Adult hippocampal neuroplasticity and depression

成人海马神经可塑性与抑郁

• 批准号: 9056561
• 负责人: Maura Boldrini
• 金额: $ 66.97万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-09 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9056561
• 关键词: Adult; Affect; Age; Anterior; Antidepressive Agents; Apoptosis; Autopsy; BCL2 gene; Behavior; Blood; Brain; CREB1 gene; Cell Count; Cell Cycle Progression; Cell Death; Cell Maturation; Cell Proliferation; Cell Survival; Cells; Chronic; Chronic stress; Clinical; Computer software; Controlled Study; Cultured Tumor Cells; Cytoplasmic Granules; DNA Repair; Data; Dendrites; Development; Dorsal; Emotional; Emotions; Engineering; Etiology; FRAP1 gene; Fluoxetine; Funding; Genes; Genetic Polymorphism; HTR2A gene; Health; Hilar; Hippocampus (Brain); Homologous Gene; Human; Inflammation; Knock-out; Lead; Length; Major Depressive Disorder; Matched Group; Measures; Mediating; Mental Depression; Messenger RNA; Methods; Mitotic; Mus; Neuronal Plasticity; Neurons; PTEN gene; Parahippocampal Gyrus; Pathogenesis; Pathway interactions; Peptide Hydrolases; Phosphoric Monoester Hydrolases; Phosphotransferases; Poly(ADP-ribose) Polymerases; Primates; Process; Proliferating; Proteins; Proto-Oncogenes; Resolution; Rodent; Selective Serotonin Reuptake Inhibitor; Staging; Stress; Suicide; Synaptic plasticity; Testing; Tissues; Toxicology; Western Blotting; behavioral response; burden of illness; clinically relevant; density; dentate gyrus; depression model; designer receptors exclusively activated by designer drugs; disorder control; early onset; immunoreactivity; improved; laser capture microdissection; luminance; migration; mouse model; nerve stem cell; neuroblast; neurogenesis; neuropathology; new therapeutic target; prevent; psychologic; receptor; receptor coupling; response; serotonin receptor; sex; single episode major depressive disorder; targeted treatment; transcription factor

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.

描述(申请人提供)：重度抑郁障碍(MDD)的特点是海马体较小，颗粒神经元(GNS)较少。相比之下，接受选择性5-羟色胺再摄取抑制剂(MDD*SSRI)治疗的MDD患者的GNS和神经前体细胞(NPC)水平得到控制，齿状回(DG)体积也正常。我们假设MDD中DG细胞成熟和存活的缺陷被SSRI逆转，可能是通过作用于受5-羟色胺受体(HTRs)调节的细胞内级联。腹侧DG调节情绪加工，其5-羟色胺能投射高于人和小鼠背侧DG。人类前部DG的HTR1AmRNA密度与有丝分裂和成熟的GN数目相关，是SSRI对小鼠神经发生的作用所必需的。我们假设：(1)神经前体细胞、有丝分裂细胞、未成熟的神经母细胞、成熟的神经节细胞和神经母细胞树突状分支与HTR2A和HTR4的mRNA密度相关；(2)神经节细胞、神经母细胞和神经母细胞树突状分支与表达促进增殖(MTOR)、细胞成熟/树突状发育(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)在腹侧海马区特异缺失HTR1A、HTR4和HTR2A的小鼠中，SSRIs对神经发生和行为的影响发生了改变；(4)HTRs对GN活性的影响足以增加小鼠的神经发生并产生抗抑郁药样作用。我们的方法结合了人类和小鼠的研究，以测试HRT对控制成熟和存活的细胞内分子的作用机制。在匹配的未经治疗的MDD、MDD*SSRI和对照组中，我们将测定HTR1A、HTR2A和HTR4mRNA(NCI/mg)的密度，并将其与DG中的NC数量、未成熟的神经母细胞、成熟的GN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/或存活的标志物的细胞数量。我们将在人类和小鼠抑郁症模型中将它们的表达与成熟的GN和神经母细胞数量、树突长度和HTR mRNA密度相关联。我们产生了在整个或仅在腹侧DG中缺乏HTR1A或HTR4的小鼠，从肺门苔藓细胞和腹侧CA3中缺乏HTR2A的小鼠，以及在GNS或苔藓细胞中表达由特制药物(DREADD)特异性激活的抑制性和兴奋性设计受体的小鼠，这些细胞模仿HTR1A(抑制性)、HTR4和HTR2A(兴奋性)。在野生型、HTR Kos和DREADD小鼠中，我们将量化有丝分裂细胞、神经母细胞、神经母细胞、神经节细胞、神经母细胞树突长度、在人类中研究的细胞内级联、对慢性不可预测压力的行为反应以及氟西汀的慢性治疗。结果应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。