Date of Award

8-7-2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience Institute

First Advisor

Dr. Aaron Roseberry

Second Advisor

Dr. Vincent Rehder

Third Advisor

Dr. Charles Derby

Fourth Advisor

Dr. Shane Hentges

Abstract

The prevalence of obesity has doubled worldwide since the 1980s, and having a high body mass index contributes to more deaths worldwide than being underweight. Over the past 20 years, consumption of calorie-dense foods has increased, and this is considered one of the major causes of the rapid rise in obesity. Thus, understanding the neural control of food intake is important for the development of new and effective treatments of obesity. Two important brain regions that regulate food intake are the hypothalamus and the mesocorticolimbic dopamine system. The hypothalamus is essential for the homeostatic control of feeding and body weight, while the mesocorticolimbic dopamine system, also known as the reward system, is the primary circuit for reward and motivated behavior. The reward system also regulates food intake and food reward, and there is increasing evidence that hypothalamic feeding-related neuropeptides alter dopamine neuron activity to affect feeding. Nevertheless, how these neuropeptides interact with the reward system to regulate feeding is not fully understood. For example, centrally delivered neurotensin and neuropeptide-Y (NPY) increase dopamine release in the nucleus accumbens, but cause opposite effects on food reward. In addition, injection of the hypothalamic neuropeptides neurotensin, NPY, or alpha-melanocyte-stimulating hormone (a-MSH) into the ventral tegmental area (VTA), where reward-related dopamine neurons are located, alters multiple aspects of feeding, but how these neuropeptides interact with the reward system to alter feeding at both the circuit and cellular levels is not fully understood. In these studies, I have used whole cell patch-clamp electrophysiology in acute brain slices from mice to examine how neurotensin, a-MSH, and NPY affect VTA dopamine neuron activity. I have demonstrated that these neuropeptides use multiple mechanisms to alter VTA dopamine neuron activity, including both pre- and post-synaptic mechanisms. Neurotensin and a-MSH increased dopamine neuron activity, while NPY had both excitatory and inhibitory effects on dopamine neuron activity. Overall, these studies provide an important advancement in our understanding of the different mechanisms utilized by hypothalamic neuropeptides to alter VTA dopamine neuron activity and how hypothalamic neuropeptides interact with the mesocorticolimbic dopamine system to control food intake and food reward.

Available for download on Monday, July 08, 2019

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