Author ORCID Identifier

https://orcid.org/0000-0003-4838-400X

Date of Award

Spring 5-4-2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Aaron Roseberry

Second Advisor

Deborah Baro

Third Advisor

Daniel N. Cox

Fourth Advisor

Kyle Frantz

Abstract

Over two-thirds of the US population are overweight or obese with obesity’s associated co-morbidities representing 4 out of the 5 leading causes of death. Since the 1970s, a shift in the environment of developed countries has perpetuated overconsumption of calorie-rich foods which is thought to be the primary cause of the obesity epidemic. Thus, understanding neural mechanisms underlying feeding is critical for obesity prevention and treatment. Two of the systems important for feeding regulation are the hypothalamic melanocortin system and the mesocorticolimbic dopamine (DA) system. Increasing evidence indicates that these two systems interact to control feeding but the underlying mechanisms including the main site of their interaction are not understood. Neurons expressing melanocortin-3 receptor in the ventral tegmental area (VTA MC3R neurons) may be a key site for this interaction, as MC3Rs are highly expressed in the VTA, the center of the mesocorticolimbic DA system, and are an important component of the melanocortin system. Hence, I used genetic and viral approaches in mice to characterize the anatomy of VTA MC3R neurons and to determine whether changes in their activity alter feeding and body weight. I found that VTA MC3R neurons were connected to a discrete set of brain areas involved in regulation of feeding, reward, and aversion and received a surprisingly small amount of input from the hypothalamic arcuate nucleus (Arc), the center of melanocortin system. Further examination of Arc-VTA connectivity revealed that hypothalamic proopiomelanocortin (POMC) and agouti-related protein (AgRP) neurons formed few synapses on the different subtypes of VTA neurons, despite strong labeling by general retrograde tracers injected into the VTA. I also found that VTA MC3R neurons control feeding and body weight in an activity- and sex-dependent manner such that acute activation of VTA MC3R neurons decreased feeding, but only in females, and acute inhibition of these neurons decreased feeding, but only in males, whereas chronic activation transiently decreased feeding and body weight in all mice. These studies greatly contribute to our understanding of the anatomical interactions between the melanocortin and mesocorticolimbic systems and indicate that VTA MC3R neurons may be a key point in these interactions.

DOI

https://doi.org/10.57709/17543600

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