Identifying cellular and molecular substrates of treatment-resistant depression.

识别难治性抑郁症的细胞和分子基础。

• 批准号: 9013884
• 负责人: Christoph Anacker
• 金额: $ 12.99万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9013884
• 关键词: Agonist; Antidepressive Agents; Anxiety; Autopsy; Behavior; Bioinformatics; Biological Neural Networks; Brain; Brain imaging; Brain region; Calcium; Characteristics; Chronic; Clinical; Cognition; Complement; Complex; Computer Simulation; Coupled; Cytoplasmic Granules; Data; Development; Development Plans; Disease; Disease remission; Economic Burden; Fluoxetine; Foundations; Future; Gene Targeting; Genes; Goals; Head; Hippocampus (Brain); Human; Image; Image Analysis; Incidence; Individual; Individual Differences; Investigation; Knowledge; Lead; Learning; Life; Mediating; Mediator of activation protein; Mental Depression; Mental Health; Mental disorders; Methods; Microscope; Microscopy; Molecular; Moods; Mus; Neurobiology; Neurons; Neurosciences; Neurotransmitters; Pathogenesis; Patients; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Phase; Predisposition; Process; Psychiatric therapeutic procedure; Public Health; Research; Research Personnel; Research Project Grants; Resistance; Rodent Model; Role; Sampling; Selective Serotonin Reuptake Inhibitor; Serotonin; Serotonin Receptor 5-HT1A; Shapes; Signal Pathway; Signal Transduction; Signaling Protein; Stress; Techniques; Testing; Training; Transgenic Mice; Translating; Translational Research; Work; abstracting; base; behavior influence; behavioral response; brain tissue; career; career development; cell type; clinically relevant; dentate gyrus; designer receptors exclusively activated by designer drugs; disability; experience; fluorescence imaging; granule cell; health economics; improved; in vivo; in vivo imaging; innovation; insight; neural circuit; neurobiological mechanism; neuropsychopharmacology; novel; novel therapeutics; overexpression; public health relevance; responders and non-responders; response; sensor; skills; stress resilience; success; therapy resistant; tool; transcriptome sequencing; treatment response; treatment-resistant depression

Modified Project Summary/Abstract My career goal is to lead a translational research team that uses cutting-edge neuroscience techniques to investigate conceptually novel leads into how mental illness develops and how it can be successfully treated. Specifically, I, and my future lab, will investigate how molecular signaling regulates dentate gyrus function to mediate stress resilience and antidepressant responses. My research strategy will integrate innovative molecular techniques and in vivo imaging in mice, with translational work in human brain samples to increase the clinical value of our findings. My primary expertise is in neuropsychopharmacology and my career development plan expands on these methods by providing essential new training in bioinformatics, in vivo brain imaging, and analysis of human postmortem brain tissue. My career goal is to integrate these techniques to generate unique insight into the exact neural circuits and neurobiological processes that lead to disease and that could be harnessed by novel treatments. My success as an independent researcher therefore depends on developing the skills that I propose to learn in this proposal. Research Project Identifying the neurobiological mechanisms that determine response and resistance to psychiatric treatment is of paramount importance for developing improved drugs and therapies. While substantial evidence from humans and rodent models has demonstrated a crucial role for the neurotransmitter, serotonin (5HT), in antidepressant action, it is unknown why some individuals respond to treatment with selective serotonin reuptake inhibitors (SSRIs) while others do not. This lack of knowledge limits the development of effective drugs that could specifically target neurobiological substrates that confer treatment response. Our work has revealed the serotonin 1A receptor (5HT1AR) in dentate gyrus granule neurons of the hippocampus as a crucial mediator for neuronal inhibition and behavioral responses to SSRIs. However, how 5HT1ARs regulate neuronal function to elicit an antidepressant response remains elusive. Leading on from these findings, we hypothesize that antidepressant responses are mediated by inhibition of dentate gyrus activity. To test this, we will first examine the complex molecular networks by which 5HT1AR signaling inhibits dentate gyrus activity in mice and in human postmortem brain tissue. Then, we will use chemogenetic techniques to counteract or stimulate neuronal inhibition in the dentate gyrus of transgenic mice that do or do not respond to antidepressants, respectively. Finally, we will use innovative in vivo microscopy to image neuronal activity in the dentate gyrus of freely behaving responders and non-responders during stress and anxiety-related tasks. This project will provide a comprehensive investigation into how we can develop advanced antidepressant treatments based on inhibition of dentate gyrus activity.

修改后的项目摘要/摘要 我的职业目标是领导一个翻译研究团队，使用尖端神经科学技术从概念上调查精神疾病是如何发展以及如何成功治疗的新线索。具体地说，我和我未来的实验室将研究分子信号如何调节齿状回功能，以调节压力弹性和抗抑郁反应。我的研究战略将把创新的分子技术和小鼠体内成像与人脑样本的翻译工作结合起来，以增加我们发现的临床价值。我的主要专长是神经精神药理学，我的职业发展计划通过提供基本的新培训，在生物信息学、活体脑成像和人类死后脑组织分析方面扩展了这些方法。我的职业目标是整合这些技术，对导致疾病的确切神经回路和神经生物学过程产生独特的洞察力，并可以通过新的治疗方法加以利用。因此，作为一名独立研究人员，我的成功取决于我在这份提案中提议学习的技能的发展。 研究项目 确定决定对精神治疗的反应和抵抗的神经生物学机制对于开发改进的药物和治疗方法至关重要。虽然来自人类和啮齿动物模型的大量证据表明，神经递质5-羟色胺(5-HT)在抗抑郁作用中起着至关重要的作用，但尚不清楚为什么一些人对选择性5-羟色胺再摄取抑制剂(SSRI)的治疗有反应，而另一些人不是。这种知识的缺乏限制了有效药物的开发，这些药物可以专门针对赋予治疗反应的神经生物底物。我们的工作揭示了海马齿状回颗粒神经元中的5-羟色胺1A受体(5HT1AR)是神经元抑制和对SSRI的行为反应的重要中介。然而，5HT1ARs如何调节神经元功能以引发抗抑郁反应仍然是个谜。根据这些发现，我们假设抗抑郁反应是通过抑制齿状回活动来调节的。为了测试这一点，我们将首先检查复杂的分子网络，通过5HT1AR信号抑制小鼠和人类死后脑组织中的齿状回活动。然后，我们将使用化学遗传学技术分别对抗或刺激对抗抑郁药物有反应或无反应的转基因小鼠齿状回的神经元抑制。最后，我们将使用创新的活体显微镜来成像自由行为响应者和无响应者在压力和焦虑相关任务中齿状回的神经元活动。这个项目将提供一个全面的调查，我们如何能够开发先进的抗抑郁治疗的基础上抑制齿状回活动。