Adult hippocampal neuroplasticity and depression

成人海马神经可塑性与抑郁

基本信息

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
项目类别：
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

项目摘要

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）的特征是海马体较小和颗粒神经元（GN）较少。相比之下，接受选择性血清素再摄取抑制剂 (MDD*SSRI) 治疗的 MDD 受试者的 GN 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 中 DG 细胞的成熟和存活缺陷，可以通过 SSRI 逆转，可能是通过对血清素受体 (HTR) 调节的细胞内级联反应的作用。腹侧 DG 调节情绪处理，在人类和小鼠中，它比背侧 DG 具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 对小鼠神经发生的作用所必需的。我们假设：（1）人前 DG 中的 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枝与 HTR2A 和 HTR4 mRNA 密度相关； (2) GN、神经母细胞和神经母细胞树突树枝化与表达促进增殖分子（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，与分子呈负相关阻止细胞周期进展、迁移和存活 (PTEN) 或通过细胞凋亡或炎症促进细胞死亡 (Caspase3)； (3) 腹侧海马特异性缺失 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) 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。在匹配的未处理 MDD、MDD*SSRI 和对照中，我们将确定 HTR1A、HTR2A 和 HTR4 mRNA (nCi /mg) 密度，并将其与 NPC、未成熟神经母细胞、成熟 GN 和 DG 中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、BCL2、PARP）或阻止（PARP、Caspase3）细胞成熟和/或存活的标记物的细胞数量。我们将在人类和小鼠抑郁模型中将它们的表达与成熟 GN 和神经母细胞数量、树突长度和 HTR mRNA 密度相关联。我们生成了整个或仅腹侧 DG 缺乏 HTR1A 或 HTR4 的小鼠、肺门苔藓细胞和腹侧 CA3 缺乏 HTR2A 的小鼠，以及 GN 或苔藓细胞中表达仅由设计药物激活的抑制性和兴奋性设计受体 (DREADD) 的小鼠，这模拟 HTR1A（抑制性）、HTR4 和 HTR2A（兴奋性）。在野生型、HTR Kos 和 DREADD 小鼠中，我们将量化有丝分裂细胞、NPC、神经母细胞、GN、神经母细胞树突长度、人类研究的细胞内级联、对慢性不可预测压力的行为反应以及氟西汀的长期治疗。结果应揭示抑郁症的发病机制，并导致针对相关 HTR 或下游效应器的新疗法。