Astrocyte transcriptional responses to neuronal activity in the olfactory bulb

星形胶质细胞对嗅球神经元活动的转录反应

• 批准号: 10589057
• 负责人: Debosmita Sardar
• 金额: $ 9.91万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-10 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589057
• 关键词: Affect; Alzheimer' s Disease; Astrocytes; Behavior; Behavioral; Biological Assay; Biology; Brain; Calcium; ChIP-seq; Chemicals; Communication; Data; Environment; Epigenetic Process; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Models; Genetic Transcription; Goals; Hippocampus; Histones; Image; Impairment; Individual; Knowledge; Lead; Learning; Measurement; Mediating; Medicine; Membrane Transport Proteins; Memory; Mentors; Modeling; Modification; Molecular; Morphology; Mus; Mutation; Neurodegenerative Disorders; Neuroglia; Neuromodulator; Neurons; Nuclear; Odors; Olfaction Disorders; Olfactory Pathways; Olfactory dysfunction; Parkinson Disease; Phase; Phenotype; Physiological; Play; Property; Proteins; Research; Role; Sensory; Serotonin; Signal Transduction; Smell Perception; System; Testing; Training; Transcriptional Activation; Variant; career development; college; epigenetic regulation; epigenomics; experimental study; gain of function; genetic manipulation; histone modification; human old age (65+); in vivo; insight; loss of function; mouse model; nervous system disorder; neuronal circuitry; novel; novel strategies; olfactory bulb; optical sensor; overexpression; prevent; response; sensory stimulus; therapy development; transcriptomics; two photon microscopy

Project Summary/Abstract Astrocytes are non-neuronal cells widely distributed in the brain and astrocyte-neuron communication play critical roles in modulation of behavior. Sensory stimuli like chemical signals of odors activate neurons to induce gene expression changes that facilitate sensory processing. While these are well understood in neurons, whether similar transcriptomic changes also occur in astrocytes are unknown. Here, using in vivo chemogenetic models of neuronal activation, we show astrocytes indeed undergo robust gene expression changes after neuronal activation. A screen through these changes identified a neuromodulator transporter Slc22a3 in olfactory bulb astrocytes. Since preliminary studies revealed odor-evoked neuronal activation also increased astrocytic Slc22a3 in the olfactory bulb, we first asked how Slc22a3 affect astrocyte function in the olfactory bulb? We show that overexpression of astrocyte-specific Slc22a3 led to increased sensitivity to odors implying that astrocytic Slc22a3 affects astrocyte-neuron communication. This leads to the hypothesis that transcriptional activation of astrocytic Slc22a3 is essential for mediating astrocyte-neuron communication during olfactory processing. To test this hypothesis, we propose to use Slc22a3 gain-of-function and loss-of- function mouse models to investigate how astrocytic Slc22a3 affect behaviors and cellular properties of astrocytes (Aim1). Since Slc22a3 transports neuromodulators like serotonin, we next asked how Slc22a3- mediated serotonin transport affect molecular properties of olfactory bulb astrocytes? Since recent studies have shown that serotonin can be directly incorporated into histones to activate transcription, we focused on this epigenetic modification of histone serotonoylation. We show that in olfactory bulb astrocytes, overexpression of Slc22a3 controls histone serotonoylation levels. Therefore, we propose to genetically manipulate astrocytic Slc22a3 expression to determine Slc22a3-mediated histone serotonoylation dynamics in the olfactory bulb (Aim2). Furthermore, preliminary data also revealed that histone serotonoylation levels are increased in astrocytes after odor-evoked neuronal activation. Therefore, using experimental approaches established in Aims1-2, I will directly investigate the function of astrocytic histone serotonoylation in the olfactory bulb (Aim3). Taken together, these results will reveal genetic and epigenetic mechanisms of how astrocytes contribute to olfactory processing. For my career development these studies will provide training in olfactory bulb biology under my mentor Dr. Deneen (expert in astrocyte biology) and co-mentor Dr. Arenkiel (expert in olfactory bulb circuits and behaviors) at Baylor College of Medicine. Since astrocytes are intimately connected with neurons and are dysregulated in all neurological disorders, the broader goal of this proposal is to uncover how astrocytes contribute to healthy processing of the chemical senses of smell. Towards this goal, the proposed research will apply new approaches of astrocyte biology to delineate genetic and epigenetic mechanisms involved in normal function of the smell system.

项目总结/摘要 星形胶质细胞是广泛分布于大脑和星形胶质细胞-神经元通讯中的非神经元细胞 在行为调节中起着关键作用。感觉刺激，如气味的化学信号，激活神经元， 诱导基因表达变化，促进感觉加工。虽然这些都很好地理解， 类似的转录组学变化是否也发生在星形胶质细胞中尚不清楚。在这里，使用体内 神经元激活的化学遗传学模型，我们表明星形胶质细胞确实经历了强大的基因表达 神经元激活后的变化。通过对这些变化的筛选， 嗅球星形胶质细胞中的slc 22 a3。由于初步研究表明，气味诱发的神经元激活也 增加的星形胶质细胞Slc 22 a3在嗅球，我们首先问Slc 22 a3如何影响星形胶质细胞的功能， 嗅球？我们发现星形胶质细胞特异性Slc 22 a3的过度表达导致对气味的敏感性增加， 这意味着星形胶质细胞Slc 22 a3影响星形胶质细胞-神经元通讯。这就引出了一个假设， 星形胶质细胞Slc 22 a3的转录激活对于介导星形胶质细胞-神经元通讯是必需的 在嗅觉处理过程中。为了验证这一假设，我们建议使用Slc 22 a3功能获得和功能丧失。 功能小鼠模型，研究星形胶质细胞Slc 22 a3如何影响行为和细胞特性， 星形胶质细胞（Aim 1）。由于Slc 22 a3转运神经调质，如血清素，我们接下来问Slc 22 a3- 介导的5-羟色胺转运影响嗅球星形胶质细胞的分子特性？由于最近的研究 已经证明血清素可以直接掺入组蛋白中以激活转录，我们专注于 这种组蛋白去乙酰化的表观遗传修饰。我们发现嗅球星形胶质细胞， Slc 22 a3的过表达控制组蛋白脱羧酰化水平。因此，我们建议从基因上 操纵星形胶质细胞Slc 22 a3表达，以确定Slc 22 a3介导的组蛋白去乙酰化动力学， 嗅球（Aim 2）。此外，初步的数据还显示，组蛋白乙酰基化水平是 在气味诱发的神经元激活后星形胶质细胞中增加。因此，使用实验方法 在Aims 1 -2中建立的，我将直接研究星形胶质细胞组蛋白去乙酰化在 嗅球（Aim 3）。总之，这些结果将揭示遗传和表观遗传机制， 星形胶质细胞有助于嗅觉加工。为了我的职业发展，这些研究将提供以下方面的培训： 嗅球生物学在我的导师Deneen博士（星形胶质细胞生物学专家）和共同导师Arenkiel博士 （嗅球回路和行为专家）。由于星形胶质细胞与 与神经元连接，在所有神经系统疾病中失调，该提案的更广泛目标是 揭示星形胶质细胞如何促进嗅觉的化学感觉的健康处理。为了实现这一目标， 拟议中的研究将应用星形胶质细胞生物学的新方法来描述遗传和表观遗传。 嗅觉系统的正常功能。