Genomic imprinting in circuits for social behavior

社会行为回路中的基因组印记

基本信息

批准号：
10077920
负责人：
Paul Jeffrey Bonthuis
金额：
$ 24.9万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
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：
2020-04-03 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10077920
关键词：
ARHGEF5 gene Adult Affect Aggressive behavior Alleles Behavior Behavioral Assay Biological Sciences Brain Brain region Cells DOPA decarboxylase Data Development Enzymes Epigenetic Process Exhibits Female Genes Genetic Genomic Imprinting Genomic approach Heterozygote Hormonal Hybrids Hypothalamic structure Illinois In Situ Hybridization Individual Inherited Label Lead Link Liver Major Depressive Disorder Mental Depression Mental Health Mental disorders Methods Molecular Mus Muscle Mutant Strains Mice Mutation Neurodevelopmental Disorder Neurons Neurotransmitters Onset of illness Parents Pathway interactions Phase Phenotype Play Population Preoptic Areas Puberty Public Health Publications Reporter Reproductive Behavior Research Rewards Role Schizophrenia Social Behavior Structure of nucleus infundibularis hypothalami System Testing Training Programs Transgenic Organisms Tyrosine 3-Monooxygenase Universities Veterinary Medicine behavioral phenotyping cell type clinical phenotype college comparative genetic approach genetic risk factor hormonal signals imprint innovation male mental development monoamine mutant novel offspring preference response single-cell RNA sequencing social transcriptome transcriptome sequencing

项目摘要

Modified Project Summary/Abstract Section The R00 phase of this project will be conducted at the University of Illinois, Urbana-Champaign in the Department of Comparative Biosciences, College of Veterinary Medicine. Major psychiatric disorders, such as schizophrenia (SZ) and major depression, involve abnormal social behaviors and onset typically occurs after puberty. The genetic risk factors for SZ are frequently heterozygous in affected individuals and the clinical phenotypes can be highly variable. However, the factors that contribute to phenotypic variance and the timing of the onset of these disorders are poorly understood. Genomic imprinting is an epigenetic mechanism that causes preferential expression of the maternal or paternal allele for some genes. Imprinting causes parent-of-origin effects that influence the phenotype of inherited mutations. Canonical imprinting involves complete silencing of one parent’s allele and impacts a small number of genes. However, the author’s lab discovered that hundreds of genes in the mouse that exhibit a maternal or paternal allele expression bias. This phenomenon is called noncanonical imprinting. Noncanonical imprinting is highly enriched in the brain compared to the liver or muscle. Using a novel allele-specific in situ hybridization approach, the author found that noncanonical imprinted genes exhibit monoallelic expression in subpopulations of cells in the brain, suggesting a highly cell-type specific form of imprinting. Currently, it is not known whether noncanonical imprinting is a cell-type specific form of imprinting in the brain. Further, the field does not know whether noncanonical imprinting can change at puberty or whether social behaviors are impacted. The author found that tyrosine hydroxylase (Th) and dopa decarboxylase (Ddc) are noncanonical imprinted genes with a maternal allele bias in specific regions of the brain. TH and DDC synthesize monoamine neurotransmitters, which have important roles in social behavior and mental illness. Here, the author will test the hypothesis that noncanonical imprinting effects in monoaminergic circuits are a highly cell-type specific form of imprinting that can change in response to pubertal development and impact social behaviors with roles in mental illness. Aim 1 will determine whether noncanonical imprinting is a cell-type specific form of imprinting in the monoamine system of the hypothalamus and uncover the hormone signaling mechanisms operational within each monoamine cell type using single-cell RNASeq. Aim 2 will determine whether noncanonical imprinting in the preoptic area (POA) and arcuate nucleus (ARN) changes at puberty by profiling imprinting before and after puberty using RNASeq methods. The POA and ARN play important roles in puberty and social behaviors and preliminary data shows that noncanonical imprinting can change in these regions in response to hormonal signaling. In Aim 3, Ddc heterozygous mutant mice will be used to determine whether noncanonical imprinting in monoamine circuits impacts offspring social behaviors. Social behaviors that are impacted in mental illness will be tested, including aggression, social recognition, social reward and reproductive behaviors.

修改的项目摘要/摘要部分该项目的R00阶段将在兽医学院比较生物科学系的伊利诺伊大学，乌尔巴纳 - 坎普恩大学进行。精神分裂症（SZ）和严重抑郁症等主要的精神疾病涉及异常的社会行为和发作，通常发生在青春期后。 SZ的遗传危险因素在受影响的个体中经常是杂合的，临床表型可能是高度可变的。但是，对表型差异和这些疾病发作的时间的影响的因素知之甚少。基因组印记是一种表观遗传机制，可导致某些基因的母体或父亲等位基因的优先表达。烙印会引起产物父母的影响，影响遗传突变的表型。规范的印记涉及对一个父母的等位基因的完全沉默，并影响少数基因。但是，作者的实验室发现，小鼠中的数百个基因暴露了母体或父亲等位基因表达偏见。这种现象称为非规范印迹。与肝脏或肌肉相比，非规范的印迹在大脑中高度富集。使用一种新的等位基因特异性原位杂交方法，作者发现非规范的印迹基因在大脑中细胞的亚群中暴露了单相的表达，这表明具有高度细胞类型的印迹形式。目前，尚不清楚非规范印记是否是大脑中印迹的细胞类型特异性形式。此外，该领域不知道非规范的烙印在青春期是否可以改变，或者社交行为是否受到影响。作者发现，酪氨酸羟化酶（Th）和DOPA脱羧酶（DDC）是非规范的印迹基因，在大脑的特定区域中具有母体等位基因偏置。 TH和DDC合成单胺神经递质，它们在社会行为和精神疾病中具有重要作用。在这里，作者将检验以下假设：单胺能电路中的非规范印迹效应是一种高度细胞类型的烙印形式，可以改变青春期发展并影响社会行为，并在精神疾病中影响社会行为。 AIM 1将确定是否是在下丘脑的单胺系统中印迹的细胞类型的特定形式，并使用单细胞RNASEQ揭示了每种单胺细胞类型中在每种单胺细胞中运行的激素信号机制。 AIM 2将通过使用RNASEQ方法在青春期之前和之后进行烙印来确定在青春期和青春期的核核（POA）和弧形核us（ARN）变化中的非规范印记。 POA和ARN在青春期和社会行为中起着重要作用，并且初步数据表明，这些区域的非规范印迹可能会因响应于马的信号传导而改变。在AIM 3中，DDC杂合突变小鼠将用于确定单胺电路中的非规范印记是否会影响后代社会行为。在精神疾病中受到影响的社会行为将进行测试，包括积极的，社会认可，社会奖励和生殖行为。