Thesis (M.S.)--University of Wisconsin--Madison, 1970. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis--Wisconsin. / Vita. Includes bibliographical references (leaves 68-84).

Thesis (M.A.)--University of Wisconsin--Madison, 1966. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis--Wisconsin. / Vita. Includes bibliographical references (leaves 147-158).

Thesis (Ph. D.)--University of Wisconsin--Madison, 1970. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliography.

Thesis (M.S.)--University of Wisconsin--Madison, 1966. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (M. Phil.)--University of Hong Kong, 2005. / Title proper from title frame. Also available in printed format.

The microinjection of noradrenaline (NA) into the hypothalamic paraventricular nucleus (PVN) of the rat results in feeding. This response was shown; contrary to previous reports; to be mediated through both a-1 and a-2 NA receptors. Selective blockade of these two receptor sub-types, in conjunction with re-uptake blockade was used to examine the individual contributions of each receptor type to the whole response. It is suggested that the previously reported a-2 receptor specificity of the response to microinjected NA is a result of the location of these receptors. The post-synaptic a-1 receptor being located close to the pre-synaptic re-uptake mechanism, whilst the post-synaptic a-2 receptor is located outside the synapse and thus away from the re-uptake mechanism. The re-uptake mechanism acts to create a concentration difference of microinjected NA between the two receptor sub-types, resulting in a higher concentration and thus a preferential action at a-2 receptors. The involvement of the paraventricular NA system in stress induced eating was examined using a tail pinch procedure. Microinjection of NA antagonists into PVN prior to the onset of the pinch had no effect on the duration or latency of the eating response, thus there was no evidence for the involvement of this system in tail pinch elicited feeding. Further to the suggestion that the NA a-2 receptor is extra-synaptic whilst a-1 is intrasynaptic, the actions of NA were examined at a second site. NA microinjected into the ventral striatum elicited a vigorous locomotor response, although the origins of this showed a clear priming effect. However, this response was unaffected by prior microinjection of NA a-antagonists, preventing an analysis of receptor involvement comparable with that performed in PVN.

The nucleus accumbens (N.Acc.) has been ascribed an important role in mediating locomotor activity and exploration, as well as more complex processes such as reinforcement, reward and the acquisition of displacement activities. Previous investigations of N.Acc. functions have primarily been based on pharmacological manipulations of activity of one of the main neurotransmitters in the N.Acc., dopamine (DA), either through administration of dopaminergic agonists or antagonists or through depletion of DA terminal fields in the N.Acc. In the present thesis, the functional role of the N.Acc. in a number of different forms of behaviour has been investigated further using specific, fibre-sparing excitotoxic lesions of intrinsic neurones, intra-accumbens injections of DA and in vivo electrochemical measurements of extracellular levels of DA in the N.Acc. Excitotoxic lesions in the N.Acc. were found to enhance spontaneous locomotion and exploratory behaviours while leaving intact the locomotor- stimulating effects of an indirect dopaminergic agonist, displacement drinking in response to intermittent food-reinforcement (SIP) and amphetamine-induced conditioned place preference (CPP). Thus, fibre-sparing excitotoxic lesions induced a pattern of behaviour distinct from that observed following terminal depletion in the N.Acc. Further, microinjection and in vivo electrochemical experiments showed no direct relationship between DA activity in the N.Acc. and SIP. Overall, these results are discussed in terms of a theoretical model proposing that the N.Acc. may function as an interface between sensory input and locomotor output and that inhibitory activity in the N.Acc. is needed to channel activity levels appropriately in response to cortical input about the direction of change. It is suggested that rather than viewing it as a unitary structure with specific functions, the N.Acc. should be considered as a heterogeneous part of the striatal complex with a number of distinct subsystems that exist within a complex framework of interactive processes, where changes in one structure can only be understood by taking into account other, related structures.

Orientador: Licio Augusto Velloso / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-07T04:07:10Z (GMT). No. of bitstreams: 1 Bertelli_DanielaFaleiros_D.pdf: 2445017 bytes, checksum: 2a78cdd0f1bc8fc197cb47c83deb0c0b (MD5) Previous issue date: 2006 / Resumo: A enzima fosfatidilinositol 3-quinase (PI3-kinase) exerce uma importante função na transdução dos sinais anorexigênicos e termogênicos enviados pela insulina e leptina em primeira ordem aos neurônios do núcleo arqueado no hipotálamo. A cascata de sinais intracelulares gerados pela ativação da PI3-kinase depende da atividade coordenada de inositol-fosfatases específicas. Neste trabalho, mostramos que a phosphoinositide-specific inositol polyphosphate 5-phosphatase IV (5ptase IV) está altamente expressa em neurônios do núcleo arqueado e lateral do hipotálamo. Submetido ao tratamento intracerebroventricular (ICV) com insulina, a 5ptase IV sofre fosforilação em tirosina de acordo com um padrão tempo-dependente, a qual segue os mesmos moldes da sinalização da insulina através do seu receptor (IR), seu substrato-2 (IRS2) e da PI3-kinase. Para avaliar a participação da 5ptase IV na ação da insulina no hipotálamo, trabalhamos com um oligonucleotídeo antisense específico para esta enzima. O tratamento dos ratos com este oligonucleotídeo durante quatro dias reduziu a expressão hipotalâmica da 5ptase IV em aproximadamente 80%. Tal fato foi acompanhado pela redução de 70% na sua fosforilação induzida pela insulina, e ainda pelo aumento na quantidade basal dos inositóis fosforilados no hipotálamo. Finalmente, a inibição da expressão da 5ptase IV no hipotálamo pelo oligonucleotídeo antisense, resultou na redução da ingestão média diária de alimentos, na perda de massa corporal e ainda na redução da ingestão alimentar em 12 horas. Desta forma, a 5ptase IV é um potente regulador da sinalização através da PI3kinase no hipotálamo e pode tornar-se um alvo interessante para a terapêutica da obesidade e para as desordens relacionadas / Abstract: The enzyme phosphatidylinositol 3-kinase (PI 3-kinase) exerts an important role in the transduction of the anorexigenic and thermogenic signals delivered by insulin and leptin to first-order neurons of the arcuate nucleus in the hypothalamus. The termination of the intracellular signals generated by the activation of PI 3-kinase depends on the coordinated activity of specific inositol phosphatases. Here, we show that phosphoinositide-specific inositol polyphosphate 5-phosphatase IV (5ptase IV) is highly expressed in neurons of the arcuate and lateral nuclei of the hypothalamus. Upon intracerebroventicular (ICV) treatment with insulin, 5ptase IV undergoes a time-dependent tyrosine phosphorylation, which follows the same patterns of canonical insulin signaling through the insulin receptor, IRS-2, and PI 3-kinase. To evaluate the participation of 5ptase IV in insulin action in hypothalamus, we employed a phosphorthioate modified antisense oligonucleotide specific for this enzyme. The treatment of rats with this oligonucleotide for four days reduced the hypothalamic expression of 5ptase IV by ~80%. This was accompanied by a ~70% reduction of insulin-induced tyrosine phosphorylation of 5ptase IV and by an increase in basal accumulation of phosphorylated inositols in the hypothalamus. Finally, inhibition of hypothalamic 5ptase IV expression by the antisense approach resulted in reduced daily food intake, body weight loss and decreased 12 h spontaneous food intake. Thus, 5ptase IV is a powerful regulator of signaling through PI 3-kinase in hypothalamus and may become an interesting target for therapeutics of obesity and related disorders / Doutorado / Biologia Estrutural, Celular, Molecular e do Desenvolvimento / Doutor em Fisiopatologia Medica