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.

项目概要/摘要 该提案代表了一个高度创新的研究路线，重点研究两者之间的界面 慢性应激中的神经炎症和血清素信号传导。慢性压力是一个重要的危险因素 许多神经系统和神经精神疾病；它会引起神经回路和行为的变化 这可能会促进与动机和动机相关的大脑区域的适应不良整合和功能 情绪行为。人们对压力诱发之间的关系越来越感兴趣 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 (CASP1) 缺陷会导致应激诱发的快感缺失行为减弱并降低 动机，同时减少神经炎症，因为 CASP1 是 炎症小体。我们提出了新的证据表明慢性应激诱导的 CASP1 激活降低 伏核（NAc）中响应血清素信号的谷氨酸神经传递， 特异性由血清素 1B 受体 (5-HT1B) 介导，5-HT1B 是 NAc 中高度表达的受体。 慢性压力诱导的 CASP1 激活会导致血清素信号传导功能障碍。我们将测试我们的 假设 5-HT1B 是非经典 CASP1 信号传导的新型底物，并且 CASP1- 介导的过程在调节血清素信号传导中发挥作用。我们将阐明分子和细胞 NAc 中的 CASP1 调节血清素信号传导的机制。这可以提供一个稳健的 了解慢性病适应不良反应机制的科学基础 压力。我们希望我们的结果能够为未来的发展提供基于证据的原理证明 针对典型和非典型神经炎症 NAc 通路的转化疗法 在压力引起的疾病中。