Ghrelin's Role in Mood

说明(申请人提供)：Ghrelin是一种具有多种作用的激素，其中研究最多的是它对体重的影响。我们最近的工作也证明了Ghrelin的抗抑郁药样行为作用。因此，Ghrelin水平不仅随着饥饿和禁食而上升，从而导致食物摄入量的刺激和能量储存的节约，而且还会导致长期的压力。随着应激的升高，似乎最大限度地减少了通常与应激相关的抑郁样行为，因为急性外周注射Ghrelin到野生型小鼠中可以诱导抗抑郁样行为，并且由于缺乏Ghrelin受体(生长激素促分泌素受体；GHSR)的小鼠表现出比野生型小鼠更多的抑郁样行为。Ghrelin的升高也介导了长期热量限制所产生的抗抑郁药样效应。这些Ghrelin效应可能是通过与其受体在一个或多个中枢神经系统部位相互作用而发生的，这些受体构成了GHSR明确定义的离散表达模式。例如，GHSR在多巴胺能腹侧被盖区(VTA)神经元中表达，这些神经元参与大脑奖赏回路，并且在啮齿动物抑郁的发展过程中也扮演着必需的角色。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效果有良好影响的部位。在目前的应用中，我们提供了旨在进一步探索Ghrelin在促进抗抑郁药样行为方面的作用的研究。我们将研究长期给予Ghrelin和药物阻断Ghrelin作用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，在该模型中，GHSR的表达可以选择性地定位于多巴胺能VTA神经元或海马神经元或从中删除，以及中枢神经系统特异性Ghrelin微量注射研究，以确定VTA和海马区在Ghrelin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)在VTA和海马回路中的信号级联作用来进一步探讨Ghrelin的抗抑郁作用的机制。我们希望这些研究将发现与情绪障碍发展有关的新途径，包括与已知胃促生长素生理学扰动的条件密切相关的抑郁。 与公共健康相关：这项研究中提出的实验旨在调查Ghrelin在情绪和对慢性压力的反应中所起的作用。人们希望这些研究将发现与抑郁症发展有关的新途径，并将导致治疗情绪障碍的新疗法，特别是与慢性压力和已知Ghrelin生理学扰动的抑郁症密切相关的抑郁症。

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.