The Nature and Function of Genomic Imprinting in Monoaminergic Neurons

精神疾病是复杂的，受压力和代谢因素的影响，并涉及多种变化， 行为成分和决策过程。数以千计的影响很小的遗传变异， 通常涉及。因此，我们缺乏一个连贯的遗传、细胞和进化模型来理解和 改变影响决策、活动和压力的重要行为成分。如果这样的 一个基本的控制模型可以被揭示，用于保守的，自然主义的行为，我们的能力， 对理解和治疗行为障碍的作用将得到改善。觅食有 人们已经研究了几十年，以揭示决策的基本原则和机制。研究 通常使用简化的二元选择测试。然而，我们最近发表了一项自然觅食试验， 无监督机器学习方法来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、基因控制的行为序列组成的，我们称之为 "模块"。利用这些方法，我们研究了母系和父系印记基因在 控制男性和女性的自然决策模式。典型的印记包括完整的 一个父母的等位基因沉默;然而，我们以前描述的基因与"非典型的印记效应" 在组织水平上涉及亲本等位基因表达偏差。我们现在有证据表明， 组织水平的印记效应涉及细胞亚群中的等位基因沉默。此外，我们发现， 非典型印记效应在控制自然觅食和风险-回报-努力中的重要作用 决策模式目前，我们还不能完全理解不同的非规范行为的作用， 印记基因MEG（母系表达基因）和PEG（父系表达基因）被假定为 具有相反的功能作用，这表明哺乳动物的一个诱人的遗传和进化模型， 决策控制印迹效应在不同细胞群体中可以调控其表达形式、表达时间、表达量、 和/或觅食的不同行为成分的顺序。因此，我们提出的研究测试 非典型MEG和PEG对离散行为有相反影响的假设 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 控制离散行为的群体。在目标1中，我们将确定MEG和PEG如何共表达 与Th（酪氨酸羟化酶）和Ddc（多巴脱羧酶）在单胺能脑细胞影响自然 决策在目标2中，我们将定义具有印记效应的离散细胞群体之间的功能联系， 自然觅食和决策模式的特定基因和离散行为组件。我们 这项研究意义重大，因为它将有助于确定一个重要的遗传，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的机械模型， 控制决策模式，帮助描绘治疗改变人类行为的目标。

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.