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.

修改后的项目摘要/摘要部分该项目的 R00 阶段将在伊利诺伊大学厄巴纳-香槟分校兽医学院比较生物科学系进行。主要精神疾病，如精神分裂症 (SZ) 和重度抑郁症，涉及异常的社会行为和发病。通常发生在青春期后，受影响个体的遗传风险因素通常是杂合的，并且临床表型可能存在很大差异，但导致表型变异的因素和发生时间也不同。人们对这些疾病的发病机制知之甚少。基因组印记是一种表观遗传机制，可导致某些基因优先表达母本或父本等位基因。典型的印记会影响遗传突变的表型。父母之一的等位基因沉默并影响少数基因然而，作者的实验室发现小鼠中有数百个基因表现出母本或父本等位基因表达偏差，这种现象称为非典型现象。与肝脏或肌肉相比，非典型印记在大脑中高度丰富，作者使用一种新颖的等位基因特异性原位杂交方法，发现非典型印记基因在大脑细胞亚群中表现出单等位基因表达，这表明非典型印记基因具有高度细胞性。目前，尚不清楚非规范印记是否是大脑中的细胞类型特定形式的印记。作者发现，酪氨酸羟化酶 (Th) 和多巴脱羧酶 (Ddc) 是非典型印记基因，在大脑的特定区域具有母体等位基因偏差。，在社会行为和精神疾病中发挥着重要作用，在这里，作者将检验单胺能回路中的非规范印记效应的假设。是一种高度细胞类型特异性的印记形式，可以随着青春期发育而改变，并影响社会行为，在精神疾病中发挥作用。目标 1 将确定非规范印记是否是单胺系统中的细胞类型特异性印记形式。下丘脑并使用单细胞 RNASeq 揭示每种单胺细胞类型中运作的激素信号传导机制，将确定视前区 (POA) 和弓状核中是否存在非规范印记。通过使用 RNASeq 方法分析青春期前后的印记（ARN）变化，POA 和 ARN 在青春期和社会行为中发挥着重要作用，初步数据表明，非规范印记可以响应激素信号而改变。 , Ddc 杂合突变小鼠将用于确定单胺回路中的非规范印记是否会影响后代的社会行为。测试包括攻击性、社会认可、社会奖励和生殖行为。