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- Alkhori, Liza
(författare)
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Mechanisms of sensory neuron diversification during development and in the adult Drosophila : How to make a difference
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The nervous system contains a vast number of neurons and displays a great diversity in cell types and classes. Even though this has been known for a long time, the exact mechanism of cell specification is still poorly understood. How does a cell know what type of neuron to which it should be specified? It is important to understand cellular specification, not only for our general understanding of biological processes, but also to allow us to develop treatments for patients with destructive diseases, such as Alzheimer’s, Parkinson, cancer or stroke. To address how neuronal specification and thereby diversification is evolved, we have chosen to study a complex but defined set of neurons, the Drosophila olfactory system. Olfactory sensory neurons (OSNs) detect an enormous variety of small volatile molecules with extremely high specificity and sensitivity. The adult Drosophila olfactory system contains 34 OSN classes each defined by their expression of a specific odorant receptor (OR). In both insects and vertebrates, each OSN expresses only one OR. In mouse there are approximately 1200 and in Drosophila 60 different OR genes. Despite the range of mechanisms known to determine cell identity and that the olfactory system is remarkably conserved across the phyla, it is still unclear how an OSN chooses to express a particular OR from a large genomic repertoire. In this thesis, the specification and diversification of the final steps establishing an OSN identity is addressed. We find seven transcription factors that are continuously required in different combinations for the expression of all ORs. The TFs can in different gene context both activate and repress OR expression, making the regulation more economical and indicating that repression is crucial for correct gene expression. We further identified a repressor complex that is able to segregate OR expression between OSN classes and propose a mechanism on how one single co-repressor can specify a large number of neuron classes.Exploring the OSN we found the developmental Hh signalling pathway is expressed in the postmitotic neuron. We show several fundamental similarities between the canonical Drosophila Hh pathway and the cilia mediated Hh transduction in component function. Further investigation revealed a function of cilia mediated Hh signalling in sensory neuron modulator. The results generated here will create a greater in vivo understanding of how postmitotic processes generate neurons with different fates and contribute to the maintaining of neuron function.
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| 2. |
- Bagheri, Maryam
(författare)
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Neuroprotective Effect of Genistein : Studies in Rat Models of Parkinson’s and Alzheimer’s Disease
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Parkinson’s disease (PD) and Alzheimer’s disease (AD) are neurodegenerative disorders that mainly affect the elderly population. It is believed that oxidative stress is involved in development of both these diseases and that estrogen deficiency is a risk factor for development of AD. Genistein is a plant-derived compound that is similar in structure to estrogen and has anti-oxidative properties. The general objective of the present research was to evaluate the effects of genistein on neurodegeneration in rat models of PD and AD.Using a rat model of PD, we found that a single intraperitoneal dose of genistein 1 h before intrastriatal injection of 6-hydroxydopamine (6-OHDA) attenuated apomorphine-induced rotational behavior and protected the neurons of substantia nigra pars compacta against 6-OHDA toxicity.To produce an animal model of AD, we injected Aβ1–40 into the hippocampus of rats. Using groups of these Aβ1–40-lesioned animals, the involvement of estrogen receptors (ERs) was evaluated by intracerebroventricular injection of the estrogen receptor antagonist fulvestrant, and the role of oxidative stress was studied by measuring levels of malondialdehyde (MDA), nitrite, and superoxide dismutase (SOD) activity. The results showed that intrahippocampal injection of Aβ1–40 caused the following: lower spontaneous alternation score in Y-maze tasks, impaired retention and recall capability in the passive avoidance test, and fewer correct choices and more errors in a radial arm maze (RAM task), elevated levels of MDA and nitrite, and a signiHcant reduction in SOD activity in the brain tissue. Furthermore, hippocampus in theses rats exhibited Aβ1–40 immunoreactive aggregates close to the lateral blade of the dentate gyrus (DGlb), extensive neuronal degeneration in the DGlb, high intracellular iNOS+ and nNOS+ immunoreactivity, and extensive astrogliosis.Genistein pretreatment ameliorated the Aβ-induced impairment of short-term spatial memory, and this effect occurred via an estrogenic pathway and through attenuation of oxidative stress. Genistein also ameliorated the degeneration of neurons, inhibited the formation of Aβ1–40-positive aggregates, and alleviated Aβ1–40-induced astrogliosis in the hippocampus.
