Ghrelin and Reward

描述（由申请人提供）：Ghrelin是一种具有多种作用的激素，研究最多的是其对体重稳态的影响。例如，饥饿素水平上升与饥饿和禁食有关。此外，胃饥饿素刺激食物摄入，减少能量消耗，并在高浓度时引起肥胖。Ghrelin的作用是通过其受体——生长激素促分泌受体（GHSR； Ghrelin受体）的相互作用来调节的，Ghrelin受体在大脑中有一个明确的、离散的表达模式。这包括大脑腹侧被盖区（VTA）中含有多巴胺的神经元的高度表达。由于这些多巴胺能VTA神经元参与大脑奖励回路，例如与成瘾相关的回路，因此已被高度研究。目前的应用提供了一系列的研究，旨在增加我们对胃饥饿素在促进寻求奖励行为中的参与以及VTA在胃饥饿素作用中的作用的理解。特别是，胃饥饿素在旨在获得食物奖励和可卡因的动机行为中所起的作用将被调查。为了实现这一目标，将使用独特的小鼠模型，其中饥饿素受体的表达被删除或饥饿素受体的功能被特定拮抗剂阻断。我们将对这些小鼠进行一系列试验，以确定基因和药物阻断饥饿素信号通路对食物增强和可卡因增强的寻求奖励行为的影响。此外，一个独特的小鼠模型中，胃饥饿素受体的表达可以选择性地靶向多巴胺能VTA神经元，以研究胃饥饿素参与这些特定神经元的充分性，其对奖励行为和体重的作用。这种选择性靶向将涉及最先进的神经解剖学和转基因技术。人们希望这些研究能带来新的靶向疗法，以治疗某些形式的肥胖（如Prader-Willi综合征）所特有的无情的觅食行为，以及其他不适应的奖励行为，如与成瘾相关的行为。本研究提出的实验旨在调查胃饥饿素在获得食物奖励和成瘾药物（如可卡因）的动机行为中所起的作用。人们希望这些研究最终能带来新的靶向疗法，以治疗某些形式的肥胖（如Prader-Willi综合征）所特有的持续寻找食物的行为，以及其他不适应的奖励行为，如与成瘾相关的行为。

DESCRIPTION (provided by applicant): 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.