Serotonergic genetic influences on the impact of maternal environment

血清素能遗传对母体环境的影响

• 批准号: 7383799
• 负责人: Laurence H. Tecott
• 金额: $ 18.91万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-15 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7383799
• 关键词: Adult Children; Affect; Animals; Anxiety; Area; Behavior; Behavioral; Behavioral Sciences; Biological Assay; Biological Models; Brain; Caring; Child Development; Complex; Condition; Development; Dopamine; Endowment; Environment; Environmental Risk Factor; Exhibits; Fostering; Genes; Genetic; Genetic Models; Genotype; Human; Infant; Laboratories; Long-Term Effects; Maternal Behavior; Mediator of activation protein; Microdialysis; Mission; Modeling; Molecular Genetics; Monitor; Mothers; Motor; Mus; Mutant Strains Mice; Mutation; National Institute of Child Health and Human Development; Nature; Neurosecretory Systems; Neurotransmitters; Phenotype; Physiological; Predisposition; Procedures; Publishing; Rattus; Reflex action; Regulation; Relative (related person); Reporting; Research Personnel; Retrieval; Review Literature; Rodent; Rodent Model; Role; Serotonin; Serotonin Receptor 5-HT2C; Shapes; Staging; Standards of Weights and Measures; Stress; System; Temperament; Testing; Thinking; Ultrasonics; Ursidae Family; Work; awake; biological adaptation to stress; dopamine system; dopamine transporter; extracellular; gene environment interaction; in vivo; interest; mouse model; multidisciplinary; mutant; neurobehavioral disorder; neurotransmission; null mutation; psychostimulant; pup; relating to nervous system; response; serotonin receptor; trait; vocalization

DESCRIPTION (provided by applicant): Susceptibility to neurobehavioral disorders, temperament, and stress responses arise from a complex interplay between genetic endowment and environmental factors, such as the mother/infant interaction. In both humans and rodent models, mother/infant interactions have been demonstrated to produce long-term effects on stress responsiveness, anxiety-like behavior and psychostimulant response. Many of these effects are thought to result from influences on the development and function of central dopamine systems. The availability of serotonin 5-HT2C receptor mutant mice affords a unique opportunity to dissect the role of the serotonin neurotransmitter system in influencing gene/environment interactions on neural substrates of stress responses and dopaminergic neurotransmission. Serotonin 5-HT2C receptor mutants exhibit alterations in the regulation of maternal behavior, novelty responses and enhanced dopaminergic neurotransmission (Preliminary Results). This proposal will test the hypothesis that the 5-HT2C receptor is an important mediator of serotonergic influences on mother/infant interactions and their long-term impact on offspring behavior. The proposal consists of three specific aims: Aim 1. Examination of the effects of a 5- HT2C receptor null mutation on maternal and pup behavior. Aim 2. Examination of the influence of maternal and offspring serotonin 5-HT2C receptor genotype on neural substrates of offspring stress responsiveness. This will be examined through fostering studies in which wild type and mutant pups are fostered to wild type, heterozygous and homozygous mutant mothers. Adult offspring will be examined using neuroendocrine, neuroanatomical and behavioral approaches. Aim 3. Examination of the influence of maternal and offspring 5-HT2C receptor genotype on offspring dopamine system function. Several approaches will be applied to examine central dopamine systems in adult offspring of the fostering groups described in Aim 2. Neuroanatomical assessment of genes implicated dopaminergic neurotransmission will be performed, and in vivo microdialysis procedures will be used to assess extracellular dopamine levels in awake, behaving mice.

描述（由申请人提供）：对神经行为障碍、气质和应激反应的易感性源于遗传禀赋和环境因素（例如母亲/婴儿的相互作用）之间复杂的相互作用。在人类和啮齿动物模型中，母婴互动已被证明会对压力反应、焦虑样行为和精神刺激反应产生长期影响。许多这些影响被认为是由于对中枢多巴胺系统的发育和功能的影响造成的。血清素 5-HT2C 受体突变小鼠的出现提供了一个独特的机会来剖析血清素神经递质系统在影响应激反应和多巴胺能神经传递的神经基质上的基因/环境相互作用中的作用。 5-羟色胺 5-HT2C 受体突变体表现出母体行为调节、新奇反应和增强的多巴胺能神经传递的改变（初步结果）。该提案将检验以下假设：5-HT2C 受体是血清素能影响母婴互动及其对后代行为长期影响的重要介质。该提案包含三个具体目标： 目标 1. 检查 5-HT2C 受体无效突变对母体和幼崽行为的影响。目的 2. 检查母体和后代血清素 5-HT2C 受体基因型对后代应激反应神经基质的影响。这将通过寄养研究进行检验，其中将野生型和突变体幼崽与野生型、杂合子和纯合突变体母亲一起寄养。将使用神经内分泌、神经解剖学和行为方法对成年后代进行检查。目的3.考察母体和子代5-HT2C受体基因型对子代多巴胺系统功能的影响。将采用多种方法来检查目标 2 中描述的饲养组成年后代的中枢多巴胺系统。将对涉及多巴胺能神经传递的基因进行神经解剖学评估，并使用体内微透析程序来评估清醒、行为时的细胞外多巴胺水平。老鼠。