Genetic and Neuroendocrine Control of Behavioral Systems

描述（由申请人提供）：本研究计划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。神经系统疾病、正常和异常行为的性别差异有很好的记录，但差异背后的机制却没有。许多行为障碍（即精神分裂症、抑郁症、自闭症等）有一个普遍的症状;非典型的社交互动。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。在过去的几年中，我们已经确定雄激素受体（AR）是一个主要组成部分的性别分化的社会亲和行为的小鼠。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下游性分化的遗传调控来推进这一发现，我们将发现必要的AR靶基因。在目标1 - 3中，我们将验证一个潜在的AR靶基因，钙结合蛋白D28k。钙结合蛋白在内侧视前区定义了一个两性异形细胞簇。此外，这种钙结合蛋白在脑中具有良好的抗凋亡作用，因此很可能是性分化途径的贡献者。我们将利用大量的基因工程小鼠，采用分子、遗传和行为学的方法，从mRNA和蛋白质水平来表征AR和Calbindin之间的关系。我们还将使用钙结合蛋白敲除小鼠来评估该基因功能丧失的行为后果。最后，我们将进行微阵列实验，以发现新的候选基因是雄激素反应。我们将采取的策略描绘了AR在调节基因中的作用，该基因是神经保护途径的一部分，可能参与性分化。这种相同的策略可以再循环以鉴定其他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的精神疾病至关重要，其中包括异常的社会行为作为主要症状。此外，性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让我们了解神经发育，神经保护和修复。

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.