Sex, Physiological State, and Genetic Background Dependent Molecular Characterization of CircuitsGoverning Parental Behavior

控制父母行为的回路的性别、生理状态和遗传背景依赖性分子特征

• 批准号: 10661884
• 负责人: Brandon Logeman
• 金额: $ 12.31万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-13 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661884
• 关键词: ATAC-seq; Address; Adult; Advisory Committees; Affect; Alleles; Animal Behavior; Animals; Award; Behavior; Behavioral; Biophysics; Calcitonin Receptor; Caregivers; Caring; Cell Nucleus; Child Rearing; Chromatin; Chromosome Mapping; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Electrophysiology (science); Environment; Epigenetic Process; Exhibits; Fathers; Female; Future; Gene Expression; Genes; Genetic; Genetic Screening; Genetic Transcription; Genetic Variation; Genomics; Goals; Hormones; Hour; Hypothalamic structure; Individual; Infant; Infant Care; Investments; Knowledge; Laboratories; Lactation; Maps; Measures; Mediating; Mentors; Molecular; Mothers; Mouse Strains; Mus; Neurons; Parents; Pathologic; Personal Satisfaction; Phase; Physiological; Population; Population Control; Positioning Attribute; Preoptic Areas; Prolactin; Quantitative Trait Loci; Research; Resolution; Role; Scientist; Sex Differences; Signal Pathway; Signal Transduction; Slice; Stimulus; Testing; Testosterone; Training; Transcriptional Regulation; Universities; Variant; Ventricular; Vocational Guidance; Work; behavior influence; behavioral outcome; biophysical properties; biophysical techniques; bombesin receptor subtype 3; causal variant; cell type; differential expression; epigenomics; experimental study; galanin receptor; gene regulatory network; genetic approach; genetic variant; genomic locus; male; neural circuit; neuronal circuitry; offspring; parental influence; pharmacologic; sex; sexual dimorphism; single cell analysis; single nucleus RNA-sequencing; skills; tool; trait; vesicular glutamate transporter 2

PROJECT SUMMARY/ABSTRACT Parental care is essential for offspring well-being and survival yet requires a significant invest from adults without immediate benefit, suggesting the existence of hard-wired mechanisms governing its control. Despite the importance of this evolutionarily controlled behavior, parental behaviors vary greatly between animals of different sex, physiological state, and genetic background. Previous studies examining sex- and state- dependent influences on parental behavior have lacked the cell-type resolution critical to understanding how specific circuit components are modulated. The long timescale (hours to days) of changes affecting parenting behaviors suggests that neural circuits respond through dynamic gene expression changes. Through the use of intersectional genetics and single cell analysis I have established exquisitely specific access to two key neuronal hubs controlling parenting behavior. Preliminary results comparing Mothers, Fathers, and Virgin animals suggest potential transcriptional, epigenetic, and biophysical differences that are dependent on the animal’s sex and physiological state. During the K99 phase of the work proposed here I will rigorously assess sex- and state-dependent transcriptional changes, as well as their biophysical and behavioral implications, using the latest tools for cell-type specific recording and manipulation. I will uncover gene regulatory networks that give rise to observed transcriptional changes and will develop new intersectional tools to modulate gene expression in a cell-type specific manner. The successful completion of these Aims will reveal the molecular mechanisms though which sex and state mediate transcriptional reprograming to affect the function of this conserved behavioral circuit. Genetic variation also contributes to differences in the display of parental care. Preliminary results utilizing genetically distinct mouse strains show dramatic differences in parenting behavior and suggest a genetic contribution to behavioral variation. In the independent R00 phase of this proposal, I will perform a forward-genetic screen utilizing a well-characterized panel of genetically diverse mice to find genomic variants that contribute to parental behavior. The cell-type specific gene regulatory networks revealed in the previous Aims will then be used to assess the causal role of individual variants, providing a level of molecular explanation unobtainable with previous genetic mapping experiments. Furthermore, the successful completion of this project will provide a platform for future experiments aimed at understanding how genetic variants contribute to gene expression that ultimately affects animal behavior. The training phase of the award will be conducted in the laboratory of Dr. Catherine Dulac at Harvard University. In addition, I will be mentored by the outstanding team of scientists on my advisory committee that will assist with specific training goals as well as career guidance. In my application I have outlined a comprehensive plan for the acquisition of conceptual, technical, and professional skills that will enable my transition to an independent research position.

项目总结/摘要 父母的照顾对后代的幸福和生存至关重要，但需要成年人的大量投资 没有直接的好处，这表明存在着控制它的硬连线机制。尽管 这种进化控制的行为的重要性，父母的行为在动物之间有很大的差异， 不同的性别、生理状态和遗传背景。以前的研究考察了性别和状态- 对父母行为的依赖性影响缺乏对理解如何产生依赖性影响的关键细胞类型分辨率。 调制特定的电路组件。影响养育子女的变化的时间尺度很长（数小时至数天） 行为表明，神经回路通过动态基因表达变化作出反应。通过使用 交叉遗传学和单细胞分析，我已经建立了两个关键的 控制养育行为的神经中枢比较母亲、父亲和处女的初步结果 动物表明潜在的转录，表观遗传和生物物理差异，这取决于 动物的性别和生理状态。在这里提出的K99阶段工作中，我将严格评估 性别和状态依赖的转录变化，以及它们的生物物理和行为影响， 使用最新的工具进行细胞类型特定的记录和操作。我将揭开基因调控网络 这会引起可观察到的转录变化，并将开发新的交叉工具来调节基因 以细胞类型特异性方式表达。这些目标的成功完成将揭示分子 性别和状态介导转录重编程以影响这一功能的机制 保守行为回路遗传变异也会导致父母在照顾孩子方面的差异。 利用遗传上不同的小鼠品系的初步结果显示，养育行为存在显着差异 并暗示了行为变异的遗传因素。在本提案的独立R 00阶段，我将 利用一组特征良好的遗传多样性小鼠进行正向遗传筛选， 基因组变异对父母行为的影响。细胞类型特异性基因调控网络揭示了 然后，将使用先前目标中的方法来评估个体变异的因果作用， 用以前的遗传作图实验无法得到的分子解释。此外，成功的 该项目的完成将为未来的实验提供一个平台，旨在了解基因是如何遗传的。 变异有助于基因表达，最终影响动物行为。 该奖项的培训阶段将在哈佛大学凯瑟琳迪拉克博士的实验室进行 大学此外，我的顾问委员会中杰出的科学家团队将指导我， 将协助具体的培训目标以及职业指导。在我的申请中，我概述了 一个全面的计划，用于获得概念，技术和专业技能，使我能够 向独立研究方向转型。