Adult hippocampal neuroplasticity and depression

描述（由申请人提供）：重度抑郁症（MDD）的特征是海马较小，颗粒神经元（GN）较少。相比之下，用选择性5-羟色胺再摄取抑制剂（MDD*SSRI）治疗的MDD受试者具有控制水平的GN和神经元祖细胞（NPC）以及正常的齿状回（DG）体积。我们假设缺陷的成熟和生存的DG细胞在MDD中，逆转SSRI，可能通过对细胞内级联调节的5-羟色胺受体（HTRs）的行动。腹侧DG调节情绪处理，在人类和小鼠中，腹侧DG比背侧DG具有更高的多巴胺能投射。在人类中，前DG中的HTR 1A mRNA密度与有丝分裂和成熟GN数量相关，并且是SSRI对小鼠神经发生作用所必需的。我们假设：（1）人前DG的NPC、有丝分裂细胞、未成熟神经母细胞、成熟GN和神经母细胞树突分支与HTR 2A和HTR 4 mRNA密度相关;（2）GN、神经母细胞和神经母细胞树突分支与表达促进增殖分子（mTOR）、细胞成熟/树突发育（CREB）、细胞存活（BCL 2）、DNA修复和突触可塑性（PARP）的细胞相关，并且与阻止细胞周期进展、迁移和存活（PTEN）或通过凋亡或炎症促进细胞死亡的分子负相关（3）SSRIs对腹侧海马特异性HTR 1A、HTR 4和HTR 2A缺失小鼠神经发生和行为的影响;（4）HTR对GN活性的影响足以增加小鼠的神经发生并产生抗抑郁样作用。我们的方法结合了人类和小鼠的研究来测试HRT对控制成熟和存活的细胞内分子的作用机制。在匹配的未治疗MDD、MDD*SSRI和对照中，我们将测定HTR 1A、HTR 2A和HTR 4 mRNA（nCi /mg）密度，并将其与DG中NPC、未成熟神经母细胞、成熟GN和神经母细胞树突长度的数量相关联。我们将评估表达促进（mTOR、CREB、BCL 2、PARP）或阻止（PARP、Caspase 3）细胞成熟和/或存活的标志物的细胞数量。我们将在人类和小鼠抑郁模型中将它们的表达与成熟GN和成神经细胞数量、树突长度和HTR mRNA密度相关联。我们产生了在整个或仅腹侧DG中缺乏HTR 1A或HTR 4的小鼠，来自门苔藓细胞和腹侧CA 3的缺乏HTR 2A的小鼠，以及在GN或苔藓细胞中表达抑制性和兴奋性设计者受体的小鼠，其模拟HTR 1A（抑制性），HTR 4和HTR 2A（兴奋性）。在野生型、HTR科斯和DREADD小鼠中，我们将定量有丝分裂细胞、NPC、成神经细胞、GN、成神经细胞树突长度、在人体中研究的细胞内级联、对慢性不可预测的应激和氟西汀长期治疗的行为反应。研究结果应该告知抑郁症的发病机制，并导致针对相关HTR或下游效应物的新疗法。

DESCRIPTION (provided by applicant): Major Depressive Disorder (MDD) is characterized by smaller hippocampus and fewer granule neurons (GNs). In contrast, MDD subjects treated with selective serotonin reuptake inhibitors (MDD*SSRI) have control levels of GNs and neuronal progenitor cells (NPCs) and normal dentate gyrus (DG) volume. We hypothesize a deficit of maturation and survival of DG cells in MDD, reversed by SSRI, possibly through action on intracellular cascades regulated by serotonin receptors (HTRs). The ventral DG regulates emotional processing, it has higher serotonergic projections than the dorsal DG in humans and mice. HTR1A mRNA density in anterior DG correlates in humans with mitotic and mature GN number and is necessary for SSRI action on neurogenesis in mice. We hypothesize: (1) NPCs, mitotic cells, immature neuroblasts, mature GNs and neuroblast dendrite arborization in human anterior DG correlate with HTR2A and HTR4 mRNA density; (2) GNs, neuroblasts and neuroblast dendrite arborization correlate with cells expressing molecules promoting proliferation (mTOR), cell maturation/dendritic development (CREB), cell survival (BCL2), DNA repair and synaptic plasticity (PARP), and inversely correlate with molecules preventing cell cycle progression, migration, and survival (PTEN) or promoting cell death via apoptosis or inflammation (Caspase3); (3) The effects of SSRIs on neurogenesis and behavior are altered in mice with ventral hippocampus-specific deletions of HTR1A, HTR4 and HTR2A; (4) The effects of HTRs on GN activity are sufficient to increase neurogenesis and produce antidepressant-like effects in mice. Our approach combines human and mouse studies to test mechanisms of HRTs action on intracellular molecules controlling maturation and survival. In matched untreated MDD, MDD*SSRI, and controls, we will determine HTR1A, HTR2A, and HTR4 mRNA (nCi /mg) density and will correlate that with number of NPCs, immature neuroblasts, mature GNs and neuroblast dendrite length in the DG. We will assess numbers of cells expressing markers promoting (mTOR, CREB, BCL2, PARP) or preventing (PARP, Caspase3) cell maturation and/or survival. We will correlate their expression with mature GN and neuroblast number, dendrite length and HTR mRNA densities in human and in a mice depression model. We generated mice lacking HTR1A or HTR4 in whole or just ventral DG, mice lacking HTR2A from hilar mossy cells and ventral CA3, as well as mice expressing inhibitory and excitatory Designer Receptors Exclusively Activated by Designer Drugs (DREADD) in GNs or mossy cells, which mimic HTR1A (inhibitory), HTR4 and HTR2A (excitatory). In wild type, HTR Kos and DREADD mice, we will quantify mitotic cells, NPCs, neuroblasts, GNs, neuroblast dendrite length, intracellular cascades studied in human, behavioral responses to chronic unpredictable stress and chronic treatment with fluoxetine. Results should inform the pathogenesis of depression and lead to new therapies that target relevant HTRs or downstream effectors.