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，其中研究最多的是其对体重的影响。我们最近的工作也证明了ghrelin的抗抑郁样行为作用。因此，生长激素释放肽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。这些压力的升高似乎使通常与压力相关的抑郁样行为最小化，因为急性外周输注生长激素释放肽到野生型小鼠中诱导抗抑郁样行为，并且缺乏生长激素释放肽受体（生长激素促分泌素受体; GHSR）的小鼠比野生型小鼠表现出更多的抑郁样行为。胃饥饿素的升高还介导了长期热量限制的抗抑郁作用。这些生长激素释放肽的作用可能是通过与其受体在一个或多个中枢神经系统的网站，包括GHSR的明确定义，离散的表达模式的相互作用。例如，GHSR在多巴胺能腹侧被盖区（VTA）神经元内表达，所述神经元参与脑奖励回路，并且还在啮齿动物抑郁症的发展中起强制性作用。GHSR也在海马体中高度表达，海马体是另一个对情绪和抗抑郁功效具有良好影响的部位。在本申请中，我们提供了旨在进一步探索生长激素释放肽在促进抗抑郁样行为中的作用的研究。我们将研究长期给予生长激素释放肽和药物阻断生长激素释放肽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作的小鼠模型，其中GHSR表达可以位点选择性地靶向或删除多巴胺能腹侧被盖区神经元或海马神经元，以及中枢神经系统位点特异性生长激素释放肽显微注射研究，以确定腹侧被盖区和海马在生长激素释放肽的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）信号级联在腹侧被盖区和海马回路中的作用，进一步探讨ghrelin的抗抑郁作用机制。我们希望这些研究将揭示情绪障碍发展的新途径，包括与已知的生长激素释放肽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.