Mechanisms of noncanonical caspase 1 signaling in the brain.

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。这可以提供强大的 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

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.