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。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asd被认为是发育障碍，但很少有研究人员采用发育方法来模拟asd相关的社会缺陷。最近的证据表明，一些社交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，这些缺陷在以前的自闭症相关表型研究中未被注意到。社会和代谢缺陷的相关框架尚不清楚，这些模型显示的社会缺陷在多大程度上与代谢（如热）稳态紊乱有关。我们将测试一个框架，在这个框架中，社会和代谢表型在整个发育时间尺度上被视为密切相关，在这个框架中，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）产热作为小鼠模型中与社会和代谢表型相关的模型系统。首先，我们将追踪高社会性和低社会性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，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，我们将在许多小鼠品系和基因工程基因“敲除”构建体中表征社会和代谢功能，这些构建体选择了在社会或代谢功能方面存在缺陷的基因，目的是验证我们的假设，即代谢和社会表型在小鼠品系和构建体内部和之间表现出共同变异。我们还将在几种已知具有显著热调节缺陷的asd相关表型小鼠模型中测试动物饲养和测试期间的热条件对社会和情感功能常用测试的表现的贡献。本实验将阐明体温调节缺陷在这些小鼠表现出的社交和情感缺陷中的作用。最后，我们将通过对BAT和催产素功能的药理学操作，检验BAT产生的代谢热在小鼠模型中介导催产素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小鼠模型中ASD相关表型的发育和表达的认识，并且鉴于ASD中存在鲜为人知的代谢缺陷，这些实验将具有很高的翻译价值。

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.