A synaptic substrate for ketamine-mediated amelioration of stress-induced anhedonia

氯胺酮介导的改善应激性快感缺失的突触底物

基本信息

批准号：
10684093
负责人：
Marco Pignatelli
金额：
$ 38.88万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10684093
关键词：
AMPA Receptors Acute Address Affect Anesthetics Anhedonia Antidepressive Agents Atrophic Behavior Behavioral Brain Cells Chronic stress Clinical Consensus DRD2 gene Data Dendritic Spines Dissection Dose Drug usage Electrophysiology (science)Elements Exposure to Functional disorder Genetic Glutamates Goals Guanosine Triphosphate Phosphohydrolases Homosynaptic Depression Hour Ketamine Knock-in Mouse Laboratory Animals Link Literature Major Depressive Disorder Medial Mediating Mental Depression Molecular Molecular Target Morbidity - disease rate Motivation Mus NMDA receptor antagonist Neurons Nucleus Accumbens Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Physiology Population Prefrontal Cortex Protein Biosynthesis Protein Synthesis Inhibition Proteins Resistance Rewards Slice Specific qualifier value Stress Symptoms Synapses Synaptic Transmission Synaptic plasticity Technology Testing Transgenic Mice Treatment Efficacy antagonist antidepressant effect behavioral outcome burden of illness cell type depressive symptoms design disability experimental study genetic approach improved in vivo innovation insight interest mortality neurotransmission new therapeutic target novel optogenetics pharmacologic pleasure pre-clinical prevent promoter public health priorities rational design reward circuitry spatiotemporal synaptogenesis therapeutic target transmission process

项目摘要

SUMMARY Depression is a leading cause of morbidity and mortality worldwide and it is projected to become the second leading cause of disability by 2030. Despite these results indicate the urgent need to address depression as a public-health priority to reduce disease burden and disability, current pharmacotherapies for depression require prolonged administration (weeks if not months) for clinical improvement and they are often associated with high non-response rate. In contrast, recent clinical evidence has shown that a single sub-anesthetic dose of ketamine induces a robust and rapid (within matter of hours) antidepressant effect in 70% of treatment-resistant patients. Notably, ketamine is the first rapid-acting antidepressant with efficacy for treatment-resistant symptoms of major depression disorder such as anhedonia. Anhedonia, defined as diminished pleasure from, or interest in, previously rewarding activities is commonly precipitated by exposure to chronic stress and it is well suited to study in laboratory animals. Whereas ketamine’s primary molecular target is under debate, there is broad consensus in the literature that activation of the AMPAR as well as induction of synaptogenesis driven by de novo protein synthesis-dependent mechanisms are required for ketamine’s ability to ameliorate stress-induced anhedonia. Nevertheless, major technical barriers have hindered a circuit and synaptic-level dissection of such mechanisms. Therefore, understanding the detailed circuit and synaptic mechanisms and establishing a causal link between ketamine- evoked AMPAR-mediated synaptic plasticity and specific behavioral outcomes is crucial for designing novel and safer therapeutic targets. Here, we will tackle this question by using electrophysiology, optogenetics and recently developed technologies that offer the unprecedented opportunity to block AMPAR as well as de novo protein synthesis within genetically specified cells. Accordingly, the following hypotheses will be tested: (i) increased AMPAR-mediated synaptic transmission on D1-MSNs mediates the anti-anhedonic effects of ketamine, (ii) mPFC->NAc input is necessary for ketamine-mediated amelioration of stress-induced anhedonia, and (iii) ketamine-induced de novo protein synthesis-dependent plasticity in D1-MSNs drives ketamine-mediated amelioration of stress-induced anhedonia. Altogether, results from these studies will increase our understanding of the mechanisms of action of ketamine and might lead to new potential targets to treat stress-induced anhedonia.

概括抑郁症是全球发病率和死亡率的主要原因，预计将成为第二大原因到 2030 年，抑郁症将成为导致残疾的主要原因。尽管这些结果表明，迫切需要将抑郁症作为一种减轻疾病负担和残疾是公共卫生的优先事项，目前治疗抑郁症的药物疗法需要延长给药时间（数周甚至数月）以改善临床效果，并且通常与高相比之下，最近的临床证据表明单次亚麻醉剂量的氯胺酮。对 70% 的耐药患者产生强大而快速（数小时内）的抗抑郁作用。值得注意的是，氯胺酮是第一种速效抗抑郁药，可有效治疗主要抑郁症的难治性症状。抑郁症，例如快感缺失，定义为对以下事物的快乐或兴趣减少。以前有益的活动通常是由于长期承受压力而引发的，它非常适合在实验动物中进行研究。氯胺酮的主要分子靶标尚有争议，但文献中存在广泛共识： AMPAR 的激活以及由从头蛋白质合成依赖性驱动的突触发生的诱导氯胺酮改善压力引起的快感缺失的机制是必要的。技术上已经阻碍了电路和突触级解剖这种机制的障碍。了解详细的电路和突触机制，并建立氯胺酮之间的因果关系诱发 AMPAR 介导的突触可塑性和特定的行为结果对于设计新颖且在这里，我们将通过电生理学、光遗传学和最近的研究来解决这个问题。开发的技术为阻断 AMPAR 以及 de novo 蛋白质提供了前所未有的机会因此，将测试以下假设：（i）增加。 D1-MSN 上的 AMPAR 介导的突触传递介导氯胺酮的抗快感缺乏作用，(ii) mPFC->NAc 输入对于氯胺酮介导的应激性快感缺失的改善是必要的，并且 (iii) 氯胺酮诱导的 D1-MSN 中的从头蛋白质合成依赖性可塑性驱动氯胺酮介导总而言之，这些研究的结果将增加我们的理解。氯胺酮的作用机制，并可能导致治疗压力引起的新的潜在目标快感缺乏。