The Nature and Function of Genomic Imprinting in Monoaminergic Neurons

单胺能神经元基因组印记的性质和功能

基本信息

批准号：
10693307
负责人：
Chris Gregg
金额：
$ 68.6万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-04 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10693307
关键词：
Adrenal Glands Adrenal Medulla Affect Alleles Behavior Behavior Control Behavior Disorders Behavioral Behavioral Model Biological Assay Brain Brain region Catecholamines Cells Complex DOPA decarboxylase Decision Making Dependovirus Enzymes Epigenetic Process Epinephrine Exhibits Fasting Female Genes Genetic Genetic Models Genomic Imprinting Goals Heritability Heterozygote Human Hydrocortisone Hypothalamic structure Length Link Mammals Mental disorders Metabolic Methods Modeling Mus Mutant Strains Mice Mutation Nature Neurons Parents Pathology Pattern Population Population Control Process Public Health Publishing Reporter Reproducibility Research Resources Rewards Risk Role Serotonin Stress Testing Therapeutic Tissues Tyrosine 3-Monooxygenase behavior test behavioral phenotyping behavioral response brain cell cell type genetic risk factor genetic variant hypothalamic-pituitary-adrenal axis imprint improved machine learning method male maternal imprint monoamine novel offspring parental involvement paternal imprint sex stressor targeted treatment unsupervised learning

项目摘要

Mental illnesses are complex, affected by stressors and metabolic factors and involve changes to multiple behavioral components and decision-making processes. Thousands of genetic variants with small effects are typically involved. Thus, we lack a coherent genetic, cellular and evolutionary model for understanding and modifying important behavioral components affecting decision-making, activity and stress. If such a fundamental model of control could be uncovered for conserved, naturalistic behavior, our capabilities for understanding and therapeutically modifying behavioral disorders would be improved. Foraging has been studied for decades to uncover the basic principles and mechanisms of decision-making. Studies typically use simplified binary choice tests. However, we recently published a naturalistic foraging assay and unsupervised machine-learning methods to study complex, naturalistic decision patterns in mice. We discovered that foraging is composed of reproducible, genetically controlled behavioral sequences that we call “modules”. Using these methods, we investigated roles for maternally and paternally imprinted genes in controlling naturalistic decision patterns in males and females. Canonical imprinting involves complete silencing of one parent’s allele; however, we previously described genes with “noncanonical imprinting effects” that involve parental allele expression biases at the tissue level. We now have evidence that noncanonical imprinting effects at the tissue level involve allele silencing in subpopulations of cells. Moreover, we uncovered important roles for noncanonical imprinting effects in controlling naturalistic foraging and risk-reward-effort decision patterns. Currently, we do not fully understand the behavioral roles for different noncanonical imprinted genes. MEGs (maternally expressed genes) and PEGs (paternally expressed genes) are postulated to have opposing functional roles, suggesting an enticing genetic and evolutionary model of mammalian decision control. Imprinting effects in different cell populations could regulate the form, expression, timing and/or sequential order of different behavioral components of foraging. Therefore, our proposed study tests the hypothesis that noncanonical MEGs and PEGs have opposing effects on discrete behavioral components of naturalistic foraging and their cell-type specific imprinting effects reveal cell populations controlling discrete behaviors. In Aim 1, we will determine how MEGs and PEGs co-expressed with Th (tyrosine hydroxylase) and Ddc (dopa decarboxylase) in monoaminergic brain cells affect naturalistic decisions. In Aim 2, we will define functional links between discrete cell populations with imprinting effects for particular genes and discrete behavioral components of naturalistic foraging and decision patterns. Our proposed study is significant because it will help define an important genetic, cellular and evolutionary model of behavioral and decision control. Our long-term objective is to define a new conserved mechanistic model of control over decision patterns that helps delineate targets for therapeutically modifying human behavior.

