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。

基本信息

批准号：
9234601
负责人：
Christoph Anacker
金额：
$ 12.63万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2018-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9234601
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 Genetic Transcription Goals Head Hippocampus (Brain)Human Image Image Analysis Incidence Individual Individual Differences Injectable Investigation Knowledge Lead Learning Mediating Mediator of activation protein Mental Depression Mental Health Mental disorders Methods Microscope Microscopy Molecular Molecular Analysis Moods Mus Neurobiology Neurons Neurosciences Neurotransmitters Pathogenesis Patients Pattern Pharmaceutical Preparations Pharmacology 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 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 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

项目摘要

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转化研究团队，利用尖端的神经科学技术来研究概念上新颖的线索，了解精神疾病如何发展以及如何成功治疗。具体来说，我和我未来的实验室将研究分子信号传导如何调节齿状回功能以介导压力恢复和抗抑郁反应。我的研究策略将整合创新的分子技术和小鼠体内成像，以及人脑样本的转化工作，以提高我们研究结果的临床价值。我的主要专业知识是神经精神药理学，我的职业发展计划通过提供生物信息学、体内脑成像和人类死后脑组织分析方面的重要新培训来扩展这些方法。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见解，并可以通过新的治疗方法加以利用。因此，作为一名独立研究员，我的成功取决于我在本提案中建议学习的技能的发展。研究项目确定决定对精神病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疗法至关重要。虽然来自人类和啮齿动物模型的大量证据表明神经递质血清素 (5HT) 在抗抑郁作用中发挥着至关重要的作用，但尚不清楚为什么有些人对选择性血清素再摄取抑制剂 (SSRI) 治疗有反应，而另一些人却没有。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神经生物学底物，从而产生治疗反应。我们的工作揭示了海马齿状回颗粒神经元中的血清素 1A 受体 (5HT1AR) 作为神经元抑制和对 SSRI 的行为反应的关键介质。然而，5HT1AR 如何调节神经元功能以引发抗抑郁反应仍不清楚。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介导的。为了测试这一点，我们将首先检查 5HT1AR 信号传导抑制小鼠和人类死后脑组织中齿状回活动的复杂分子网络。然后，我们将使用化学遗传学技术来抵消或刺激分别对抗抑郁药有反应或无反应的转基因小鼠齿状回的神经元抑制。最后，我们将使用创新的体内显微镜对压力和焦虑相关任务期间自由行为的反应者和非反应者的齿状回神经元活动进行成像。该项目将全面研究如何开发基于抑制齿状回活动的先进抗抑郁疗法。