Developmental Linkage of Metabolic Homeostasis and Sociality

描述（由申请人提供）：自闭症谱系障碍（ASD）的特征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。ASD的代谢特征很少受到研究小鼠模型中ASD相关表型的研究人员的关注。此外，尽管ASD被理解为发育障碍，但很少有研究人员采用发展方法来建模ASD相关的社会缺陷。最近的证据表明，一些社会功能障碍的小鼠模型（例如，催产素和催产素受体敲除）具有显著的代谢和体温调节缺陷，这在先前的ASD相关表型研究中未被注意到。缺乏一个将社交和代谢缺陷联系起来的框架，并且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紊乱有关（例如，热）稳态。我们将测试一个框架，在这个框架中，社会和代谢表型被视为在整个发展时间尺度上密切相关，并且预测代谢和/或体温调节稳态受损的动物在社会功能的基本方面表现出缺陷。我们将采用一套发育，遗传和药理学的方法来阐明这些关系，并将重点放在棕色脂肪组织（BAT）产热作为一个模型系统，在小鼠模型中的社会和代谢表型相关。首先，我们将跟踪高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/情感措施，目的是探索自然发生的代谢表型变异对社会和情感表型变异的影响。接下来，我们将描述一些小鼠品系和遗传工程基因“敲除”构建体中的社会和代谢功能，这些构建体被选择用于在社会或代谢功能中具有缺陷，目的是测试我们的假设，即代谢和社会表型表现出小鼠品系和构建体内部和之间的共变异。我们还将测试动物饲养和测试过程中的热条件对几种已知具有显着温度调节缺陷的ASD相关表型小鼠模型中常用的社会和情感功能测试的性能的贡献。这个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，我们将研究这一假设，即BAT产生的代谢热在介导催产素在小鼠模型中的亲社会作用中起着重要作用，使用BAT和催产素功能的药理学操作。这些实验将大大增加我们对小鼠模型中ASD相关表型的发育和表达的了解，并且鉴于ASD中存在知之甚少的代谢缺陷，将具有高翻译价值。

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.