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）：抑郁症是一种使人衰弱和反复发作的精神疾病。大约一半的抑郁症患者对目前可用的抗抑郁药没有反应。该项目的长期目标是了解抑郁症的发病机制，并为这种疾病开发新的治疗方法。这是我们为研究脂肪细胞来源的激素瘦素的抗抑郁作用的分子和细胞机制而重新提交的竞争性更新申请。我们已经提供了强有力的证据，证明瘦素具有抗抑郁的特性，支持了抑郁症的新脂肪假说。将瘦素直接注入海马体可产生类似抗抑郁的作用，而削弱该脑区功能性瘦素受体LepRb可诱发类似抑郁的行为，这表明海马体中的LepRb在调节瘦素对抑郁行为的作用中发挥了重要作用。我们已经观察到，主要在前脑谷氨酸能神经元（Lepr cKO）的LepRb消融导致抑郁样症状，并促进nmda诱导的海马突触抑制。瘦素的抗抑郁样行为作用在Lepr cKO小鼠中被消除。这些小鼠对选择性5 -羟色胺再摄取抑制剂（SSRI）治疗有抗性，但对谷氨酸受体NMDA- NR2B（也称为GluN2B）拮抗剂有高度反应。这些发现导致假设谷氨酸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抗抑郁样作用中的作用，以及2)海马树突棘（谷氨酸突触部位）重塑对瘦素抗抑郁样作用的贡献。这些研究将对瘦素在边缘系统中的作用的分子和细胞机制产生新的见解，并导致抑郁症的新疗法的发展。