Ghrelin is a hormone with diverse actions, the most studied of which are its effects on body weight homeostasis. For instance, ghrelin levels rise in association with hunger and fasting. Also, ghrelin stimulates food intake, decreases energy expenditure, and induces obesity when present in high concentrations. Ghrelin's actions are mediated by interaction with its receptor, the growth hormone secretagogue receptor (GHSR; ghrelin receptor), which has a well-defined, discrete pattern of expression within the brain. This includes a high degree of expression in dopamine-containing neurons within a part of the brain known as the ventral tegmental area (VTA). These dopaminergic VTA neurons have been highly studied due to their involvement in brain reward circuits, such as those associated with addiction. The current application provides a series of studies designed to increase our understanding of the involvement of ghrelin in promoting reward- seeking behaviors and the role of the VTA in ghrelin action. In particular, the role ghrelin plays in motivated behaviors aimed at obtaining both food rewards and cocaine will be investigated. To accomplish this, unique mouse models in which either expression of the ghrelin receptor has been deleted or the functioning of the ghrelin receptor has been blocked by the administration of a specific antagonist will be used. These mice will be subjected to a battery of tests that will allow us to determine the effect of genetic and pharmacological blockade of ghrelin signaling pathways on food-reinforced and cocaine-reinforced reward-seeking behaviors. Also, a unique mouse model in which ghrelin receptor expression can be selectively targeted to dopaminergic VTA neurons will be used in order to investigate the sufficiency of ghrelin's engagement of these particular neurons for its actions on reward behaviors and body weight. This selective targeting will involve state-of-the- art neuroanatomical and transgenic techniques. It is hoped that these studies will result in new targeted therapies to treat the unrelenting food-seeking behaviors characteristic of certain forms of obesity, such as Prader-Willi Syndrome, as well as other maladaptive reward behaviors, such as those associated with addiction. PUBLIC HEALTH RELVANCE The experiments proposed in this study have been designed to investigate the role ghrelin plays in motivated behaviors aimed at obtaining both food rewards and addictive drugs such as cocaine. It is hoped that these studies will eventually result in new targeted therapies to treat the unrelenting food-seeking behaviors characteristic of certain forms of obesity, such as Prader-Willi Syndrome, as well as other maladaptive reward behaviors, such as those associated with addiction. ? ? ?
| Müller, T D; Nogueiras, R; Andermann, M L et al. (2015) Ghrelin. Mol Metab 4:437-60 |
| Walker, A K; Rivera, P D; Wang, Q et al. (2015) The P7C3 class of neuroprotective compounds exerts antidepressant efficacy in mice by increasing hippocampal neurogenesis. Mol Psychiatry 20:500-8 |
| Wang, Qian; Liu, Chen; Uchida, Aki et al. (2014) Arcuate AgRP neurons mediate orexigenic and glucoregulatory actions of ghrelin. Mol Metab 3:64-72 |
| Frazao, Renata; Dungan Lemko, Heather M; da Silva, Regina P et al. (2014) Estradiol modulates Kiss1 neuronal response to ghrelin. Am J Physiol Endocrinol Metab 306:E606-14 |
| Mason, B L; Wang, Q; Zigman, J M (2014) The central nervous system sites mediating the orexigenic actions of ghrelin. Annu Rev Physiol 76:519-33 |
| Mani, Bharath K; Walker, Angela K; Lopez Soto, Eduardo J et al. (2014) Neuroanatomical characterization of a growth hormone secretagogue receptor-green fluorescent protein reporter mouse. J Comp Neurol 522:3644-66 |
| Frazão, Renata; Cravo, Roberta M; Donato Jr, Jose et al. (2013) Shift in Kiss1 cell activity requires estrogen receptor ?. J Neurosci 33:2807-20 |
| Uchida, Aki; Zigman, Jeffrey M; Perelló, Mario (2013) Ghrelin and eating behavior: evidence and insights from genetically-modified mouse models. Front Neurosci 7:121 |
| Cravo, Roberta M; Frazao, Renata; Perello, Mario et al. (2013) Leptin signaling in Kiss1 neurons arises after pubertal development. PLoS One 8:e58698 |
| Perello, Mario; Scott, Michael M; Sakata, Ichiro et al. (2012) Functional implications of limited leptin receptor and ghrelin receptor coexpression in the brain. J Comp Neurol 520:281-94 |
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