Characterization of leptin's antidepressant activity

瘦素抗抑郁活性的表征

• 批准号: 8446885
• 负责人: Xin-Yun Lu
• 金额: $ 33.4万
• 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 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8446885
• 关键词: AMPA Receptors; Ablation; Actins; Adipocytes; Affect; Antidepressive Agents; Attenuated; Behavior; Behavioral; Brain region; Chronic; Dendritic Spines; Depressive disorder; Development; Disease; Escitalopram; Fluoxetine; Functional disorder; Funding; Genetic Transcription; Glutamate Receptor; Glutamates; Goals; 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; Plastics; Play; Property; Prosencephalon; Protein Biosynthesis; Recurrence; Research Project Grants; Resistance; Role; Selective Serotonin Reuptake Inhibitor; Signal Transduction; Site; Stimulus; Stress; Structure; Symptoms; Synapses; System; Testing; Therapeutic; Vertebral column; depolymerization; depressive symptoms; human FRAP1 protein; inhibitor/antagonist; insight; leptin receptor; mTOR inhibition; neurotransmission; novel; novel therapeutic intervention; 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. PUBLIC HEALTH RELEVANCE: Major depression is a severe and recurrent mental illness that is highly prevalent worldwide. Currently available antidepressant drugs are only effective in a subset of patients, and the onset of therapeutic actions requires weeks to months of treatment. The goals of this research project are to understand the mechanisms of the pathophysiology and pathogenesis of depression-related behaviors and to identify novel molecular and neural targets for treatments.

描述（由申请人提供）：抑郁症是一种使人衰弱且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物没有反应。该项目的长期目标是了解抑郁症的发病机制并开发治疗该疾病的新方法。这是我们当前资金竞争性更新申请的重新提交，该资金用于研究脂肪细胞衍生激素瘦素的抗抑郁样作用背后的分子和细胞机制。我们提供了强有力的证据，证明瘦素具有类似抗抑郁的特性，支持抑郁症的新脂肪抑制假说。将瘦素直接注入海马体会产生抗抑郁样作用，而该大脑区域的功能性瘦素受体 LepRb 的消融会诱发抑郁样行为，这表明海马体中的 LepRb 在介导瘦素对抑郁行为的作用中发挥着重要作用。我们进行了新的观察，主要在前脑谷氨酸能神经元 (Lepr cKO) 中消除 LepRb 会导致抑郁样症状，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。这些小鼠对选择性血清素再摄取抑制剂 (SSRI) 治疗有抵抗力，但对谷氨酸受体 NMDA-NR2B（也称为 GluN2B）拮抗剂高度敏感。这些发现导致了这样的假设：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）海马树突棘（谷氨酸突触位点）的重塑对瘦素的抗抑郁样作用的贡献。这些研究将对边缘系统瘦素作用的分子和细胞机制产生新的见解，并导致抑郁症新疗法的开发。 公共卫生相关性：重度抑郁症是一种严重且反复发作的精神疾病，在全世界范围内非常普遍。目前可用的抗抑郁药物仅对一小部分患者有效，并且治疗作用需要数周至数月的治疗才能发挥作用。该研究项目的目标是了解抑郁相关行为的病理生理学和发病机制，并确定新的分子和神经治疗靶点。