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人员在小鼠模型中研究ASD相关表型的关注。此外，尽管自闭症被理解为发育障碍，但很少有研究人员采用发展的方法来模拟与自闭症相关的社会缺陷。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)存在显著的代谢和体温调节缺陷，这些缺陷在以前对ASD相关表型的研究中没有注意到。缺乏一个将社会和代谢缺陷联系起来的框架，目前还不清楚这些模型显示的社会缺陷在多大程度上与代谢(例如，热)内稳态的破坏有关。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育时间尺度上密切相关，代谢和/或体温调节稳态受损的动物被预测在社会功能的基本方面表现出缺陷。我们将使用一套发育、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)热生成作为联系小鼠模型中社会和代谢表型的模型系统。首先，我们将跟踪小鼠在高和低社交压力下的个体发育轨迹，在发育过程中采用一系列新陈代谢和社会/情绪指标，目的是探索代谢表型自然发生的变化对社会和情绪表型变化的影响。接下来，我们将在一些小鼠品系和被选为具有社会或代谢功能缺陷的基因敲除结构中表征社会和代谢功能，目的是检验我们的假设，即代谢和社会表型在小鼠品系和结构内和之间表现出协同变化。我们还将在已知存在重大体温调节缺陷的ASD相关表型的几个小鼠模型上，测试动物饲养和测试期间的热条件对常用的社交和情绪功能测试的性能的影响。这项实验将阐明体温调节缺陷在这些小鼠表现出的社会和情绪缺陷中所起的作用。最后，我们将通过对BAT和催产素功能的药理学操作，检验BAT产生的代谢热在调节催产素在小鼠模型中的亲社会效应中发挥重要作用的假设。这些实验将极大地增加我们对ASD相关表型在小鼠模型中的发展和表达的知识，并将具有很高的翻译价值，因为ASD存在着鲜为人知的代谢缺陷。

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.