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.
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.
|Billings, Emily A; Lee, Chang Sup; Owen, Katherine A et al. (2016) The adhesion GPCR BAI1 mediates macrophage ROS production and microbicidal activity against Gram-negative bacteria. Sci Signal 9:ra14|
|Penberthy, Kristen K; Ravichandran, Kodi S (2016) Apoptotic cell recognition receptors and scavenger receptors. Immunol Rev 269:44-59|
|Lee, Chang Sup; Penberthy, Kristen K; Wheeler, Karen M et al. (2016) Boosting Apoptotic Cell Clearance by Colonic Epithelial Cells Attenuates Inflammation In Vivo. Immunity 44:807-20|
|Medina, C B; Ravichandran, K S (2016) Do not let death do us part: 'find-me' signals in communication between dying cells and the phagocytes. Cell Death Differ 23:979-89|
|Arandjelovic, Sanja; Ravichandran, Kodi S (2015) Phagocytosis of apoptotic cells in homeostasis. Nat Immunol 16:907-17|
|Hochreiter-Hufford, Amelia E; Arandjelovic, Sanja; Ravichandran, Kodi S (2015) Using phosphatidylserine exposure on apoptotic cells to stimulate myoblast fusion. Methods Mol Biol 1313:141-8|
|Sullivan, Chelsea S; Scheib, Jami L; Ma, Zhong et al. (2014) The adaptor protein GULP promotes Jedi-1-mediated phagocytosis through a clathrin-dependent mechanism. Mol Biol Cell 25:1925-36|
|Poon, Ivan K H; Lucas, Christopher D; Rossi, Adriano G et al. (2014) Apoptotic cell clearance: basic biology and therapeutic potential. Nat Rev Immunol 14:166-80|
|Arandjelovic, Sanja; Ravichandran, Kodi S (2013) A MERry response after myocardial infarction. Circ Res 113:949-51|
|Smirnov, Igor; Walsh, James T; Kipnis, Jonathan (2013) Chronic mild stress eliminates the neuroprotective effect of Copaxone after CNS injury. Brain Behav Immun 31:177-82|