Genetic and Neuroendocrine Control of Behavioral Systems

描述（由申请人提供）：本研究项目的长期目标是确定控制社会行为性别分化的基因和信号通路。神经疾病、正常和异常行为的性别差异已被充分记录，但差异背后的机制尚不清楚。许多行为障碍（如精神分裂症、抑郁症、自闭症等）都有一个普遍的症状；非典型社会互动。我们的目标是了解正常社会行为的发展，并利用这些信息揭示行为障碍患者的新基因突变。在过去的几年里，我们已经确定雄激素受体（AR）是小鼠社会附属行为性别分化的主要组成部分。这是令人兴奋的，因为AR与包括人类在内的灵长类动物的性别分化有关。我们将通过研究AR下游性别分化的遗传调控来推进这一发现，并发现AR必需的靶基因。在目标1-3中，我们将验证一个潜在的AR靶基因Calbindin D28k。Calbindin定义内侧视前区有性异形细胞群。此外，这种钙结合蛋白在大脑中具有良好的抗凋亡作用，因此它很可能是性别分化途径的一个贡献者。我们将使用一些基因工程小鼠，分子，遗传和行为方法来表征AR与Calbindin在mRNA和蛋白质水平上的关系。我们还将使用Calbindin敲除小鼠来评估该基因功能丧失的行为分支。最后，我们将进行微阵列实验，以发现新的候选基因，雄激素反应。我们将采取的策略是描述AR在调节一个基因中所起的作用，该基因是神经保护途径的一部分，可能与性别分化有关。同样的策略可以重复用于识别其他AR靶基因。公共卫生相关性：了解控制行为性别分化的基因和信号通路对于最终治疗性别偏见性精神疾病至关重要，其中包括作为主要症状的异常社会行为。此外，性别分化是神经发育的一个范例，了解指导这些过程的分子机制可以帮助我们了解神经发育、神经保护和修复的一般情况。

Description (provided by applicant): The long term goal of this research program is to identify the genes and signaling pathways that control sexual differentiation of social behavior. Sex differences in neurological diseases, normal and abnormal behaviors are well documented, but the mechanisms underlying the differences are not. Many behavioral disorders (i.e. schizophrenia, depression, autism etc.) have one universal symptom; atypical social interactions. Our goal is to understand development of normal social behavior and use this information to reveal novel genetic mutations in patients with behavioral disorders. In the past few years we have established that the androgen receptor (AR) is a major component in the sexual differentiation of social affiliative behaviors in the mouse. This is exciting because the AR has been implicated in sexual differentiation of primates, including humans. We will advance this finding by studying the genetic regulation of sexual differentiation downstream of AR, and we will discover the essential AR target genes. In Aims 1-3 we will validate one potential AR target gene, Calbindin D28k. Calbindin defines a sexually dimorphic cell cluster in the medial preoptic area. In addition, this calcium binding protein has well characterized anti-apoptotic actions in brain, and for these reasons it is very likely a contributor to the sexual differentiation pathway. We will use a number of genetically engineered mice, molecular, genetic and behavioral methods to characterize the relationship between the AR and Calbindin at the level of mRNA and protein. We will also use Calbindin knockout mice to assess the behavioral ramification of the loss of function of this gene. Finally we will conduct Microarray experiments to uncover novel candidate genes that are androgen responsive. The strategy we will pursue delineates the role AR plays in regulation of a gene that is part of a neuroprotection pathway and is likely involved in sexual differentiation. This same strategy can be recycled to identify other AR target genes. PUBLIC HEALTH RELEVANCE: Understanding the genes and signaling pathways that control sexual differentiation of behavior is essential for eventual treatment of sex-biased mental illnesses, which include abnormal social behavior as a major symptom. Further, sexual differentiation is an exemplar of neural development, and understanding the molecular mechanisms directing these processes informs us about neural development, neuroprotection and repair generally.