The Genetic Control of Social Behavior in the Mouse

小鼠社会行为的基因控制

• 批准号: 7652586
• 负责人: ROBERT J BLANCHARD
• 金额: $ 34.6万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7652586
• 关键词: Algorithms; Animal Experimentation; Animal Model; Animals; Attention; Autistic Disorder; BTBR Mouse; Behavior; Behavior Control; Behavioral; Behavioral Assay; Biological Factors; Biology; Breeding; Candidate Disease Gene; Cereals; Chromosomes; Classification; Collaborations; Communication; Data; Diagnostic; Disease; Employee Strikes; Evaluation; Fragile X Syndrome; Gene Mutation; Genes; Genetic; Goals; Hereditary Disease; Hour; Impairment; Inbred Strains Mice; Laboratories; Link; Measures; Memory; Methyl-CpG-Binding Protein 2; Motivation; Mouse Strains; Movement; Mus; Mutant Strains Mice; Mutate; Mutation; Neurodevelopmental Disorder; Neurologic; Oxytocin; Pattern; Phenotype; Protocols documentation; Publishing; Reciprocal Social Interaction; Recording of previous events; Research; Rodent; Role; Running; Signal Transduction; Social Behavior; Social Interaction; Specificity; Speed; Stereotyped Behavior; Stereotyping; Stimulus; Structure; Symptoms; System; Techniques; Testing; Ursidae Family; V1b vasopressin receptor; Video Recording; Work; approach behavior; autism spectrum disorder; base; behavior change; communication behavior; experimental analysis; locomotor deficit; male; mouse model; mutant; novel; preference; programs; public health relevance; research study; social; social communication; stereotypy

DESCRIPTION (provided by applicant): Autism spectrum disorders (ASD) are defined solely in terms of behavior. Their diagnostic symptoms: Impairment in social interaction; in communication; and restricted, repetitive, and stereotyped patterns of behavior; have presented a challenge in terms of the mouse models that facilitate research on the biology of these disorders. This laboratory, with its focus on behavioral analysis, will work with 3 outstanding behavioral geneticists, Drs. Jacki Crawley, Valerie Bolivar, and W. Scott Young, to integrate novel behavioral approaches with the use of candidate genes for involvement in the control of behaviors potentially related to ASD. Our preliminary studies using ethological and experimental approaches to mouse sociality have identified two interactive amicable or eusocial (i.e. not based on aggressive or sexual motivations) behaviors in C57BL/6J mice (huddling and frontal approach), and one mouse communication behavior, scent marking, that may provide parallels to these diagnostic symptoms of ASD. The project will utilize mice with mutations/targeted deletions of each of six genes: Engrailed 2; Reelin; Fragile X; Methyl-CpG-binding protein 2; Oxytocin, and arginine vasopressin 1b receptor, that have previously shown associations with deficient social behaviors, or enhanced representation in ASD or related conditions. The BTBR T+ tf/J mouse strain that has shown striking social deficiencies in previous work, will be used as a [low-social strain]. It will be compared to the C57BL/6J mice that are the background strain for many of these mutations. These mice will be evaluated in three tests: 1) The seminatural Visible Burrow System, in which interactive amicable or eusocial behaviors have been characterized and stereotypicalbehaviors can be detected. 2) Scent marking, using a protocol that measures both social olfactory communication in mice, and, the ability of the subject to form a relatively long-duration social memory differentiating between familiar and an unfamiliar conspecifics. Third, a well-established three-compartment test that measures both sociability to conspecifics vs. nonsocial stimuli, and preference for novel vs familiar conspecifics. These tests will also provide nearly 25 hours of videorecordings of each mouse in seminatural and structured situations, enabling a fine-grained analysis of repetitive or stereotyped behaviors, an additional focus of this laboratory. Mice showing significant changes in these behaviors will be evaluated for neurological/locomotor deficits, to assess specificity of changes and subjected to a breeding algorithm to determine if their behavior changes are due to mutant or ablated genes, or to flanking regions on the chromosome. This program will integrate a much finer and more detailed evaluation of behaviors potentially related to ASD with analysis of the effects of mutations in genes that may be related to these disorders. PUBLIC HEALTH RELEVANCE: Autism spectrum disorder (ASD) is an increasingly common neurodevelopmental disorder defined by interactive social deficits, communication deficits, and the presence of ritualistic, repetitive behaviors. Although considerable information is available on genetic conditions that may be associated with ASD, experimental animal research to characterize and verify these gene-symptom relationships has been hampered by the lack of a broad-based and detailed analysis of relevant behaviors in mice. This proposal begins with broad-based and detailed ethological and experimental analyses of mouse social behavior (preliminary studies), and with this laboratory's history of identifying and evaluating repetitive or stereotyped behaviors in rodents, and proposes to work in collaboration with leading behavior geneticists in analyzing these behaviors in mice with mutations in a number of candidate genes for ASD.

