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: 10193355
• 负责人: Kristine Anne Lyon
• 金额: $ 2.08万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10193355
• 关键词: Accounting; Acoustics; Aggressive behavior; Agonist; Animals; Area; Attenuated; Auditory; Award; Axon; BRAIN initiative; Bacterial Artificial Chromosomes; Behavior; Behavioral; Biological Assay; Biological Models; Bite; Brain Stem; Brain region; Cell Count; Cells; Complement; Complex; DRD2 gene; Data; Development; Doctor of Philosophy; Dopamine; Dopamine D2 Receptor; Dopamine Receptor; Fellowship; Female; Fiber; Future; Genetic; Goals; Head; Health; Human; In Situ; Individual; Intermittent Explosive Disorders; Knock-out; Knowledge; Label; Loudness; Mentors; Molecular; Molecular Genetics; Mus; Nervous system structure; Neurobiology; Neurons; Neurotransmitters; Noise; Organism; Partner in relationship; Pathway interactions; Pattern; Population; Post-Traumatic Stress Disorders; Prosencephalon; Rabies; Reporter; Research; Research Personnel; Research Project Grants; Resolution; Resources; Role; Schizophrenia; Serotonergic System; Serotonin; Sex Differences; Signal Transduction; Social Behavior; Source; Startle Reaction; Structure; Synapses; Synaptophysin; System; Techniques; Territoriality; Testing; Therapeutic; Training; Transgenes; Violence; Viral; Viral Vector; Work; Writing; autism spectrum disorder; awake; behavioral phenotyping; brain circuitry; career; cell type; experimental study; in vivo; interest; male; maternal aggression; mouse model; nerve supply; neuronal circuitry; neuropsychiatric disorder; neuroregulation; novel; offspring; pre-doctoral; receptor; screening; screening panel; sex; sexual dimorphism; skills; stem; tool; transcription factor; virus genetics

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 攻击性对有机体的生存至关重要，因为它允许个人获得和保卫资源和 保护配偶或后代。然而，当攻击性升级和不受约束时，可能会变得不适应， 有时会导致人类的暴力行为。此外，升级的攻击性可能发生在神经精神障碍中。 如间歇性爆发性精神障碍、精神分裂症和自闭症。因此，在理解 攻击性背后的细胞、分子和回路通路将对人类健康产生重大影响。这两个 5-羟色胺能和多巴胺能神经调节系统与攻击有关，但特定的细胞类型 以及所涉及的电路都是未知的。这项拟议的研究使用尖端的遗传和病毒工具来 了解一种特殊的多巴胺反应性5-羟色胺能(5-HT)神经元亚型的作用 攻击性调制，采用鼠标模型系统。这种5-羟色胺神经元亚型的区别在于 2型多巴胺受体(DRD2)和PAN 5-羟色胺能转录因子Pet1的表达，以及 被称为Drd2-Pet1神经元。很大程度上是未知的，是涉及Drd2-Pet1神经元的电路和 对DRD2受体在其行为调节中的需求。通过输入识别大脑区域 跨节(依赖Cre和FLP)突触示踪的新型病毒载体--Drd2-Pet1神经元 被开发(目标1)。此外，为了探讨Drd2在这一亚群5-羟色胺神经元中的功能重要性， 建立5-羟色胺神经元特异性缺失Drd2小鼠模型，分析其行为表型 在行为筛查小组中。本工作发现DRD2的5-羟色胺神经元表达对 调节男性的攻击性和女性的听觉惊吓反应，暗示潜在的性行为 双态角色(目标1)。拟议中的实验将进一步检验Drd2的潜在的性二态作用 女性攻击行为中Drd2-Pet1神经元调控在5-羟色胺神经元的表达 2.1)和使用小鼠分子遗传工具和病毒对潜在电路结构的表征 神经元回路追踪技术(目标2.2)。这个博士论文项目将告知分子， 在测试新的病毒遗传工具时，攻击和惊吓反应的细胞、和电路通路 这将广泛适用于神经元亚型连通性的研究。