Developmental Linkage of Metabolic Homeostasis and Sociality

代谢稳态和社交性的发展联系

基本信息

批准号：
9250799
负责人：
JEFFREY R ALBERTS
金额：
$ 29.04万
依托单位：
TRUSTEES OF INDIANA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-13 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9250799
关键词：
Address Adolescent Adult Animal Model Animals Attention BALB/cByJ Mouse Behavioral Biological Models Brown Fat Characteristics Clinical Cognitive Complex Development Documentation Emotional Employee Strikes Epidemiology Etiology Exhibits Functional disorder Generations Genetic Genetic Engineering Genetically Engineered Mouse Growth Homeostasis Human Impairment Inbred BALB C Mice Individual Knock-out Link Mammals Measures Mediating Metabolic Methods Mitochondria Modeling Mouse Strains Mus Neuropeptides Organism Outcome Oxytocin Oxytocin Receptor Patients Performance Pharmacology Phenotype Play Predisposition Regulation Research Research Personnel Rodent Role Route Sampling Sex Characteristics Social Behavior Social Development Social Functioning System Testing Thermogenesis Variant autism spectrum disorder base comparative developmental disease developmental genetics endophenotype experimental study knockout gene metabolic phenotype mitochondrial dysfunction mouse model novel public health relevance response social virtual

项目摘要

DESCRIPTION (provided by applicant): Autism spectrum disorders (ASDs) are characterized by a suite of cognitive and social deficits, as well as by a range of somatic abnormalities, including mitochondrial, metabolic, and thermoregulatory deficits. The metabolic features of ASDs have received little attention from researchers investigating ASD-related phenotypes in mouse models. In addition, few researchers have taken a developmental approach to modeling ASD-related social deficits, despite the ASDs being understood as developmental disorders. Recent evidence indicates that several mouse models of social dysfunction (e.g., oxytocin and oxytocin receptor knockouts) have striking metabolic and thermoregulatory deficits that have gone unnoticed in previous studies of ASD-related phenotypes. A framework for relating social and metabolic deficits is lacking, and it is unclear to what extent the social deficits displayed b these models may relate to disrupted metabolic (e.g., thermal) homeostasis. We will test a framework in which social and metabolic phenotypes are seen as intimately related across developmental timescale, and in which animals with compromised metabolic and/or thermoregulatory homeostasis are predicted to exhibit deficits in basic aspects of social functioning. We will employ a suite of developmental, genetic, and pharmacological methods to elucidate these relations, and will focus on brown adipose tissue (BAT) thermogenesis as a model system for relating social and metabolic phenotypes in mouse models. First, we will track individual developmental trajectories in mice from high- and low-social strains, employing a battery of metabolic and social/emotional measures during development, with the aim of exploring the impact of naturally occurring variation in metabolic phenotypes on variation in social and emotional phenotypes. Next, we will characterize social and metabolic functioning in a number of mouse lines and genetically-engineered gene 'knockout' constructs selected for having deficits in either social or metabolic functioning, with the aim of testing our hypothesis that metabolic and social phenotypes manifest co-variations within and across mouse strains and constructs. We will also test the contribution of thermal conditions during animal rearing and testing to performance on commonly used tests of social and emotional functioning in several mouse models of ASD-related phenotypes already known to possess significant thermoregulatory deficits. This experiment will clarify the role that thermoregulatory deficits pla in the social and emotional deficits displayed by these mice. Lastly, we will examine the hypothesis that metabolic heat generated by BAT plays a significant role in mediating the prosocial effects of oxytocin in mouse models using pharmacological manipulation of BAT and oxytocin functioning. These experiments will greatly add to our knowledge of the development and expression ASD- related phenotypes in mouse models, and will have high translational value, given the presence of poorly understood metabolic deficits in ASD.

描述（由申请人提供）：自闭症谱系障碍（ASD）的特点是一系列认知和社交缺陷，以及一系列躯体异常，包括线粒体、代谢和体温调节缺陷。在小鼠模型中研究 ASD 相关表型的研究人员很少关注 ASD 的代谢特征。此外，尽管自闭症谱系障碍被理解为发育障碍，但很少有研究人员采用发育方法来模拟与自闭症谱系障碍相关的社会缺陷。最近的证据表明，几种社交功能障碍小鼠模型（例如催产素和催产素受体敲除）具有显着的代谢和体温调节缺陷，而这些缺陷在之前的 ASD 相关表型研究中并未被注意到。目前缺乏将社交和代谢缺陷联系起来的框架，并且尚不清楚这些模型显示的社交缺陷在多大程度上可能与代谢（例如热）稳态破坏有关。我们将测试一个框架，在该框架中，社会和代谢表型被视为在整个发育时间尺度上密切相关，并且在该框架中，代谢和/或体温调节稳态受损的动物预计会在社会功能的基本方面表现出缺陷。我们将采用一套发育、遗传和药理学方法来阐明这些关系，并将重点关注棕色脂肪组织（BAT）生热作用，作为与小鼠模型中的社会和代谢表型相关的模型系统。首先，我们将跟踪高社会品系和低社会品系小鼠的个体发育轨迹，在发育过程中采用一系列代谢和社会/情感测量方法，目的是探索代谢表型自然发生的变化对社会性变化的影响。和情绪表型。接下来，我们将表征许多小鼠品系和基因工程基因“敲除”构建体的社会和代谢功能，这些小鼠系和基因工程基因“敲除”构建体被选择为具有社会或代谢功能缺陷，目的是检验我们的假设，即代谢和社会表型表现出共同的特征。小鼠品系和结构内部和之间的变异。我们还将测试动物饲养和测试期间的热条件对几种已知具有显着体温调节缺陷的 ASD 相关表型小鼠模型的常用社交和情绪功能测试的影响。该实验将阐明体温调节缺陷在这些小鼠表现出的社交和情绪缺陷中的作用。最后，我们将通过对 BAT 和催产素功能的药理学操作，检验以下假设：在小鼠模型中，BAT 产生的代谢热在介导催产素的亲社会效应中发挥着重要作用。这些实验将极大地增加我们对小鼠模型中自闭症谱系障碍相关表型的发育和表达的了解，并且鉴于对自闭症谱系障碍中存在的代谢缺陷知之甚少，因此将具有很高的转化价值。