Serotonergic genetic influences on the impact of maternal environment

描述(由申请人提供)：神经行为障碍、气质和压力反应的易感性源于遗传天赋和环境因素之间的复杂相互作用，例如母婴相互作用。在人类和啮齿动物模型中，母婴相互作用已经被证明对压力反应、焦虑样行为和心理刺激反应产生长期影响。这些效应中的许多被认为是由于对中枢多巴胺系统的发育和功能的影响所致。5-HT2C受体突变小鼠的出现为分析5-羟色胺神经递质系统在影响应激反应神经底物和多巴胺能神经传递的基因/环境相互作用中的作用提供了独特的机会。5-羟色胺5-HT2C受体突变在母体行为的调节、新奇反应和增强的多巴胺能神经传递方面表现出改变(初步结果)。这一建议将检验5-HT2C受体是5-羟色胺能影响母婴相互作用及其对后代行为的长期影响的重要中介这一假设。该提案包括三个具体目标：目标1.检测5-HT2C受体零突变对母体和幼崽行为的影响。目的2.检测母子代5-HT2C受体基因对子代应激反应神经底物的影响。这将通过寄养研究来检验，在这些研究中，野生型和突变型幼崽被培养成野生型、杂合子和纯合子突变的母亲。成年后代将使用神经内分泌、神经解剖学和行为方法进行检查。目的3.检测母子代5-HT2C受体基因对子代多巴胺系统功能的影响。将使用几种方法来检测目标2中描述的寄养群体的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，并将使用体内微透析程序来评估清醒、行为正常的小鼠的细胞外多巴胺水平。

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.