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（GNs）较少。相比之下，使用选择性5 -羟色胺再摄取抑制剂（MDD*SSRI）治疗的MDD受试者的GNs和神经元祖细胞（npc）水平得到控制，齿状回（DG）体积正常。我们假设MDD患者的DG细胞成熟和存活缺陷被SSRI逆转，可能通过5 -羟色胺受体（hts）调节的细胞内级联作用。在人类和小鼠中，腹侧DG调节情绪处理，它比背侧DG有更高的血清素能投射。人类前DG中的HTR1A 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。我们推测：(1)人前DG的npc、有丝分裂细胞、未成熟神经母细胞、成熟神经母细胞和神经母细胞树突树突化与HTR2A和HTR4 mRNA密度相关；(2) GNs、成神经细胞和成神经细胞树突树突化与细胞表达促进增殖（mTOR）、细胞成熟/树突发育（CREB）、细胞存活（BCL2）、DNA修复和突触可塑性（PARP）的分子相关，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（Caspase3）的分子负相关；(3)在海马腹侧特异性缺失HTR1A、HTR4和HTR2A的小鼠中，SSRIs对神经发生和行为的影响发生改变；(4) HTRs对小鼠GN活性的影响足以促进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研究来测试hrt对细胞内分子控制成熟和存活的作用机制。在匹配的未治疗MDD、MDD*SSRI和对照组中，我们将测定HTR1A、HTR2A和HTR4 mRNA （nCi /mg）密度，并将其与DG中npc数量、未成熟神经母细胞数量、成熟神经母细胞数量和神经母细胞树突长度相关联。我们将评估表达促进（mTOR， CREB, BCL2， PARP）或阻止（PARP, Caspase3）细胞成熟和/或存活标记的细胞数量。我们将在人类和小鼠抑郁模型中，将它们的表达与成熟GN和神经母细胞数量、树突长度和HTR mRNA密度联系起来。我们在整个或仅腹侧DG中产生缺乏HTR1A或HTR4的小鼠，从门侧苔藓细胞和腹侧CA3中产生缺乏HTR2A的小鼠，以及在GNs或苔藓细胞中表达由设计药物独占激活的抑制性和兴奋性设计受体（DREADD）的小鼠，其模拟HTR1A（抑制性），HTR4和HTR2A（兴奋性）。在野生型、HTR Kos和DREADD小鼠中，我们将量化人类研究的有丝分裂细胞、NPCs、神经母细胞、GNs、神经母细胞树突长度、细胞内级联、对慢性不可预测应激的行为反应和氟西汀慢性治疗。研究结果将为抑郁症的发病机制提供信息，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.