Phagocytosis of dying cells, adult neurogenesis and depression

描述（由申请人提供）：成年哺乳动物的大脑通过称为“成人神经发生”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其有益效果。由于抑郁症影响了大约10%的美国成年人，了解导致抑郁症的病理过程和寻找新的治疗方法是很重要的。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，其余的都死亡，随后被小胶质细胞（由其他人工作）和神经元祖细胞（我们的新观察）移除。然而，对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关联，人们知之甚少。这个应用程序的目的是为了更好地理解在抑郁症的背景下死亡神经元的清除。我们提出了与这一建议有关的三个新的意见。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，抑郁症小鼠的DCX+细胞的吞噬能力下降；其次，体内对死亡神经元清除的破坏，无论是遗传上（通过敲除参与吞噬的基因）还是药理学上，都会导致神经源性壁龛中凋亡核的积累，并损害神经发生。第三，我们注意到皮质酮对吞噬有很强的抑制作用，这种抑制作用随着抑郁症而升高；相反，抗抑郁药物氟西汀可以增强DCX+细胞和小胶质细胞对死亡细胞的吞噬作用。在本研究中，我们验证了一种假设，即抑郁症中观察到的神经发生减少部分是由于神经源性小生境吞噬细胞（DCX+细胞和小胶质细胞）的吞噬活性受损，以及由此产生的凋亡细胞的积累对成人神经发生产生负面影响。我们将通过以下具体目标来验证这一假设：(1)确定抑郁症中神经源性小生境吞噬细胞的吞噬活性受损是否为神经发生受损的基础；(2)检验抗抑郁药物是否至少部分通过增强吞噬活性来调节其作用；(3)探讨促进体内吞噬活性是否可以缓解抑郁症的症状。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人神经发生中神经祖细胞和小胶质细胞的吞噬细胞清除及其与抑郁症的关系提供新的见解。我们的研究也可能指出潜在的治疗抑郁症的新方法，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. 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.