Mechanisms of noncanonical caspase 1 signaling in the brain.

大脑中非典型 caspase 1 信号传导机制。

• 批准号: 10353135
• 负责人: Julio Licinio
• 金额: $ 24.3万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10353135
• 关键词: Alzheimer' 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; Pharmacology; Phenotype; Play; 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; base; 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; preclinical study; programs; receptor; response; synaptic depression; therapeutic development; therapeutic target; translational therapeutics; transmission process

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.

项目摘要/摘要 这一建议代表了一条高度创新的研究路线，专注于研究 慢性应激中的神经炎症和5-羟色胺信号。慢性应激是一项重要的风险因素 许多神经和神经精神障碍；它引起神经回路和行为的改变 这可能会促进大脑区域的适应不良整合和功能，这些区域与动机和 情绪化行为。越来越多的人对压力诱导的 神经炎性过程及其对脑功能的影响。我们和其他人已经报道了 Caspase-1(CASP1)缺乏导致快感障碍应激性行为减弱 动机，同时减少神经炎症，因为CASP1是 炎症者。我们提出了慢性应激诱导的CASP1活性降低的新证据 伏隔核内5-羟色胺信号反应的谷氨酸能神经传递 特异性地由5-HT1B受体(5-HT1B)介导，5-HT1B是NAC中的一种高表达受体。 慢性应激诱导的CASP1激活导致5-羟色胺信号转导功能障碍。我们将测试我们的 假设5-HT1B是非规范CASP1信号的新底物，并且CASP1- 中介过程在调节5-羟色胺信号方面发挥作用。我们将阐明分子和细胞 NAC中CASP1调节5-羟色胺信号的机制。这可能会提供一个健壮的 了解慢性精神分裂症适应不良反应机制的科学基础 压力。我们期望我们的结果为未来的发展提供以证据为基础的原则证明 以NAC为基础的典型和非典型神经炎性通路为靶点的翻译疗法 在压力诱导的精神障碍中。