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.

项目概要/摘要 攻击对于生物体的生存至关重要，因为它允许个体获取和保护资源 保护配偶或后代。然而，当攻击性升级且不受限制时，可能会变得适应不良， 有时会导致人类暴力。此外，神经精神疾病中可能会出现攻击性升级的情况 例如间歇性爆发性障碍、精神分裂症和自闭症。因此，理解的进步 攻击行为背后的细胞、分子和回路通路对人类健康具有重要意义。两者都 血清素能和多巴胺能神经调节系统与攻击行为有关，但特定的细胞类型 以及涉及的电路未知。拟议的研究使用尖端的遗传和病毒工具 了解特殊的多巴胺反应性血清素能 (5-HT) 神经元亚型对 使用小鼠模型系统调节攻击性。这种 5-HT 神经元亚型的特点是 II 型多巴胺受体 (Drd2) 和泛血清素转录因子 Pet1 的表达，并且是 称为 Drd2-Pet1 神经元。涉及 Drd2-Pet1 神经元和 Drd2 受体在行为调节中的需求。识别具有输入的大脑区域 到 Drd2-Pet1 神经元上，用于交叉（Cre 和 Flp 依赖）跨突触追踪的新型病毒载体 已开发（目标 1）。此外，为了探究 Drd2 在 5-HT 神经元子集中的功能重要性， 生成了 Drd2 5-HT 神经元特异性缺失的小鼠并分析了它们的行为表型 在行为筛选小组中。这项工作发现 Drd2 的 5-HT 神经元表达对于 男性攻击性和女性听觉惊吓反应的调节，表明潜在的性行为 二态角色（目标 1）。拟议的实验将进一步检验 Drd2 潜在的两性二态作用 通过分析 Drd2-Pet1 神经元对女性攻击性的调节来观察 5-HT 神经元的表达（目的 2.1) 使用小鼠分子遗传工具和病毒表征底层电路结构 神经元回路追踪技术（目标 2.2）。该博士论文项目将介绍分子、 在测试新型病毒遗传工具时，研究攻击性和惊吓反应性的细胞和电路通路 这将广泛适用于神经元亚型连接的研究。