Toxicant Induced dysregulation of parvalbumin interneuron development and function

有毒物质引起的小白蛋白中间神经元发育和功能失调

基本信息

批准号：
10305591
负责人：
Jessica Susan Plavicki
金额：
$ 40.75万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10305591
关键词：
Adult Affect Agonist Alkanesulfonates Alzheimer&apos s Disease Aryl Hydrocarbon Receptor Behavior Benzo(a)pyrene Brain Calcium-Binding Proteins Chlorpyrifos Complex Data Development Developmental Process Dioxins Disease Embryo Epilepsy Equilibrium Ethers Etiology Exposure to Extracellular Matrix Functional disorder Generations Genes Genetic Genetic Transcription Genetic study Goals Health Homologous Gene Hyperactivity Impairment Intellectual functioning disability Interneuron function Interneurons Invertebrates Learning Mediating Memory Memory impairment Mental disorders Modeling Molecular Monitor National Institute of Environmental Health Sciences Neurons Outcome Parvalbumins Pathology Phenotype Population Predisposition Protein Isoforms Public Health Radial Receptor Activation Research Personnel Role Schizophrenia Signal Transduction Source Structure Testing Tetrachlorodibenzodioxin Tissues Toxic Environmental Substances Toxicant exposure Transcription Coactivator Transgenic Organisms Valproic Acid Work Zebrafish age related autism spectrum disorder burden of illness calcium indicator cell type critical period developmental disease developmental genetics gene function genetic manipulation in vivo information processing insight loss of function monobutyl phthalate nervous system disorder neural circuit neuroimaging neurotoxicity optogenetics prevent progenitor relating to nervous system stem cells tool toxicant transcription factor

项目摘要

PROJECT SUMMARY/ABSTRACT Neurological diseases and psychiatric disorders account for ~28% of the global burden of disease. Our ability to prevent and treat these diseases and disorders is hindered by their complex, multifactorial etiologies. Our long- term goal is to help prevent neurological diseases and psychiatric disorders by using functional neuroimaging studies in zebrafish to understand the susceptibility of neural populations to toxicant exposures during critical periods of development. Disruptions in the balance of excitatory and inhibitory signaling contribute to a number of neurological diseases and psychiatric disorders including hyperactivity, autism, intellectual disabilities, schizophrenia, epilepsy, and Alzheimer’s Disease. A common theme connecting these diverse diseases and disorders is the disrupted development of parvalbumin (PV) interneurons. Our immediate goal is to gain insight into the molecular mechanisms mediating PV development and function and how these critical developmental processes are disrupted by toxicant exposure. To achieve this goal, we are developing a suite of genetic tools for visualizing the development, connectivity, and functioning of PV interneurons in vivo as well as tools for manipulating gene function specifically in PV interneurons. In addition, we are generating transgenic lines that allow us to visualize the assembly and functioning of excitatory circuitry in the context of our PV interneuron- specific manipulations. Our preliminary data indicate that dlx1, 5 and 6, known regulators of GABAergic and PV interneuron development, and multiple isoforms of PV, are downregulated following exposure to 2,3,7,8- Tetrachlorodibenzo-p-dioxin (dioxin, TCDD), a prototypical aryl hydrocarbon receptor (AHR) agonist. In Aim 1, we will utilize our genetic tool kit and functional neuroimaging to determine if exposure to different AHR agonists disrupts PV interneuron development and function. We will use cell-type specific genetic manipulations to activate AHR in PV interneurons and determine if AHR activation alters PV interneuron function, the assembly of excitatory circuits in the developing brain, and is sufficient to produce larval hyperactivity as well as deficits in adult learning and memory. Mammalian Sox9 and zebrafish sox9b are AHR targets and are also downregulated following exposure to a number of toxicants including mono-butyl phthalate, 6:2 chlorinated polyfluorinated ether sulfonate, valproic acid, and chlorpyrifos. Mammalian Sox9 marks radial progenitor cells (RGP), an important source of GABAergic interneurons. In Aim 2, we will determine whether zebrafish sox9b is an important transcriptional regulator of PV development, and if PV-interneuron specific loss of sox9b is sufficient to disrupt PV interneuron function and larval and adult behavior. In Aim 3, we will use photoconvertible indicators of neural activity to determine the differential effects of AHR agonist exposure on embryonic and larval brain function. Together, these studies will provide insight into the molecular mechanisms mediating PV interneuron development and toxicant-induced disruption of this critical cell-type. The proposed studies directly contribute to NIEHS’s Strategic Goal 1, parts c, d, & e.

项目概要/摘要神经系统疾病和精神疾病约占全球疾病负担的 28%。这些疾病和病症的预防和治疗受到其复杂、多因素的病因的阻碍。长期目标是通过使用功能性神经影像学帮助预防神经系统疾病和精神疾病对斑马鱼进行研究，以了解神经群体在关键时期对有毒物质暴露的敏感性兴奋性和抑制性信号平衡的破坏会导致许多问题。神经系统疾病和精神疾病，包括多动症、自闭症、智力障碍、精神分裂症、癫痫症和阿尔茨海默病是连接这些不同疾病和疾病的共同主题。疾病是小清蛋白 (PV) 中间神经元的发育受到干扰。我们的直接目标是获得洞察力。研究介导PV发育和功能的分子机制以及这些关键的发育如何为了实现这一目标，我们正在开发一套遗传工具。用于可视化体内 PV 中间神经元的发育、连接和功能以及工具特别是在PV中间神经元中操纵基因功能此外，我们正在产生转基因品系。让我们能够在PV中间神经元的背景下可视化兴奋性电路的组装和功能我们的初步数据表明，dlx1、5 和 6 是 GABAergic 和 PV 的已知调节因子。暴露于 2,3,7,8- 后，中间神经元发育和 PV 的多种亚型都会下调四氯二苯并-对-二恶英（二恶英，TCDD），一种典型的芳烃受体（AHR）激动剂。我们将利用我们的遗传工具包和功能神经影像学来确定是否暴露于不同的 AHR 激动剂破坏 PV 中间神经元的发育和功能。我们将使用细胞类型特异性基因操作来进行治疗。激活 PV 中间神经元中的 AHR，并确定 AHR 激活是否会改变 PV 中间神经元功能、组件发育中大脑的兴奋性回路，足以产生幼虫过度活跃以及神经元缺陷哺乳动物 Sox9 和斑马鱼 sox9b 是 AHR 目标，也被下调。接触多种有毒物质（包括邻苯二甲酸单丁酯、6:2 氯化多氟醚）后磺酸盐、丙戊酸和毒死蜱是哺乳动物 Sox9 的标记，是一种重要的径向祖细胞 (RGP)。在目标 2 中，我们将确定斑马鱼 sox9b 是否是一个重要的来源。 PV 发育的转录调节因子，如果 PV 中间神经元特异性丢失 sox9b 足以破坏 PV 中间神经元功能以及幼虫和成虫的行为在目标 3 中，我们将使用神经光转换指标。活性以确定 AHR 激动剂暴露对胚胎和幼虫脑功能的差异影响。总之，这些研究将深入了解介导 PV 中间神经元的分子机制拟议的研究直接有助于这种关键细胞类型的发育和毒物诱导的破坏。 NIEHS 的战略目标 1，c、d 和 e 部分。