Circuits, serotonergic neurons, and the modulation of behavior: Characterization of a specialized serotonergic neuron subtype responsive to dopamine and central to social behavior

电路、血清素能神经元和行为调节：对多巴胺敏感且对社会行为至关重要的特殊血清素能神经元亚型的表征

• 批准号: 10469095
• 负责人: Kristine Anne Lyon
• 金额: $ 8.07万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10469095
• 关键词: Circuits; serotonergic; neurons; modulation; behavior

Project Summary/ Abstract Aggression is essential to the survival of organisms as it allows individuals to obtain and defend resources and protect mates or offspring. Yet, aggression can become maladaptive when escalated and unrestrained, sometimes leading to violence in humans. Further, escalated aggression can occur in neuropsychiatric disorders such as intermittent explosive disorder, schizophrenia, and autism. Therefore, advances in understanding the cellular, molecular, and circuit pathways underlying aggression will be significant to human health. Both the serotonergic and dopaminergic neuromodulatory systems are implicated in aggression, yet the specific cell types and circuitry involved are unknown. The proposed research uses cutting-edge genetic and viral tools to understand the role of a specialized dopamine-responsive serotonergic (5-HT) neuron subtype critical to the modulation of aggression, using a mouse model system. This 5-HT neuron subtype is distinguished by the expression of type-II dopamine receptor (Drd2) and the pan serotonergic transcription factor Pet1, and are referred to as Drd2-Pet1 neurons. Largely unknown, is the circuitry involving Drd2-Pet1 neurons and the requirement for the Drd2 receptor in their modulation of behavior. Towards identifying brain regions with inputs onto Drd2-Pet1 neurons, novel viral vectors for intersectional (Cre- and Flp-dependent) trans-synaptic tracing were developed (Aim 1). Additionally, to probe the functional importance of Drd2 in this subset of 5-HT neurons, mice with 5-HT neuron specific deletion of Drd2 were generated and their behavioral phenotype was analyzed in a behavioral screening panel. This work has found that 5-HT neuron expression of Drd2 is critical for the modulation of male aggression and acoustic startle reactivity in females, suggesting a potential sexually dimorphic role (Aim 1). Proposed experiments will further examine the potential sexually dimorphic role of Drd2 expression in 5-HT neurons through the analysis of Drd2-Pet1 neuron modulation of female aggression (Aim 2.1) and characterization of the underlying circuit structure using mouse molecular genetic tools and viral neuronal circuit tracing techniques (Aim 2.2). This PhD dissertation project will inform upon the molecular, cellular, and circuit pathways underlying aggression and startle reactivity while testing novel viral-genetic tools that will be broadly applicable to the study of neuronal subtype connectivity.

项目摘要/摘要 侵略对于生物的生存至关重要，因为它允许个人获得和捍卫资源， 保护材料或后代。然而，侵略会在升级和不受约束时会变得不良适应性， 有时会导致人类暴力。此外，在神经精神疾病中可能会升级侵略 例如间歇性爆炸性疾病，精神分裂症和自闭症。因此，了解 细胞，分子和电路攻击的途径对人类健康将是重要的。两者 血清素能和多巴胺能神经调节系统与侵略性有关，但特定细胞类型 涉及的电路是未知的。拟议的研究使用尖端的遗传和病毒工具来 了解特殊多巴胺反应性血清素能（5-HT）神经元亚型的作用 使用鼠标模型系统调制攻击性。这个5-HT神经元亚型由 II型多巴胺受体（DRD2）和PAN血清素能转录因子PET1的表达， 称为DRD2-PET1神经元。在很大程度上未知，是涉及DRD2-PET1神经元的电路和 在其行为调节中对DRD2受体的需求。用输入来识别大脑区域 在DRD2-PET1神经元上，用于交叉（CRE-和FLP依赖性）反式突触的新型病毒载体 被开发（目标1）。此外，为了探测此5-HT神经元子集中DRD2的功能重要性， 产生了具有5-HT神经元特异性缺失DRD2的小鼠，并分析了其行为表型 在行为筛选面板中。这项工作发现DRD2的5-HT神经元表达对 男性侵略性和女性声音惊吓反应性的调节，表明潜在的性行为 双态角色（目标1）。拟议的实验将进一步研究DRD2的潜在性二态作用 通过分析DRD2-PET1神经元对女性侵略的调节，在5-HT神经元中的表达（AIM 2.1）使用小鼠分子遗传工具和病毒的基础电路结构的表征 神经元电路跟踪技术（AIM 2.2）。该博士学位论文项目将告知分子， 在测试新型病毒遗传工具的同时，细胞和电路途径是侵略性和惊吓反应性的基础 这将广泛适用于神经元亚型连接性的研究。