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（ASDS）的特征是认知和社会缺陷套件，以及包括线粒体，代谢和温度调节缺陷在内的一系列体细胞异常。 ASD的代谢特征很少受到研究人员研究小鼠模型中与ASD相关表型的关注。此外，尽管ASD被理解为发育障碍，但很少有研究人员采用开发方法来建模与ASD相关的社会缺陷。最近的证据表明，几种社会功能障碍的小鼠模型（例如，催产素和催产素受体敲除）具有惊人的代谢和温度调节缺陷，在先前对ASD相关表型的研究中未被注意到。缺乏联系社会和代谢缺陷的框架，目前尚不清楚这些模型可能与破坏的代谢（例如，热）稳态有关的社会缺陷在多大程度上。我们将测试一个框架，在该框架中，社会和代谢表型在发育时间范围内被视为密切相关的框架，其中预计患有代谢性和/或温度调节性稳态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，并将重点放在棕色脂肪组织（BAT）热生成作为小鼠模型中社交和代谢表型的模型系统。首先，我们将在发育过程中采用一系列代谢和社交/情感度量的小鼠中的小鼠中的个体发育轨迹，目的是探索代谢表型自然发生变化对社会和情感表型变异的影响。接下来，我们将在许多小鼠线条中表征社会和代谢功能，以及选择用于在社会或代谢功能中缺陷的基因设计的基因“敲除”构建体，目的是测试我们的假设，即代谢和社交表型在小鼠菌株中和跨小鼠菌株和构造中表现出共同差异。我们还将测试动物饲养和测试期间热条件对在已经已知具有大量热调节缺陷的ASD相关表型的几种小鼠模型的社会和情绪功能测试中的性能的贡献。该实验将阐明温度调节缺陷在这些小鼠表现出的社会和情感缺陷中的作用。最后，我们将研究以下假设：蝙蝠产生的代谢热在介导小鼠模型中使用BAT和催产素功能的药理学操纵在小鼠模型中的亲社会作用中起重要作用。这些实验将大大增加我们对小鼠模型中ASD与ASD相关表型的知识，并且鉴于ASD中的代谢缺陷尚未理解，因此具有很高的翻译价值。