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: 9766187
• 负责人: Kristine Anne Lyon
• 金额: $ 3.62万
• 依托单位: HARVARD UNIVERSITY
• 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 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766187
• 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; Phenotype; Population; Post-Traumatic Stress Disorders; Prosencephalon; Rabies; Reporter; Research; Research Personnel; Research Project Grants; Resolution; Resources; Role; Schizophrenia; Serotonergic System; Serotonin; 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; brain circuitry; career; cell type; experimental study; in vivo; interest; intersectionality; 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.

项目总结/摘要 侵略性对生物体的生存至关重要，因为它使个体能够获得和捍卫资源， 保护配偶或后代。然而，当攻击性升级和不受限制时， 有时会导致人类的暴力此外，神经精神疾病也可能导致攻击行为升级 例如间歇性爆发性障碍、精神分裂症和自闭症。因此，在了解 细胞、分子和电路通路潜在的侵略将是重要的人类健康。两者 多巴胺能和多巴胺能神经调节系统与攻击性有关，但特定的细胞类型 和电路都是未知的这项拟议中的研究使用了尖端的遗传和病毒工具， 了解一个专门的多巴胺反应性多巴胺能（5-HT）神经元亚型的作用， 调节攻击性，使用小鼠模型系统。这种5-HT神经元亚型的区别在于 II型多巴胺受体（Drd 2）和泛多巴胺能转录因子Pet 1的表达， 称为Drd 2-Pet 1神经元。目前尚不清楚的是，涉及Drd 2-Pet 1神经元的回路和 在其行为调节中需要Drd 2受体。通过输入来识别大脑区域 到Drd 2-Pet 1神经元上，用于交叉（Cre和Flp依赖性）跨突触追踪的新型病毒载体 目标1（Aim 1）此外，为了探索Drd 2在5-HT神经元亚群中的功能重要性， 建立了5-HT神经元特异性缺失Drd 2的小鼠，并对其行为表型进行了分析 行为筛选小组的成员这项工作已经发现，5-HT神经元表达Drd 2对于神经元的生长至关重要。 调节男性的侵略和女性的声音惊吓反应，这表明潜在的性 二态性作用（目的1）。拟议的实验将进一步研究Drd 2的潜在性二态性作用。 通过分析Drd 2-Pet 1神经元对女性攻击行为的调节， 2.1)以及使用小鼠分子遗传工具和病毒来表征底层电路结构。 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， 在测试新型病毒遗传工具时， 这将广泛适用于神经元亚型连接的研究。