Phagocytosis of dying cells, adult neurogenesis and depression

描述(申请人提供)：成年哺乳动物的大脑每天通过一种称为“成年神经发生”的过程继续产生新的神经元。成人神经发生减少通常与精神抑郁有关。抗抑郁药物，如氟西汀(百忧解)，部分通过维持成人神经发生来调节它们的有益效果。由于抑郁症影响了大约10%的美国成年人口，了解导致抑郁的病理过程并找到新的治疗方法是重要的。在每天产生的数以千计的新神经元中，只有一小部分新分化的神经元存活并成熟，其余的死亡，随后被小胶质细胞(其他人的研究)和神经前体细胞(我们的新观察)移除。然而，关于死亡神经元的清除如何影响持续的神经发生，以及它与抑郁症的可能相关性，人们知之甚少。这个应用程序的目标是更好地理解抑郁症背景下死亡神经元的清除。我们提出了三个与这一提议相关的新观察结果。首先，新分化的(DCX+)神经元本身表现出吞噬活性，在初步研究中，抑郁症小鼠表现出DCX+细胞的吞噬能力降低；第二，体内死亡神经元的清除受到干扰，无论是遗传上的(通过敲除吞噬相关基因)还是药物上的导致神经源性壁龛中细胞凋亡的核积累，并损害神经发生。第三，我们注意到皮质酮对吞噬的强烈抑制，这种抑制随着抑郁而增加；相反，抗抑郁药物氟西汀增强了DCX+细胞和小胶质细胞对死亡细胞的吞噬作用。在这项建议中，我们检验了一种假设，即抑郁症中观察到的神经发生减少的部分原因是神经源性利基吞噬细胞(DCX+细胞和小胶质细胞)的吞噬活性受损，由此导致的凋亡细胞的积累对成人的神经发生产生了负面影响。我们将通过以下具体目标来验证这一假说：(1)确定神经源性利基吞噬细胞的吞噬活性受损是否是抑郁症神经发生受损的原因；(2)测试抗抑郁药物是否至少部分通过增强吞噬活性来调节其效果；以及(3)解决体内促进吞噬细胞活性是否可以缓解抑郁症症状。我们将在体内、体外和体外模型的背景下使用遗传学、药理学和生化方法的组合。总而言之，我们相信这些研究将有助于对成人神经发生中神经前体细胞和小胶质细胞的吞噬细胞清除以及这与抑郁症的关系的新见解。我们的研究还可能指出潜在的治疗抑郁症的新方法，即增强神经源性壁龛吞噬细胞的吞噬功能。 公共卫生相关性：抑郁性精神障碍影响了大约1880万美国成年人，约占美国18岁及以上人口的10%。在这项提议中，我们测试了一个新的概念，即死亡神经元的吞噬作用会影响成年大脑中的神经发生，进而影响抑郁症。由于神经发生与抑郁症直接相关，我们相信了解大脑中死亡神经元的清除将为精神抑郁的病理提供新的见解。我们的研究也可能为广泛使用的抗抑郁药物百忧解提供新的机制见解，并可能指向其他未来的治疗方法。

DESCRIPTION (provided by applicant): Adult mammalian brain continues to generate new neurons on a daily basis by a process termed "adult neurogenesis". Reduced adult neurogenesis is commonly associated with mental depression. Anti-depressant drugs such as fluoxetine (Prozac) mediate their beneficial effects, in part, through maintenance of adult neurogenesis. Since depressive disorders affect about 10% of the adult U.S. population, understanding the pathological processes leading to depression and finding new therapeutic approaches are important. Among the thousands of new neurons that arise daily, only a small fraction of newly differentiated neurons survive and mature The rest die and are subsequently removed by microglial cells (work by others) and neuronal progenitor cells (our new observations). However, relatively little is known about how the clearance of dying neurons impacts the continued neurogenesis, and its possible relevance to depression. The goal of this application is to better understand the clearance of dead neurons in the context of depression. We have made three novel observations that are relevant for this proposal. First, the newly differentiated (DCX+) neurons themselves exhibit phagocytic activity, and in preliminary studies mice with depression show decreased phagocytic ability of DCX+ cells; second, disruption of the clearance of dying neurons in vivo, either genetically (via knockout of genes involved in engulfment) or pharmacologically leads to accumulation of apoptotic nuclei in the neurogenic niches, and impaired neurogenesis. Third, we note a strong inhibition of engulfment by corticosterone, which is elevated with depression; conversely, the antidepressant drug fluoxetine enhances phagocytosis of dying cells by both DCX+ cells and microglia. In this proposal we test the hypothesis that reduced neurogenesis observed in depression results in part from impaired phagocytic activity of neurogenic niche phagocytes (DCX+ cells and microglia), and the resultant accumulation of apoptotic cells negatively impacts the adult neurogenesis. We will test this hypothesis through the following specific aims: (1) Establish whether impaired phagocytic activity of neurogenic niche phagocytes underlies impaired neurogenesis in depression; (2) Test whether the antidepressant drugs mediate their effect, at least in part, through boosting phagocytic activity; and (3) Address whether promoting phagocytic activity in vivo could alleviate symptoms of depression. We will use a combination of genetic, pharmacological, and biochemical approaches in the context of in vivo, ex vivo and in vitro models. Collectively, we believe these studies would contribute to new insights on phagocytic cell clearance by neural progenitor cells and microglia in adult neurogenesis and how this relates to depression. Our studies might also point to potentially new therapeutic approaches for depression, i.e. enhancing the phagocytic function of neurogenic niche phagocytes. PUBLIC HEALTH RELEVANCE: Depressive mental disorders affect approximately 18.8 million American adults or about 10% of the U.S. population age 18 and older. In this proposal, we test a new concept that phagocytosis of dying neurons influences neurogenesis in the adult brain, and, in turn, depression. Since neurogenesis is directly linked to depression, we believe understanding the clearance of dying neurons in the brain would provide new insights on the pathology of mental depression. Our studies may also provide new mechanistic insights on the widely used antidepressant drug Prozac, and could possibly point to other future therapies.