Role of serotonergic IL-1R1 in modulating physiological and behavioral responses to peripheral inflammation

项目摘要/摘要 5-羟色胺能回路参与与情绪、奖励、食欲和社会行为相关的复杂行为。 这些回路的功能障碍被认为支持包括焦虑在内的多种神经精神障碍， 抑郁症、自闭症和精神分裂症。虽然经常被单层治疗，但5-羟色胺能投射产生于 提供不同行为结果的神经元亚群。5-羟色胺(5-HT)神经元的一个子集 支持将外周先天免疫系统的激活转化为离散行为的改变， 尽管人们对此的机械性细节知之甚少。更好地了解该中心的位置、功能和 这些神经元的行为输出将有助于阐明观察到的免疫系统之间的共病 功能障碍和神经精神障碍。先天免疫系统的激活会迅速增加这种活性。 突触前5-羟色胺转运体(SERT)参与5-羟色胺的神经传递。体外和体外 研究支持炎症细胞因子IL-1β通过其受体IL-1R1的信号作用来影响 通过p38αMAPK插入。5-羟色胺能IL-1R1的分布及其支持细胞自主的能力 5-羟色胺神经元的调节及IL-1R1在慢性阻塞性肺疾病功能表现中的必要性/充分性 5-羟色胺能信号尚不清楚。解决这些问题将提高我们对外围设备如何 免疫系统将激活传递给CNS，从而建立适应性行为反应，如 一种应对全球炎症状态的手段。目前的提案旨在1)量化和验证 5-羟色胺能IL-1R1的表达模式和免疫系统相关的激活，2)决定投射 5-羟色胺能IL-1R1表达神经元的部位，3)决定了5-羟色胺能IL-1R1的必要性/充分性 在体内介导炎症诱导的CNS SERT活性和5-羟色胺释放的变化，以及4)研究 行为被证明依赖于5-羟色胺能IL-1R1的激活。拟议的研究将利用 新近发展的从5-羟色胺神经元中消除了IL-1R1的小鼠，以及缺乏全身的小鼠 IL-1R1，但在5-羟色胺神经元中有功能标记的IL-1R1恢复。这些目标将阐明一个基本的 外周炎症调节5-羟色胺神经元功能的途径及阐明两者之间的联系 炎症标志物升高和神经精神障碍的观察。此外，他们还可以建立 开发针对解剖和功能离散方面的新药的基本原理 5-羟色胺能神经调节。我的培训计划，它提供了独立发展的机会 调查员，主要专注于上述研究以及与职业发展有关的活动 包括RCR培训、参加科学会议、神经科学界的参与和外联， 和初级科学家的指导。我的项目将在兰迪·布莱克利博士和一个 FAU脑研究所高级咨询委员会，并得到先进技术核心设施的支持 以及FAU、佛罗里达州斯克里普斯和佛罗里达州马克斯·普朗克研究所的神经科学研究社区。

Project Summary/Abstract Serotonergic circuits are involved in complex behaviors linked to mood, reward, appetite, and social behavior. Dysfunction of these circuits is believed to support multiple neuropsychiatric disorders including anxiety, depression, autism, and schizophrenia. Although often treated monolithically, serotonergic projections arise from subpopulations of neurons that confer distinct behavioral outcomes. A subset of serotonin (5-HT) neurons support the transduction of peripheral innate immune system activation into changes in discrete behaviors, though mechanistic details of this are poorly understood. A better understanding of the location, function and behavioral output of these neurons will help elucidate the comorbidity observed between immune system dysfunction and neuropsychiatric disorders. Activation of the innate immune system rapidly increases the activity of the presynaptic 5-HT transporter (SERT), which contributions to 5-HT neurotransmission. In vitro and ex vivo studies support a role for signaling by the inflammatory cytokine, IL-1β, through its receptor IL-1R1, to influence SERT via p38α MAPK. The distribution of serotonergic IL-1R1, their ability to support cell autonomous modulation of 5-HT neurons, and the necessity/sufficiency of IL-1R1 in the functional manifestations of serotonergic signaling is unknown. Resolving these issues will improve our understanding of how the peripheral immune system communicates activation to the CNS and thereby establishes adaptive behavioral responses as a means of coping with global states of inflammation. The current proposal aims to 1) quantify and validate patterns of serotonergic IL-1R1 expression and immune system-related activation, 2) determine the projection sites of serotonergic IL-1R1-expressing neurons, 3) determine the necessity/sufficiency of serotonergic IL-1R1 in mediating inflammation-induced changes in in vivo CNS SERT activity and 5-HT release, and 4) investigate behaviors demonstrated to depend on serotonergic IL-1R1 activation. The proposed studies will make use of recently-developed mice that have IL-1R1 eliminated from 5-HT neurons, as well as mice that lack whole-body IL-1R1, but have a functional tagged IL-1R1 restored in 5-HT neurons. These aims will elucidate a fundamental pathway by which the function of 5-HT neurons is modulated by peripheral inflammation and clarify links between observations of elevated inflammatory markers and neuropsychiatric disorders. Moreover, they may establish the rationale for the development of novel medications that target anatomically and functionally discrete aspects of serotonergic neuromodulation. My training plan, which provides opportunities to develop as an independent investigator, primarily focuses on the above research, along with activities related to career development including RCR training, participation at scientific meetings, neuroscience community engagement and outreach, and junior scientist mentorship. My project will be pursued under the mentorship of Dr. Randy Blakely and a senior Advisory Committee at the FAU Brain Institute and supported by the advanced technology core facilities and neuroscience research community of FAU, Scripps Florida, and the Max Planck Florida Institute.