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| 3. |
- Ruud, Johan, 1978-
(författare)
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Central Nervous System and Innate Immune Mechanisms for Inflammation- and Cancer-induced Anorexia
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Anyone who has experienced influenza or a bacterial infection knows what it means to be ill. Apart from feeling feverish, experiencing aching joints and muscles, you lose the desire to eat. Anorexia, defined as loss of appetite or persistent satiety leading to reduced energy intake, is a hallmark of acute inflammatory disease. The anorexia is part of the acute phase response, triggered as the result of activation of the innate immune system with concomitant release of inflammatory mediators, which interact with the central nervous system. A chronic condition, and a severe medical problem, that resembles inflammation-induced anorexia is cachexia. Cachexia, which is commonly associated with malignant cancer, is typified as a cytokine-associated metabolic derangement leading to weight loss, mediated by activation of the immune system. Paradoxically, weight loss in cancer patients is often associated with reduced food intake, indicating that the normal coupling of energy intake to body weight is disarranged. Accumulating evidence indicates that inflammation- and cancer-induced anorexia are associated with Toll-like receptor and cycloxygenase (Cox) activation. However, the nature of these pathways is far from understood, and a series of experiments addressing this issue was therefore undertaken.In paper I, we injected Morris hepatoma 7777 cells or vehicle into rats, and we analyzed the distribution pattern of the transcription factor Fos, an index of neuronal activity, in the brainstem. We found that the anorexia and weight loss in tumor-bearing rats were associated with extensive expression of Fos in the area postrema and the general visceral region of the nucleus of the solitary tract in the medulla oblongata, as well as in the external lateral pontine parabrachial nucleus, and that the magnitude of the Fos expression correlated positively with tumor weight and negatively with body weight development, respectively. The Fos expression occurred without any obvious signs of peripheral or central inflammation, and was not secondary to alterations in body weight or reduced food intake. Thus, in paper I, we found a tumor-elicited activation of three interconnected autonomic structures, which integrate and transmit afferent visceral and sensory information, and which are known to play vital roles for energy homeostasis.In paper II we evaluated the effects of tumor growth on feeding behaviour in mice as well as the role of Cox-1 and Cox-2, and prostaglandin E2 (PGE2) for the decreased appetite. We implanted mice with a MCG 101 tumor, which resulted in decreased meal frequency but not decreased meal size or meal duration. We found that indomethacin, a non-selective Cox-inhibitor, attenuated the anorexia as well as the tumor growth. When given acutely at manifest anorexia, Cox-inhibitors rescued the loss of appetite and prevented body weight loss without affecting tumor weight. Despite Cox-2 gene induction in the brain and Cox-2 protein induction in cells associated to the blood-brain barrier in tumor-bearing mice, a Cox-2 inhibitor had no impact on tumor-induced anorexia. By contrast, manipulating Cox-1 activity with a selective Cox-1 inhibitor delayed the onset of the anorexic response. Tumor growth was associated with large elevations in plasma PGE2, a response that was prevented by indomethacin. In contrast, however, PGE2 levels in liquor were largely unaffected, in line with tumor-bearing mice being afebrile. Neutralisation of peripheral PGE2 with anti-PGE2 antibodies did not temper the anorexia, and deletion of host mPGES-1 did not affect the anorexia or tumor growth. Furthermore, we found that tumor-bearing mice lacking EP4 receptors in the nervous system, created by Cre-LoxP-targeted mutagenesis, developed anorexia. The most important conclusions from paper II are that decreased meal frequency caused the anorexia, and that Cox-enzymes, most likely Cox-1, are critical for cancer-elicited anorexia and weight loss and that these changes occur independently of host mPGES-1, PGE2 and neuronal EP4 receptor signaling.In paper III, we investigated whether the inflammatory response critical for tumor-induced anorexia (paper II) was a result of innate immune signaling mechanisms. In paper IV, we also included measurements of food intake in mice injected with bacterial endotoxin, lipopolysaccharide (LPS; a Toll-like receptor 4 ligand), and aimed at identifying at which site(s) the activation of the innate immune system occurs during acute (LPS) as well as chronic (tumor) inflammation. To do so we examined the anorexic response in mice ubiquitously lacking (born without the gene in every cell) MyD88, the intracellular adaptor for Toll-like receptor and IL-1/18 receptor signalling, or lacking MyD88 in specific cell types. We found that a ubiquitous null deletion conferred complete resistance to LPS- and tumor-induced anorexia, as well as protected against weight loss. MyD88 knock-out mice, which had been subjected to whole-body irradiation to delete hematopoietic cells, and then transplanted with wild-type bone-marrow, developed anorexia when challenged with LPS. In line with this, mice lacking MyD88 in hematopoietic cells were largely protected against LPS-induced anorexia. Similarly, inactivation of MyD88 in hematopoietic cells attenuated the tumor-induced anorexia development and protected from body weight loss. In contrast, genetic disruption of MyD88 signaling in neural cells or cerebrovascular endothelial cells affected neither LPS- or tumor-induced anorexia, nor weight loss. Thus, the key findings in paper III and IV are that genetic inactivation of MyD88 protects mice from developing cancer- and LPS-induced anorexia, indicating that innate immune signaling mechanisms are critical for this response. The findings also identify hematopoietic cells, but not neural cells or cerebrovascular endothelial cells, as a critical nexus for inflammatory driven anorexia and weight loss associated with acute (LPS) and chronic (malignant) disease.
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