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; 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.

项目摘要/摘要 父母护理对于后代的福祉和生存至关重要，但需要成人大量投资 没有直接的好处，暗示存在控制其控制的硬连线机制。尽管 这种进化控制行为的重要性，父母的行为在 不同的性别，身体状态和遗传背景。先前研究性别和状态的研究 对父母行为的依赖影响缺乏对了解如何理解如何了解的细胞类型分辨率 特定电路组件进行调制。影响育儿的变化的长时间尺度（小时到几天） 行为表明神经回路通过动态基因表达的变化做出反应。通过使用 交叉遗传学和单细胞分析我已经确定了对两个键的特定访问 神经元中心控制育儿行为。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取决于 动物的性别和身体状态。在这里提出的工作的K99阶段，我将严格评估 性别和状态依赖性的转录变化及其生物物理和行为含义， 使用用于细胞类型的特定记录和操作的最新工具。我将发现基因调节网络 这引起了观察到的转录变化，并将开发新的交叉工具来调节基因 以细胞类型的特定方式表达。这些目标的成功完成将揭示分子 虽然哪种性别和状态介导了转录重编程以影响此功能 保守的行为回路。遗传变异也导致父母护理表现的差异。 使用一般不同小鼠菌株的初步结果显示出育儿行为的巨大差异 并提出对行为变化的遗传贡献。在本提案的独立R00阶段，我将 使用特征良好的遗传多样的小鼠进行前向遗传屏幕，以找到 有助于父母行为的基因组变体。细胞类型的特异性基因调节网络显示 然后，在上一个目标中，将用于评估单个变体的因果作用，提供一定程度的水平 与以前的遗传学映射实验无法获得的分子解释。此外，成功 该项目的完成将为将来的实验提供一个平台，以了解遗传 变体有助于最终影响动物行为的基因表达。 该奖项的培训阶段将在哈佛的凯瑟琳·杜拉克（Catherine Dulac）博士实验室进行 大学。此外，我的咨询委员会的杰出科学家团队将考虑我 将协助实现特定的培训目标以及职业指导。在我的应用中，我概述了 获取概念，技术和专业技能的全面计划，这将使我 过渡到独立的研究职位。