Ghrelin's Role in Mood

描述（由申请人提供）：Ghrelin是一种具有多种作用的激素，其中研究最多的是对体重的影响。我们最近的工作也证明了胃饥饿素的抗抑郁行为作用。因此，胃饥饿素水平的上升不仅与饥饿和禁食有关，从而导致食物摄入的刺激和能量储存的保存，而且还与慢性压力有关。压力升高似乎使通常与压力相关的抑郁样行为最小化，因为向野生型小鼠急性外周输注胃饥饿素可诱导抗抑郁样行为，并且缺乏胃饥饿素受体（生长激素促分泌受体；GHSR）的小鼠比野生型小鼠表现出更多的抑郁样行为。胃饥饿素的升高也介导了长时间热量限制的抗抑郁作用。这些生长素效应可能是通过与GHSR在一个或多个中枢神经系统部位的受体相互作用而发生的，这些中枢神经系统部位包括GHSR明确的、离散的表达模式。例如，GHSRs在多巴胺能腹侧被盖区（VTA）神经元中表达，该神经元与大脑奖励回路有关，并且在啮齿动物抑郁测量的发展中也起着必不可少的作用。GHSRs也在海马体中高度表达，海马体是另一个对情绪和抗抑郁疗效有良好影响的部位。在当前的应用中，我们提供了旨在进一步探索ghrelin在促进抗抑郁样行为中的作用的研究。我们将研究慢性胃饥饿素给药和药物阻断胃饥饿素对雄性和雌性小鼠这些行为的影响。我们将采用独特的基因操纵小鼠模型，其中GHSR表达可以选择性地靶向或从多巴胺能VTA神经元或海马神经元中删除，以及中枢神经系统特异性胃饥饿素显微注射研究，以确定VTA和海马在胃饥饿素抗抑郁作用中的作用。最后，我们将通过研究脑源性核因子（BDNF）信号级联在VTA和海马回路中的作用，进一步探讨胃饥饿素抗抑郁作用的机制。我们希望这些研究将揭示涉及情绪障碍发展的新途径，包括与已知胃饥饿素生理紊乱密切相关的抑郁症。

DESCRIPTION (provided by applicant): Ghrelin is a hormone with diverse actions, the most studied of which are its effects on body weight. Our recent work also demonstrates antidepressant-like behavioral effects of ghrelin. As such, ghrelin levels rise not only in association with hunger and fasting, thus leading to stimulation of food intake and conservation of energy stores, but also upon chronic stress. These elevations with stress seem to minimize the depression-like behaviors normally associated with stress, as acute peripheral infusions of ghrelin into wild-type mice induce antidepressant-like behaviors, and as mice lacking ghrelin receptors (growth hormone secretagogue receptor; GHSR) demonstrate even more depression-like behaviors than wild-type mice. Ghrelin rises also mediate the antidepressant-like effects of prolonged caloric restriction. These ghrelin effects presumably occur via interaction with its receptors in one or more of the CNS sites comprising GHSR's well-defined, discrete pattern of expression. For instance, GHSRs are expressed within dopaminergic ventral tegmental area (VTA) neurons that are involved in brain reward circuits and that also play an obligatory role in the development of rodent measures of depression. GHSRs also are highly expressed within the hippocampus, another site with well established effects on mood and antidepressant efficacy. In the current application, we provide studies designed to further explore ghrelin's actions in promoting antidepressant-like behaviors. We will investigate the effects of chronic ghrelin administration and pharmacologic blockade of ghrelin action on these behaviors in both male and female mice. We will employ unique genetically-manipulated mouse models in which GHSR expression can be site-selectively targeted to or deleted from dopaminergic VTA neurons or hippocampal neurons as well as CNS site-specific ghrelin microinjection studies to determine the role of the VTA and hippocampus in ghrelin's antidepressant effects. Finally, we will further explore the mechanism of ghrelin's antidepressant actions by examining the role of brain derived nuclear factor (BDNF) signaling cascades within both VTA and hippocampal circuits. We hope that these studies will uncover new pathways involved in the development of mood disorders, including the depression so closely linked to conditions with known perturbations of ghrelin physiology. PUBLIC HEALTH RELEVANCE: The experiments proposed in this study have been designed to investigate the role ghrelin plays in mood and the responses to chronic stress. It is hoped that these studies will uncover new pathways involved in the development of depression and will result in new therapies to treat mood disorders, and particularly the depression so closely linked to chronic stress and conditions with known perturbations of ghrelin physiology.