47 / Chapter 3.3.5. --- Effects of CGS21680 on anti-IgE induced histamine release in HEPES buffer --- p.48 / Chapter 3.3.6. --- Effects of Cl-MECA on anti-IgE induced histamine release in HEPES buffer --- p.49 / Chapter 3.3.7. --- Effects of adenosine deaminase on anti-IgE induced histamine release from rat peritoneal mast cells --- p.50 / Chapter 3.3.8. --- Effects of NECA on anti-IgE induced histamine release with and without adenosine deaminase --- p.50 / Chapter 3.3.9. --- Effects of Cl-MECA on anti-IgE induced histamine release with and without adenosine deaminase --- p.53 / Chapter 3.3.10. --- Effects of CV1808 on anti-IgE induced histamine release in HEPES buffer --- p.55 / Chapter 3.4. --- Discussion --- p.76 / Chapter 3.5. --- Conclusion --- p.83 / Chapter Chapter 4 --- Effects of adenosine receptor antagonists on mast cell activation --- p.88 / Chapter 4.1. --- Introduction --- p.89 / Chapter 4.2. --- Materials and methods --- p.90 / Chapter 4.3. --- Results --- p.91 / Chapter 4.3.1. --- Effects of A1 receptor antagonist DPCPX on modulations of anti-IgE induced histamine release by adenosine receptor agonists --- p.91 / Chapter 4.3.2. --- Effects of A2A receptor antagonist ZM241385 on modulations of anti-IgE induced histamine release by adenosine receptor agonists --- p.91 / Chapter 4.3.3. --- Effects of A2B receptor antagonist MRS 1706 on modulations of anti-IgE induced histamine release by adenosine receptor agonists --- p.92 / Chapter 4.3.4. --- Effects of A3 receptor antagonist VUF5574 on modulations of anti-IgE induced histamine release by adenosine receptor agonists --- p.93 / Chapter 4.3.5. --- Further characterization of adenosine mediated potentiation of anti-IgE histamine release using VUF5574 and ZM241385 --- p.93 / Chapter 4.3.6. --- Effects of theophylline on anti-IgE induced percentage potentiation in HEPES buffer --- p.95 / Chapter 4.4. --- Discussion --- p.130 / Chapter 4.5. --- Conclusion --- p.135 / Chapter Chapter 5 --- Further characterization of the effects of adenosine on mast cells --- p.138 / Chapter 5.1. --- Introduction --- p.139 / Chapter 5.2. --- Materials and methods --- p.141 / Chapter 5.3. --- Results --- p.142 / Chapter 5.3.1. --- Effects of anti-IgE induced histamine release in calcium free and HEPES buffers --- p.142 / Chapter 5.3.2. --- Effects of adenosine on anti-IgE induced histamine release in calcium free buffer --- p.143 / Chapter 5.3.3. --- Effects of adenosine deaminase on compound48/80 induced histamine release from rat peritoneal mast cells --- p.143 / Chapter 5.3.4. --- Effects of adenosine on compound 48/80 induced histamine release in HEPES buffer --- p.144 / Chapter 5.3.5. --- Effects of adenosine deaminase on A23187 induced histamine release from rat peritoneal mast cells --- p.144 / Chapter 5.3.6. --- Effects of adenosine on calcium ionophore A23187 induced histamine release in HEPES buffer --- p.145 / Chapter 5.3.7. --- Effects of adenosine receptor antagonists on inosine mediated enhancement of anti-IgE induced histamine release --- p.145 / Chapter 5.4. --- Discussion --- p.157 / Chapter 5.5. --- Conclusion --- p.160 / References --- p.162

The presented studies were performed to investigate the effects of motion sickness (MS) on human autonomic and behavioural thermoregulatory mechanisms during cold stress and in a thermoneutral environment. The roles of histaminergic and cholinergic neuron systems in autonomic thermoregulation and MS-dependent dysfunction of autonomic thermoregulation were studied using a histamine-receptor blocker, dimenhydrinate (DMH), and a muscarine-receptor blocker, scopolamine (Scop). In addition, the effects of these substances on MS-induced nausea and perceptual thermoregulatory responses were studied. MS was found to lower core temperature, during cold stress by attenuation of cold-induced vasoconstriction and decreased shivering thermogenesis, and in a thermoneutral environment by inducing sweating and vasodilatation. The increased core cooling during cold stress was counteracted by DMH but not by Scop. In a thermoneutral environment, the temperature was perceived as uncomfortably warm during and after the MS provocation despite decreases in both core and skin temperature. No such effect was seen during cold-water immersion. Both pharmacologic substances had per se different effects on autonomic thermoregulatory responses during cold stress. Scop decreased heat preservation, but did not affect core cooling, while DMH reduced the rate of core cooling through increased shivering thermogenesis. Both DMH and Scop per se decreased thermal discomfort during cold-water immersion.Findings support the notion of modulating roles of histamine (H) and acetylcholine (Ach) in autonomic thermoregulation and during MS. MS activates cholinergic and histaminergic pathways, thereby increasing the levels of H and Ach in several neuro-anatomical structures. As a secondary effect, MS also elevates blood levels of several neuropeptides, which in turn would influence central and/or peripheral thermoregulatory responses.In conclusion, MS may predispose to hypothermia, by impairment of autonomic thermoregulation in both cold and thermoneutral environments and by modulation of behavioural thermoregulatory input signals. This might have significant implications for survival in maritime accidents. / <p>Medicine doktorsexamen</p>

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.

Thesis (M.S.)--Oregon State University, 2008. / Printout. Includes bibliographical references (leaves 78-86). Also available on the World Wide Web.

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniv., 2000. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 5 uppsatser.

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniversitet, 2006. / Härtill 4 uppsatser.