Phagocytosis of dying cells, adult neurogenesis and depression

描述（由申请人提供）：成年哺乳动物大脑通过称为“成年神经发生”的过程每天继续产生新的神经元。成人神经发生减少通常与精神抑郁症有关。抗抑郁药物如氟西汀（百忧解）通过维持成人神经发生来调节其有益作用。由于抑郁症影响了大约10%的美国成年人，因此了解导致抑郁症的病理过程并找到新的治疗方法非常重要。在每天产生的数千个新神经元中，只有一小部分新分化的神经元存活并成熟，其余的神经元死亡，随后被小胶质细胞（其他人的工作）和神经元祖细胞（我们的新观察）去除。然而，人们对死亡神经元的清除如何影响持续的神经发生及其与抑郁症的可能相关性知之甚少。该应用程序的目标是更好地了解抑郁症背景下死亡神经元的清除。我们提出了三个与这项建议有关的新的意见。首先，新分化的（DCX+）神经元本身表现出吞噬活性，并且在初步研究中，抑郁症小鼠显示出DCX+细胞的吞噬能力降低;其次，在体内死亡神经元的清除的破坏，无论是遗传的（通过敲除参与吞噬的基因）还是生物学的，都导致凋亡核在神经原性小生境中的积累，并损害神经发生。第三，我们注意到一个强大的抑制吞噬皮质酮，这是升高与抑郁症;相反，抗抑郁药氟西汀增强吞噬死亡细胞的DCX+细胞和小胶质细胞。在这个建议中，我们测试的假设，减少抑郁症中观察到的神经发生的结果，部分从受损的吞噬活性的神经原性龛吞噬细胞（DCX+细胞和小胶质细胞），和由此产生的积累的凋亡细胞产生负面影响的成年神经发生。我们将通过以下具体目标来验证这一假设：（1）确定神经原性小生境吞噬细胞的吞噬活性受损是否是抑郁症神经发生受损的基础;（2）测试抗抑郁药物是否通过增强吞噬活性来介导其作用，至少部分是通过增强吞噬活性来介导的;（3）解决体内促进吞噬活性是否可以缓解抑郁症症状。我们将在体内、离体和体外模型的背景下使用遗传、药理学和生化方法的组合。总的来说，我们相信这些研究将有助于对成年神经发生中神经祖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有新的认识。我们的研究还可能指出抑郁症的潜在新治疗方法，即增强神经源性小生境吞噬细胞的吞噬功能。

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.