Date of Award

2017-01-01

Degree Name

Doctor of Philosophy

Department

Biological Sciences

Advisor(s)

Arshad M. Khan

Abstract

As the obesity pandemic continues to increase, so does the incidence rate of related conditions including diabetes, cardiovascular disease, and neurodegenerative disorders (Yu and Kim 2012). At the level of the brain, the hypothalamus is a key structure for the integratration of autonomic, neuroendocrine and somatomotor functions for the control of metabolism and homeostasis. It has long been implicated as a critical player in the deregulation of an animal's energy status and in the onset of obesity, diabetes and metabolic syndrome (Elmquist et al., 1999). While many ongoing studies are aimed at preventing or treating these conditions, the underlying mechanisms regulating the physiology of metabolism remain elusive given the complexity of the networks involved. Therefore, the major goal of this study was to provide a more simplifed view of the brain and the networks that are important in regulating the onset or inhibition of feeding. These networks largely remain unknown not only in the diseased state but also in the normal brain state. To inhibit feeding, satiety centers are crucial in signaling a "sense of fullness" following meal consumption. A loss of signaling in satiety nodes can result in overeating because of the loss of a feeling of satiety. The aim of Chapter 1, was to functionally identify regions in the central nervous system that act as critical centers of satiety, by looking at Fos activation in the brain in a fasted and refed animal model. By generating a detailed series of maps, several structures that may be associated with satiety were identifed including nuclei of the hypothalamus,

amygdala and hindbrain. These Of particular interest to this study was the identifcation of the arcuate hypothalamic nucleus (ARH) as one of these regions. It is a unique structure that has been shown to have diametrically opposed functions in feeding regulation. Studies have demonstrated the ability of the ARH to tilt the scales of ingestive behavior from a sated phase to an actively consummatory phase by suppressing appetite via the actions of intra-arcuate proopiomelanocortin neurons or stimulating feeding through the actions of intra-arcuate agouti-related peptide neurons. Using a food deprivation model, the aim of Chapter 2 was to further characterize this nucleus and the organization of various chemically distinct neuronal phenotypes that reside within its boundary for an increased understanding of ARH topography and function. Studies have shown that many of these neuropeptides are transduced to other brain nuclei that function as co-regulators of energy homeostasis and that share reciprocal connections with the ARH. However, while the ARH is intensively studied, a complete understanding of its afferents and efferents remain poorly understood. The aim of Chapter 3 was to comprehensively identify and map the direct inputs to the ARH using bilateral targeting of the nucleus with neuronal tract-tracers. By using a combinatorial approach-rigorous plane-of-section analysis with a defined anatomical mapping method-the detailed maps presented in chapters 1 and 3 of this Dissertation, to our knowledge, have the greatest spatial-resolution and are the most comprehensive sets of maps available of Fos activity in the refed rat brain (chapter 1) and of forebrain innervation to the ARH (chapter 3). This study lays the foundational groundwork necessary for eventually elucidating the networks that are awry in metabolic diseases.

Language

en

Provenance

Received from ProQuest

File Size

190 pages

File Format

application/pdf

Rights Holder

Anais Martinez

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