描述（由申请人提供）：自闭症谱系障碍（ASD）仅根据行为来定义。他们的诊断症状：社交互动受损；在沟通中；以及受限的、重复的和刻板的行为模式；在促进这些疾病的生物学研究的小鼠模型方面提出了挑战。该实验室专注于行为分析，将与 3 位杰出的行为遗传学家合作，Drs. Jacki Crawley、Valerie Bolivar 和 W. Scott Young 将新颖的行为方法与候选基因的使用结合起来，参与控制与自闭症谱系障碍潜在相关的行为。我们使用行为学和实验方法对小鼠社交性进行初步研究，确定了 C57BL/6J 小鼠的两种互动友好或真社会（即不是基于攻击性或性动机）行为（挤作一团和额叶接近），以及一种小鼠交流行为、气味标记、这可能与 ASD 的这些诊断症状有相似之处。该项目将利用六个基因均具有突变/定向删除的小鼠：Engrailed 2；瑞林；脆弱X；甲基-CpG结合蛋白2；催产素和精氨酸加压素 1b 受体先前已显示与社会行为缺陷或自闭症谱系障碍或相关病症的表现增强有关。 BTBR T+ tf/J 小鼠品系在之前的工作中表现出显着的社交缺陷，将被用作[低社交品系]。它将与 C57BL/6J 小鼠进行比较，C57BL/6J 小鼠是许多这些突变的背景品系。这些小鼠将在三个测试中进行评估：1）半自然的可见洞穴系统，其中互动的友好或社会行为已被表征，并且可以检测到刻板行为。 2）气味标记，使用一种协议来测量小鼠的社交嗅觉交流，以及受试者形成区分熟悉和不熟悉的同种动物的相对较长持续时间的社交记忆的能力。第三，一个完善的三部分测试，可以衡量对同种事物的社交性与非社交刺激，以及对新事物与熟悉同种事物的偏好。这些测试还将提供每只小鼠在半自然和结构化情况下近 25 小时的视频记录，从而能够对重复或刻板行为进行细粒度分析，这是该实验室的另一个重点。显示这些行为显着变化的小鼠将被评估神经/运动缺陷，以评估变化的特异性，并接受育种算法以确定它们的行为变化是否是由于突变或消融基因，或染色体上的侧翼区域所致。该计划将对可能与自闭症谱系障碍相关的行为进行更精细、更详细的评估，并分析可能与这些疾病相关的基因突变的影响。公共健康相关性：自闭症谱系障碍 (ASD) 是一种日益常见的神经发育障碍，其定义为互动性社交缺陷、沟通缺陷以及仪式性重复行为的存在。尽管有大量关于可能与 ASD 相关的遗传条件的信息，但由于缺乏对小鼠相关行为的广泛而详细的分析，表征和验证这些基因与症状关系的实验动物研究受到了阻碍。该提案首先对小鼠社会行为进行广泛而详细的行为学和实验分析（初步研究），并以该实验室识别和评估啮齿动物重复或刻板行为的历史为起点，并建议与领先的行为遗传学家合作，分析这些行为发生在一些自闭症谱系障碍候选基因发生突变的小鼠身上。