Molecular, spatial, and functional development of innate behavior in the periaqueductal gray

导水管周围灰质先天行为的分子、空间和功能发育

• 批准号: 10053235
• 负责人: Eric Vaughn
• 金额: $ 3.32万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10053235
• 关键词: ARHGEF5 gene; Activities of Daily Living; Adolescent; Adult; Age; Aggressive behavior; Amygdaloid structure; Anxiety; Behavior; Behavior Control; Behavioral; Birth; Brain; Brain Stem; Cell Nucleus; Cells; Characteristics; Child; Child Rearing; Chronic; Data; Development; Event; Exhibits; Female; Fluorescent in Situ Hybridization; Fright; Galanin; Gene Expression Profile; Genes; Genetic Transcription; Goals; Hypothalamic structure; Immediate-Early Genes; In Situ; Instinct; Knowledge; Lead; Life; Literature; Maps; Medial; Methods; Molecular; Motor; Mus; Neurons; Neuropeptides; Nuclear; Partner in relationship; Pathology; Pathway interactions; Pattern; Population; Positioning Attribute; Prefrontal Cortex; Preoptic Areas; Process; Prosencephalon; Publishing; Resolution; Role; Running; Signal Transduction; Spinal Cord; Structure; Structure of nucleus infundibularis hypothalami; Techniques; Testing; Up-Regulation; Visualization; Work; age related; cell motility; cell type; computerized tools; data integration; developmental disease; feeding; gene expression database; insight; male; midbrain central gray substance; neurodevelopment; postnatal; postnatal development; progenitor; pup; receptor; relating to nervous system; single molecule; suckling; synaptogenesis; transcriptome sequencing; vocalization

Project Summary The brain generates behavior through the concerted action of diverse cell types. Recent work has genetically identified cell types governing specific instinctive behaviors, such as neurons expressing galanin within the medial preoptic area (MPOA), which are are necessary for parenting, or Agrp and POMC-expressing neurons of the arcuate nucleus, which are critical for feeding. However, it is not well understood how and when cell types important to instinctive behaviors are defined during postnatal development. The periaqueductal gray (PAG) is thought to serve as an integrator of many forebrain signals. It receives major input from the hypothalamus, amygdala, and prefrontal cortex, and transmit proper signals to motor nuclei of the brainstem and spinal cord. While the PAG is necessary for specific functions present at birth, such as vocalization and suckling, other functions of the PAG, including mating and aggression are not manifested until later in life. This leads to the hypothesis that cell types necessary to control these behaviors are not mature until later in life. The goal of this proposal is to discover how and when cells gain their mature functional significance in the PAG. The findings from this proposal will provide insight about PAG-related behavioral pathologies and how they may arise, for example chronic anxiety and excessive aggression. Aim 1 will define PAG cell types and their postnatal developmental trajectories utilizing single nucleus RNA- sequencing from mice at P1, P7, P14, P28, and P50-P60 (adult). Aim 2 will spatially define the development and distribution of cell types in the PAG using Multiplexed Error Robust Fluorescent In Situ Hybridization. Aim 3 will determine PAG cell types active in age-dependent innate behaviors (P1/P7, vocalization; P14, fear; P28, aggression; adult, mating and parenting) using a panel of 20 immediate early genes as a readout of recent cellular activity. Preliminary data shows that cells increase the overall number of genes expressed with age. Using data computationally aligned across ages, preliminary developmental trajectories of several clusters show age- dependent increases in genes relevant for receptivity and signaling, such as neuropeptides and their receptors. This supports the hypothesis that with age, cells gain new functional capacities through upregulation of genes that allow for increased cellular crosstalk. This proposal seeks to define these functions and specifically identify which genes are upregulated concordantly with that function.

项目摘要 大脑通过不同类型细胞的协同作用产生行为。最近的研究从基因上 确定了控制特定本能行为的细胞类型，例如在神经元内表达甘丙肽的神经元。 内侧视前区（MPOA），这是必要的养育，或Agrp和POMC表达神经元 这是进食的关键然而，还不清楚细胞如何以及何时 对本能行为重要的类型是在出生后的发育过程中确定的。 中脑导水管周围灰质（PAG）被认为是许多前脑信号的整合者。它接收主要 下丘脑，杏仁核和前额皮质的输入，并将适当的信号传递到运动核团。 脑干和脊髓虽然PAG对于出生时存在的特定功能是必需的，例如 除了发声和哺乳，PAG的其他功能，包括交配和攻击，直到 在以后的生活中这就引出了一个假设，即控制这些行为所必需的细胞类型还不成熟 直到晚年这项计划的目标是发现细胞如何以及何时获得其成熟的功能， 在PAG中的重要性该提案的调查结果将提供有关寻呼相关行为的见解 病理学以及它们是如何产生的，例如慢性焦虑和过度攻击。 目的1将利用单核RNA来确定PAG细胞类型及其出生后发育轨迹， 在P1、P7、P14、P28和P50-P60（成年）时从小鼠测序。目标2将在空间上定义开发 和PAG中细胞类型的分布。目的 3将决定在年龄依赖性先天行为中活跃的PAG细胞类型（P1/P7，发声; P14，恐惧; P28， 攻击;成年，交配和养育）使用一组20个立即早期基因作为最近的读数。 细胞活动 初步数据显示，细胞随着年龄的增长表达的基因总数增加。使用数据 通过年龄计算，几个集群的初步发展轨迹显示年龄- 与感受性和信号传导相关的基因的依赖性增加，如神经肽及其受体。 这支持了这样一个假设，即随着年龄的增长，细胞通过上调基因获得新的功能能力 其允许增加的蜂窝串扰。本建议旨在界定这些职能，并具体确定 哪些基因的上调与该功能一致。