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，受压力源和代谢因素的影响，并涉及多重变化行为组成部分和决策过程。成千上万的遗传变异具有很小的影响通常涉及。这就是我们缺乏一个连贯的遗传，细胞和进化模型，无法理解和修改影响决策，活动和压力的重要行为组成部分。如果是这样可以针对构成自然主义行为，我们的能力来发现控制的基本模型觅食有被研究了数十年，以揭示决策的基本原理和机制。研究通常使用简化的二进制选择测试。但是，我们最近发表了自然主义的觅食测定法和无监督的机器学习方法研究小鼠复杂的自然决策模式。我们发现觅食是由可重复的，遗传控制的行为序列组成的 “模块”。使用这些方法，我们研究了在母体和亲子印刷基因中的作用控制男性和女性的自然主义决策模式。规范的印迹涉及完整沉默一个父母的等位基因；但是，我们先前描述了具有“非规范印迹效应”的基因这涉及在组织水平上的父母等位基因表达偏见。我们现在有证据表明非规范性在组织水平上的印迹效应涉及细胞亚群中的等位基因沉默。而且，我们发现了非规范印迹效应在控制自然主义觅食和风险奖励方面的重要作用决策模式。目前，我们不完全了解不同非规范的行为角色印迹基因。假定MEGS（母体表达的基因）和PEG（亲子表达的基因）具有相反的功能角色，提出了哺乳动物的诱人遗传和进化模型决策控制。不同细胞种群中的烙印效应可以调节形式，表达，时机和/或觅食不同行为成分的顺序。因此，我们提出的研究测试非规范性梅格斯和钉子对离散行为有反对影响的假设自然主义觅食及其细胞类型特异性印迹效应的组成部分揭示了细胞控制离散行为的人群。在AIM 1中，我们将确定MEGS和PEG如何共表达单胺能脑细胞中的Th（酪氨酸羟化酶）和DDC（DOPA脱羧酶）影响自然主义决定。在AIM 2中，我们将定义具有印迹效果的离散细胞群之间的功能联系自然主义觅食和决策模式的特定基因和离散的行为组成部分。我们的拟议的研究很重要，因为它将有助于定义一个重要的遗传，细胞和进化模型行为和决策控制。我们的长期目标是定义一个新的保守机械模型控制决策模式，该模式有助于描绘目标修改人类行为的目标。