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; 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（由申请人提供）：重度抑郁症（MDD）的特征是海马较小和颗粒神经元（GNS）较少。相反，用选择性5-羟色胺再摄取抑制剂治疗的MDD受试者（MDD*SSRI）具有GNS和神经元祖细胞（NPC）和正常齿状回（DG）体积的对照水平。我们假设DG细胞在MDD中的成熟和存活不足，SSRI逆转，可能是通过对羟色胺受体（HTRS）调节的细胞内级联反转的作用。腹侧DG调节情绪处理，其血清素能预测比人和小鼠的背侧DG更高。前DG的HTR1A mRNA密度与有丝分裂和成熟GN数的人相关，对于小鼠神经发生作用是必要的。我们假设：（1）人类前DG与HTR2A和HTR4 mRNA密度相关的NPC，有丝分裂细胞，未成熟的神经细胞，成熟的GN和神经细胞树突； （2）GN，神经母细胞和神经母细胞树突植物与表达分子促进分子（MTOR）（MTOR），细胞成熟/树突发展（CREB）的细胞相关通过凋亡或炎症促进细胞死亡（CASPASE3）； （3）SSRI对HTR1A，HTR4和HTR2A的腹侧海马特异性缺失的小鼠中SSRI对神经发生和行为的影响； （4）HTR对GN活性的影响足以增加神经发生并在小鼠中产生抗抑郁样作用。我们的方法结合了人类和小鼠研究，以测试HRTS对控制成熟和存活的细胞内分子作用的机制。在匹配的未处理的MDD，MDD*SSRI和对照组中，我们将确定HTR1A，HTR2A和HTR4 mRNA（NCI /MG）密度，并将其与NPC的数量，未成熟的神经细胞，成熟的GN和成熟的GNS和Neuroblast Dendendrite长度相关。我们将评估表达促进标记的细胞数量（MTOR，CREB，BCL2，PARP）或预防（PARP，CASPASE3）细胞成熟和/或存活。我们将将它们的表达与人类和小鼠抑郁模型中的成熟GN和神经细胞数，树突长度和HTR mRNA密度相关联。 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).在野生型，HTR KOS和DREADD小鼠中，我们将量化有丝分裂细胞，NPC，神经细胞，GNS，神经细胞树突长度，对人类对慢性不可预测的应激的行为反应的细胞内级联反应和氟西汀的慢性治疗。结果应告知抑郁症的发病机理，并导致针对相关HTRS或下游效应子的新疗法。