Ghrelin Regulates Food Intake in the Ventral Tegmental Area During Chronic Psychosocial Stress

Ghrelin is a stomach derived hormone that promotes food intake through binding to the growth hormone secretagogue receptor (GHSR).The GHSR is expressed throughout the brain, including in the hypothalamus where it responds homeostatic signals and throughout the reward system where it modulates food seeking behavior.Notably, ghrelin is also involved in the regulation of feeding behaviors in the face of chronic stress, as prolonged stress exposure induces a metabolic challenge, to which ghrelin promotes caloric intake to sustain increased energetic demands.One GHSR-expressing region that has also been implicated in the stress response is the ventral tegmental area (VTA), a principal component of the reward system.Previous research illustrates that the GHSR plays a critical role in regulating the metabolic and behavioral outcomes associated with chronic stress, little is known about how GHSR activity in the VTA contributes to such outcomes.The aim of this thesis was to investigate how the ghrelin system within the VTA modulates feeding behavior in response to chronic social defeat stress in mice.Additionally, we sought to determine how ghrelin regulates these aspects of the stress response in female mice, as they have largely been excluded from neuroendocrine research.The data described in the following thesis illustrate that chronic social defeat stress induces changes to the neurovasculature unit that results in an increase in ghrelin movement and activation within the VTA, ultimately leading to increased food intake.Within the VTA ghrelin regulates metabolic outcomes through signaling of the GHSR, as we demonstrate that, within this region, the GHSR is required to promote food intake.Female mice exposed to an adapted social defeat paradigm display similarities in ghrelin secretion, food intake but highlight differences in GHSR expression, compared to males and previous findings.In sum, the results presented in this thesis provide evidence that chronic stressors alter sensitivity to ghrelin, an effect that is mediated through the GHSR within the VTA, ultimately leading to increased caloric intake. List of FiguresChapter 2, Figure 2.1 …………………………………………………………………………………………………… Chapter 2, Figure 2.2 …………………………………………………………………………………………………… Chapter 2, Figure 2.3 …………………………………………………………………………………………………… Chapter 2, Figure 2.4 …………………………………………………………………………………………………… Chapter 2, Figure 2.5 …………………………………………………………………………………………………… Chapter 3, Figure 3.1 …………………………………………………………………………………………………… Chapter 3, Figure 3.2 …………………………………………………………………………………………………… Chapter 3, Figure 3.3 …………………………………………………………………………………………………… Chapter 4, Figure 4.1 …………………………………………………………………………………………………… Chapter 4, Figure 4.2 …………………………………………………………………………………………………… Chapter 4, Figure 4.3 …………………………………………………………………………………………………… Chapter 4, Figure 4.4 …………………………………………………………………………………………………… Chapter 3, Supplemental Figure 6.1 ……………………………………………………………………………….Chapter 4, Supplemental Figure 6.2 ……………………………………………………………………………….Chapter 4, Supplemental Figure 6.3 ……………………………………………………………………………….Chapter 4, Supplemental Figure 6.4 ……………………………………………………………………………….x List of Tables Chapter 3, SupplementalTable 6.1 ……………………………………………………………………………….98 Chapter 1 Ghrelin as a critical mediator of food intake and the response to chronic stress This chapter includes modified content from:

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