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BMP Signaling and Neurogenesis in Major Depressive Order

重度抑郁症中的 BMP 信号转导和神经发生

基本信息

批准号：
10094255
负责人：
JOHN A KESSLER
金额：
$ 45.61万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10094255
关键词：
Address Affective Anatomy Animal Model Antidepressive Agents Anxiety Area BMP4 Behavior Behavioral Biochemical Bone Morphogenetic Proteins Brain Cells Chronic Clinical Cognition Cognitive Coupled Cytoplasmic Granules Development Disease Disease model Electrophysiology (science)Etiology Exogenous Factors Exposure to Gene Expression Glycoproteins Goals Heterogeneity Hippocampus (Brain)Human Label Ligands Link Major Depressive Disorder Mediating Mental Depression Modeling Molecular Motivation Mus Negative Valence Neurons Pharmaceutical Preparations Pharmacology Physiological Play Population Positive Valence Prefrontal Cortex Prevention Production Productivity Proteins Rabies virus Resistance Role Signal Pathway Signal Transduction Signaling Protein Social Behavior Stress Stress Tests System adult neurogenesis antidepressant effect behavioral phenotyping behavioral response cell type dentate gyrus depressed patient depressive symptoms disability inhibitor/antagonist mutant nerve stem cell neurogenesis neuronal circuitry neurotransmission newborn neuron novel strategies prevent protective effect receptor response stem stem cells

项目摘要

Summary Major depressive disorder (MDD) is one of the leading causes of disability and lost productivity. Nearly half of all clinically depressed patients fail to respond to the first prescribed antidepressant, and about a third fail to respond to all medications. Development of new approaches will require better understand of the mechanisms underlying the disorder. This project has identified and is examining a signaling pathway not previously implicated in anxiety and depression-like behavior, bone morphogenetic protein (BMP) signaling. MDD is associated with reductions in volume of the hippocampus (HC) in humans and in neurogenesis in the HC in animal models of the disorder. Reduction of BMP signaling in the HC in mice is sufficient to produce antidepressant-like changes in behavior and to increase neurogenesis. Treatment with several different classes of antidepressant drugs reduces BMP signaling in the HC, and prevention of this reduction in BMP signaling blocks the effects of the drugs on both behavior and neurogenesis. Inhibition of BMP signaling in the HC also blocks the effects of unpredictable chronic mild stress on both depression- like behavior and neurogenesis. Thus BMP signaling in the hippocampus regulates both depression-like behavior. However, a causal link between the changes in neurogenesis and behavior has not been established. The proposed studies will determine whether there is a causal relationship between changes in neurogenesis, electrophysiological activity of newly generated neurons, and behavior after inhibition of BMP signaling in HC stem/progenitor cells. They also will define the role of BMP signaling in cellular and behavioral responses to stress, and test the hypothesis that that gene expression changes due to elevated BMP signaling contribute to the decrease in neurogenesis, increased proportion of quiescent neural stem cells, and behavioral changes associated with stress/depression.

总结