Characterization of leptin's antidepressant activity

瘦素抗抑郁活性的表征

• 批准号: 9115232
• 负责人: Xin-Yun Lu
• 金额: $ 19.35万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-25 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9115232
• 关键词: AMPA Receptors; Ablation; Actins; Adipocytes; Affect; Antidepressive Agents; Attenuated; Behavior; Behavioral; Brain region; Chronic; Dendritic Spines; Depressive disorder; Development; Disease; Escitalopram; FRAP1 gene; Fluoxetine; Functional disorder; Funding; Genetic Transcription; Glutamate Receptor; Glutamates; Goals; Health; Hippocampus (Brain); Hormones; Infusion procedures; Lead; Leptin; Limbic System; Major Depressive Disorder; Mediating; Mental Depression; Mental disorders; Messenger RNA; Molecular; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NR1 NMDA receptor; Neurons; Pathogenesis; Patients; Phenotype; Phosphorylation; Physiological; Play; Property; Prosencephalon; Protein Biosynthesis; Recurrence; Research Project Grants; Resistance; Role; Selective Serotonin Reuptake Inhibitor; Serotonergic System; Signal Transduction; Site; Stimulus; Stress; Structure; Symptoms; Synapses; System; Testing; Therapeutic; Vertebral column; depolymerization; depressive behavior; depressive symptoms; inhibitor/antagonist; insight; knock-down; leptin receptor; mTOR inhibition; neuronal circuitry; neurotransmission; novel; novel therapeutic intervention; novel therapeutics; patient subsets; polymerization; postsynaptic; prevent; protein expression; receptor; relating to nervous system; response; social; synaptic depression; trafficking; transmission process

DESCRIPTION (provided by applicant): Depression is a debilitating and recurring psychiatric disorder. Approximately half of the patients with depressive disorder fail to respond to currently available antidepressants. The long-term goal of this project is to understand the pathogenesis of depressive disorders and to develop new therapeutic approaches for this disease. This is a resubmission of the application for competitive renewal of our current funding to study the molecular and cellular mechanisms underlying the antidepressant-like effect of the adipocyte- derived hormone, leptin. We have provided strong evidence that leptin possesses antidepressant-like properties, supporting a new adipostatic hypothesis of depression. Direct infusion of leptin into the hippocampus produces antidepressant-like effects, and ablation of the functional leptin receptor, LepRb, in this brain region induces depressive-like behaviors, suggesting an essential role of LepRb in the hippocampus in mediating leptin action on depressive behaviors. We have made novel observations that ablation of LepRb principally in forebrain glutamatergic neurons (Lepr cKO) leads to depressive-like symptoms and facilitates NMDA-induced synaptic depression in the hippocampus. The antidepressant-like behavioral effects of leptin were abolished in Lepr cKO mice. These mice were resistant to selective serotonin reuptake inhibitor (SSRI) treatments but highly responsive to the glutamate receptor NMDA- NR2B (also termed GluN2B) antagonist. These findings led to the hypothesis that the glutamatergic system mediates leptin action on depressive behaviors. We propose to determine 1) the role of hippocampal glutamate neurotransmission in mediating the antidepressant-like effects of leptin, and 2) the contribution of remodeling of hippocampal dendritic spines, sites of glutamatergic synapses, to the antidepressant-like effects of leptin. These studies will generate novel insights into molecular and cellular mechanisms into leptin action in the limbic system and lead to the development of novel therapies for depression.

描述（由申请人提供）：抑郁症是一种令人衰弱和重复的精神疾病。大约一半的抑郁症患者无法对当前可用的抗抑郁药反应。该项目的长期目标是了解抑郁症的发病机理，并为该疾病开发新的治疗方法。这是对我们当前资金的竞争更新的申请，以研究脂肪细胞激素激素瘦素的抗抑郁样作用的分子和细胞机制。我们提供了有力的证据，表明瘦素具有抗抑郁药样特性，支持新的抑郁症假设。在该大脑区域中，将瘦素直接输注在海马中会产生抗抑郁药样作用，而功能性瘦素受体LEPRB的消融会诱导抑郁样的行为，这表明LEPRB在介导瘦素对抑郁行为的作用中的重要作用。我们已经进行了新的观察，即LEPB的消融主要是前脑谷氨酸能神经元（LEPR CKO）导致抑郁症状症状，并促进NMDA诱导的海马抑郁症。在LEPR CKO小鼠中废除了瘦素的抗抑郁样行为作用。这些小鼠对选择性5-羟色胺再摄取抑制剂（SSRI）治疗具有抗性，但对谷氨酸受体NMDA-NR2B（也称为Glun2b）拮抗剂的反应很高。这些发现导致了以下假设：谷氨酸能系统介导瘦素对抑郁行为的作用。我们建议确定1）海马谷氨酸神经传递在介导瘦素的抗抑郁样作用中的作用，以及2）2）海马树突状棘的重塑的贡献，即谷氨酸突触的位点，谷氨酸突触的位点，对乳蛋白的抗抑郁样作用。这些研究将对边缘系统中的瘦素作用产生对分子和细胞机制的新见解，并导致抑郁症的新型疗法的发展。