精神疾病很复杂，受到压力源和代谢因素的影响，涉及多种因素的变化。数千种影响较小的基因变异。因此，我们缺乏一个连贯的遗传、细胞和进化模型来理解和理解。改变影响决策、活动和压力的重要行为成分。可以揭示保守的自然行为、我们的能力的基本控制模型对于行为障碍的理解和治疗改变将会得到改善。几十年来，人们一直在研究决策的基本原理和机制。通常使用简化的二元选择测试，但是，我们最近发布了一种自然觅食测定法和无监督机器学习方法来研究小鼠复杂、自然的决策模式。发现觅食是由可复制的遗传行为序列组成的，我们称之为使用这些方法，我们研究了母系和父系印记基因的作用。控制男性和女性的自然决策模式涉及完整的印记。父母一方的等位基因沉默；然而，我们之前描述过具有“非典型印记效应”的基因我们现在有证据表明，这涉及组织水平上的亲本等位基因表达偏差。此外，我们发现组织水平的印记效应涉及细胞亚群中的等位基因沉默。非典型印记效应在控制自然觅食和风险回报努力方面的重要作用目前，我们还没有完全理解不同非规范的行为角色。假设有 MEG（母源表达基因）和 PEG（父源表达基因）。具有相反的功能作用，表明哺乳动物具有诱人的遗传和进化模型不同细胞群中的印记效应可以调节形式、表达、时间。因此，我们建议进行研究测试。非规范 MEG 和 PEG 对离散行为具有相反影响的假设自然觅食的成分及其细胞类型特异性印记效应揭示了细胞在目标 1 中，我们将确定 MEG 和 PEG 如何共表达。单胺能脑细胞中的 Th（酪氨酸羟化酶）和 Ddc（多巴脱羧酶）影响自然在目标 2 中，我们将定义具有印记效应的离散细胞群之间的功能联系。我们的自然觅食和决策模式的特定基因和离散行为成分。拟议的研究意义重大，因为它将有助于定义重要的遗传、细胞和进化模型我们的长期目标是定义一个新的保守机制模型。对决策模式的控制有助于描绘治疗性改变人类行为的目标。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Diverse Non-genetic, Allele-Specific Expression Effects Shape Genetic Architecture at the Cellular Level in the Mammalian Brain.

多种非遗传、等位基因特异性表达效应在哺乳动物大脑的细胞水平上塑造遗传结构。

DOI：
发表时间：
2017-03-08
期刊：
影响因子：
16.2
作者：
Huang, Wei;Ferris, Elliott;Cheng, Tong;Hörndli, Cornelia Stacher;Gleason, Kelly;Tamminga, Carol;Wagner, Janice D;Boucher, Kenneth M;Christian, Jan L;Gregg, Christopher
通讯作者：
Gregg, Christopher

Noncanonical genomic imprinting in the monoamine system determines naturalistic foraging and brain-adrenal axis functions.

单胺系统中的非规范基因组印记决定了自然觅食和脑-肾上腺轴功能。

DOI：
发表时间：
2022-03-08
期刊：
影响因子：
8.8
作者：
Bonthuis, Paul J;Steinwand, Susan;Stacher Hörndli, Cornelia N;Emery, Jared;Huang, Wei;Kravitz, Stephanie;Ferris, Elliott;Gregg, Christopher
通讯作者：
Gregg, Christopher

Complex Economic Behavior Patterns Are Constructed from Finite, Genetically Controlled Modules of Behavior.

复杂的经济行为模式是由有限的、基因控制的行为模块构成的。

DOI：
发表时间：
2019
期刊：
影响因子：
8.8
作者：
Stacher Hörndli, Cornelia N;Wong, Eleanor;Ferris, Elliott;Bennett, Kathleen;Steinwand, Susan;Rhodes, Alexis Nikole;Fletcher, P Thomas;Gregg, Christopher
通讯作者：
Gregg, Christopher

Simplified CRISPR tools for efficient genome editing and streamlined protocols for their delivery into mammalian cells and mouse zygotes.

简化的 CRISPR 工具可实现高效的基因组编辑，并简化了将其递送至哺乳动物细胞和小鼠受精卵的方案。

DOI：
发表时间：
2017-05-15
期刊：
影响因子：
0
作者：
Jacobi, Ashley M;Rettig, Garrett R;Turk, Rolf;Collingwood, Michael A;Zeiner, Sarah A;Quadros, Rolen M;Harms, Donald W;Bonthuis, Paul J;Gregg, Christopher;Ohtsuka, Masato;Gurumurthy, Channabasavaiah B;Behlke, Mark A
通讯作者：
Behlke, Mark A

Epigenetic and Cellular Diversity in the Brain through Allele-Specific Effects.

通过等位基因特异性效应研究大脑中的表观遗传和细胞多样性。