Genetic models for social attachment deficits in psychiatric illness

 说明(由申请人提供)：社会依恋在大多数(如果不是全部)人类互动中发挥核心作用，从亲子依恋、兄弟情谊和亲属关系、友谊和社会联系，到与伴侣的持久伙伴关系。社会依恋行为在临床上也是非常相关的，因为几种破坏性的疾病，如自闭症谱系障碍和精神分裂症，往往表现为人际互动的戏剧性崩溃。这些令人着迷的行为传统上对遗传和神经生物学方法具有抵抗力，因为对灵长类动物的工作施加了限制。到目前为止，老鼠是唯一一种遗传上容易驯化的哺乳动物模型，它似乎没有表现出成人的社交依恋行为。这项提议试图建立草原田鼠(Microtus Ochrogaster)作为一个模式系统，以检查与精神疾病相关的基因突变导致的社交依恋行为缺陷。草原田鼠是一种形似老鼠的小型啮齿动物，表现出强烈的社会依恋行为，以至于配偶通常会形成持久的伴侣纽带。结对会导致其他社会行为的戏剧性变化。这些发现表明，田鼠参与了丰富的社会依恋行为，这些行为与在人类身上观察到的许多社会行为有着惊人的相似之处。草原田鼠的开创性工作已经确定加压素(AVP)和催产素(OXT)、神经肽和激素是配对结合的关键媒介。值得注意的是，AVP和OXT信号也与人类的社交依恋类型行为有关。鉴于人类和包括草原田鼠在内的其他真兽类动物在进化上的高度相似性，这些发现表明，人类和草原田鼠之间也可能保守着社会依恋的遗传和神经控制。因此，草原田鼠的发现可能会直接帮助我们理解人类的依恋行为。因此，我们建议在这个理想的社会依恋行为模式系统中，通过产生携带与神经精神障碍有关的基因突变的草原田鼠，来模拟精神疾病中表现出的社会缺陷。虽然没有一个单一的模型系统可能概括出人类精神疾病中发生的复杂症状的全部谱系，但这个模型系统将首次允许 用来理解这些疾病深刻的社会缺陷背后的神经生物学。自闭症谱系障碍(ASD)和精神分裂症往往导致显著的社会缺陷，表现为显著有限的社会支持和关系，难以维持就业，以及社会技能的总体缺陷。我们建议1)产生与自闭症、SH3和多个强直蛋白重复区域3(SHANK3)和精神分裂症、盘状大同源2(DLG2)相关的基因突变的草原田鼠，2)检查这些基因功能丧失导致的社会依恋行为缺陷的模式，3)确定与依恋相关行为缺陷相关的神经元激活模式的变化。

 DESCRIPTION (provided by applicant): Social attachments play a central role in most, if not all, levels of human interaction, from parent-child attachment, fraternity and kinship, friendship and social affiliation, to enduring partnerships with mates. Social attachment behaviors are also clinically very relevant, as several devastating conditions such as autism spectrum disorders and schizophrenia often manifest with a dramatic collapse of inter-personal interactions. These fascinating behaviors have traditionally been resistant to genetic and neurobiological approaches because of the limitations imposed by working on primates. Mice, the only genetically tractable mammalian model to date, appear not to display adult social attachment behaviors. This proposal seeks to establish the prairie vole (Microtus ochrogaster) as a model system to examine the deficits in social attachment behaviors that result from mutations in genes associated with psychiatric illnesses. Prairie voles are small mouse-like rodents that display strong social attachment behaviors such that mates typically form an enduring pair bond. Pair bonding results in dramatic changes in other social behaviors. These findings suggest that voles engage in a rich repertoire of social attachment behaviors that bear a striking resemblance to many of the social behaviors observed in humans. Pioneering work in the prairie vole has identified vasopressin (Avp) and oxytocin (Oxt), neuropeptides and hormones, as critical mediators of pair bonding. Strikingly, AVP and OXT signaling have also been implicated in social attachment type behaviors in humans. Given the deep evolutionary similarity between humans and other eutherian mammals, including prairie voles, these findings indicate that the genetics and neural control of social attachment may also be conserved between humans and prairie voles. Thus, findings in the prairie voles may directly inform our understanding of human attachment behaviors. We therefore propose to model the social deficits that manifest in psychiatric illness in this ideal model system for social attachment behaviors by generating prairie voles bearing mutations in genes implicated in neuropsychiatric disorders. While no single model system is likely to recapitulate the entire spectrum of complex symptoms that occur in human psychiatric illness, this model system will, for the first time, allow use to understand the neurobiology underlying the profound social deficits in these disorders. Autism spectrum disorders (ASD) and schizophrenia often result in marked social deficits, which manifest as significantly limited social supports and relationships, difficulty maintaining employment, and overall deficits in social skills. We propose 1) to generate prairie voles mutant for genes implicated in autism, SH3 and multiple ankyrin repeat domains 3 (SHANK3), and schizophrenia, Disks large homolog 2 (DLG2), 2) examine the pattern of deficits in social attachment behaviors that result from the loss of function of these genes, and 3) determine the change in patterns of neuronal activation that correlate with deficits in attachment related behaviors.