Serotonergic IL-1R1 and Neuropsychiatric Traits of an Alzheimer's Mouse Model

项目摘要 除了其众所周知的认知缺陷，阿尔茨海默病（AD）通常与衰弱有关， 情感行为的变化，包括焦虑、抑郁和社交活动的改变。机械论 AD的标志性细胞病理学和神经精神特征之间的联系仍然不清楚。 AD和情绪障碍都与神经炎症有关，中枢神经系统主要神经元的升高， 促炎介质IL-1β见于两种疾病。我们和其他人已经发现血清素（5-HT） 合成神经元作为表达IL-1β受体IL-1 R1的神经元位点是相对独特的。 5-羟色胺能投射到海马，海马是一个重要的，炎性的尼古丁诱导的病理学部位， AD被认为有助于认知和情绪。我们已经证明，肾上腺素能IL-1 R1激活 导致抗抑郁药敏感的5-HT转运蛋白（SERT）活性迅速升高， 清除5-HT和减少细胞外5-HT的可用性。其他研究表明，虽然AD病理学 延伸到前脑投射的中缝核，也导致SERT的异位表达， 星形胶质细胞这些联合作用可以降低β-肾上腺素能信号传导的能力，降低抗-β-肾上腺素能信号传导的能力。 炎症性5-HT刺激小胶质细胞，进一步增加IL-1 β水平，促进负性情感 states.在这方面，最近的研究表明，5-HT选择性再摄取抑制剂的SERT拮抗作用 用于治疗AD患者情感障碍的药物SSRIs已被报道可减少A β斑块负荷 以及认知缺陷。我们认为，AD病理学导致的IL-1β升高， 导致海马区5-羟色胺信号的改变，这种改变可以通过α-羟色胺能IL-1 R1的激活， 加速细胞病理学，破坏5-HT调节的海马电路的功能和可塑性， 支持在AD中观察到的情感和认知障碍。在这里，我们通过一个 一个独特的，四向合作项目，涉及SERT和多巴胺能功能障碍专家（Blakely）， 海马生理学评估和AD遗传小鼠模型研究方面的专家（Ashery）， IL-1 R1信号传导和功能贡献方面的专家（Quan），以及评估 遗传小鼠模型的行为（Hahn）。我们利用条件策略来消除IL-1 β信号传导 特别是在AD小鼠模型（5XFAD）中的多巴胺能中缝核神经元中，注意性别问题- 依赖通过我们的努力，我们将确定是否生物化学，细胞，生理和 由5XFAD突变引起的情感/认知障碍需要IL-1 R1信号传导至5-HT神经元。数据 在这一努力中获得的资金可以通过更持续的资金来扩大，以进一步阐明时间， 机制和更广泛的电路特性驱动和响应这些变化。

Project Summary In addition to its well-known cognitive deficits, Alzheimer’s disease (AD) is often associated with debilitating changes in affective behavior, including anxiety, depression and altered social engagement. Mechanistic connections between the hallmark cytopathologies of AD and neuropsychiatric traits remains poorly defined. Both AD and mood disorders have been associated with neuroinflammation, with CNS elevations of the major pro-inflammatory mediator IL-1β seen in both disorders. We and others have found that serotonin (5-HT) synthesizing neurons are relatively unique as neuronal sites of expression of the receptor for IL-1β, IL-1R1. Serotonergic projections to the hippocampus, a site of significant, inflammatory cytokine-inducing pathology in AD, are believed to contribute to both cognition and mood. We have shown that serotonergic IL-1R1 activation leads to rapid elevations in activity of the antidepressant-sensitive 5-HT transporter (SERT), enhancing clearance of 5-HT and diminishing extracellular 5-HT availability. Others have shown that while AD pathology extends to forebrain-projecting serotonergic raphe nuclei it also leads to and ectopic expression of SERT by astrocytes. These combined effects can diminish the capacity for serotonergic signaling, reduced anti- inflammatory 5-HT stimulation of microglia, further increasing IL-1 levels and promoting negative affective states. In this regard, recent studies have indicated that SERT antagonism by 5-HT-selective reuptake inhibitors (SSRIs), drugs used to treat affective disorders in AD patients, has been reported to reduce A plaque burden as well as cognitive deficits in AD. We propose that IL-1β elevations that arise as a consequence of AD pathology lead to alterations in 5-HT signaling in the hippocampus via serotonergic IL-1R1 activation, changes that can accelerate cytopathologies, disrupt the function and plasticity of 5-HT modulated hippocampal circuitry, and support both affective and cognitive disturbances observed in AD. Here we pursue our hypothesis through a unique, four-way collaborative project involving an expert in SERT and serotonergic dysfunction (Blakely), an expert in the evaluation of hippocampal physiology and the study of AD genetic mouse models (Ashery), an expert in the signaling and functional contributions of IL-1R1s (Quan), and an expert in assessment of the behavior of genetic mouse models (Hahn). We utilize a conditional strategy to eliminate IL-1 signaling specifically in serotonergic raphe neurons in an AD mouse model (5XFAD), attentive to issues of sex- dependence. Through our efforts, we will determine whether the biochemical, cellular, physiological and affective/cognitive disturbances that arise from 5XFAD mutations require IL-1R1 signaling to 5-HT neurons. Data obtained in this effort can then be extended through more sustained funding to further elucidate the timing, mechanisms and broader circuit specificities driving, and responding to, these changes.