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Mechanisms of noncanonical caspase 1 signaling in the brain.

大脑中非典型 caspase 1 信号传导机制。

基本信息

批准号：
10536643
负责人：
Julio Licinio
金额：
$ 20.25万
依托单位：
UPSTATE MEDICAL 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：
2022-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10536643
关键词：
Alzheimer&apos s Disease Anhedonia Anxiety Anxiety Disorders Attenuated Automobile Driving Behavior Behavioral Brain Brain region CASP1 gene Chronic stress Clinical Research Cognitive Data Development Disease Drug abuse Electrophysiology (science)Emotional Etiology Foundations Functional disorder Future Genetic Glutamates Inflammasome Inflammatory Inflammatory Response Interleukins Literature Maps Mediating Mental Depression Mental disorders Molecular Motivation Neurons Neurotransmitters Nucleus Accumbens Obsessive compulsive behavior Output Parkinson Disease Pathway interactions Phenotype Process Proteins Publishing Reporting Research Rewards Risk Factors Role Serotonin Serotonin Receptor 5-HT1B Shapes Signal Transduction Stress Synapses Synaptic plasticity Techniques Testing Therapeutic addiction behavioral response cytokine disease phenotype emotional behavior emotional stimulus evidence base innovation insight interest mental state motivated behavior nervous system disorder neural circuit neuroinflammation neuropsychiatric disorder neurotransmission novel pharmacologic preclinical study programs receptor response stress reduction synaptic depression therapeutic development therapeutic target translational therapeutics transmission process

项目摘要

PROJECT SUMMARY/ABSTRACT This proposal represents a highly innovative research line focused on investigating the interface between neuroinflammation and serotonin signaling in chronic stress. Chronic stress is a significant risk factor for many neurological and neuropsychiatric disorders; it induces changes in neural circuitry and behaviors that may promote maladaptive integration and functioning of brain regions associated with motivated and emotional behaviors. There has been an increased interest in the association between stress-induced neuroinflammatory processes and their impact on brain functions. We and others have reported that Caspase-1 (CASP1) deficiency leads to attenuated stress-induced behaviors of anhedonia and decreased motivation, with concurrently reduced neuroinflammation, given that CASP1 is the effector molecule of the inflammasome. We present novel evidence that chronic stress-induced CASP1 activation decreases glutamatergic neurotransmission in response to serotonin signaling in the nucleus accumbens (NAc), specifically mediated by the serotonin 1B receptor (5-HT1B), a highly expressed receptor in the NAc. Chronic stress-induced CASP1 activation leads to serotonin signaling dysfunction. We will test our hypotheses that the 5-HT1B is a novel substrate for noncanonical CASP1 signaling and that CASP1- mediated processes play a role in modulating serotonin signaling. We will elucidate molecular and cellular mechanisms through which CASP1 in the NAc modulates serotonin signaling. This may provide a robust scientific foundation for understanding the mechanisms underlying maladaptive responses to chronic stress. We expect our results to provide evidence-based proof-of-principle for the future development of translational therapeutics targeting canonical and noncanonical neuroinflammatory NAc-based pathways in stress-induced disorders.

项目总结/摘要该提案代表了一个高度创新的研究路线，重点是调查神经炎症和5-羟色胺信号。慢性压力是一个重要的危险因素，许多神经和神经精神疾病;它会引起神经回路和行为的变化这可能会促进大脑区域的适应不良整合和功能，情绪行为人们越来越关注压力引起的神经炎症过程及其对大脑功能的影响。我们和其他人报告说， Caspase-1（CASP 1）缺乏导致应激诱导的快感缺失行为减弱，动机，同时减少神经炎症，因为CASP 1是免疫调节的效应分子。炎性小体我们提出了新的证据表明，慢性应激诱导的CASP 1激活减少丘脑核（NAc）中对5-羟色胺信号传导反应的多巴胺能神经传递，由5-羟色胺1B受体（5-HT 1B）特异性介导，5-HT 1B是NAc中高度表达的受体。慢性应激诱导的CASP 1激活导致5-羟色胺信号传导功能障碍我们将测试我们的假设5-HT 1B是非经典CASP 1信号传导的新底物，并且CASP 1- 介导的过程在调节5-羟色胺信号传导中起作用。我们将阐明分子和细胞 NAc中CASP 1调节5-羟色胺信号传导的机制。这可以提供稳健的了解慢性病适应不良反应机制的科学基础应力我们希望我们的研究结果为未来的发展提供基于证据的原则证明，靶向经典和非经典神经炎性NAc通路的转化疗法压力引起的疾病