Genetic and Neuroendocrine Control of Behavioral Systems

这项研究计划的长期目标是确定基因和信号传导 控制社会行为性别差异的途径。的性别差异 神经系统疾病，正常和异常的行为是有据可查的，但 差异背后的机制则不然。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;非典型的社会 交互.我们的目标是了解正常社会行为的发展和使用 这些信息揭示了行为障碍患者的新基因突变。在 在过去的几年里，我们已经确定雄激素受体（AR）是一个主要的 在小鼠的社会亲和行为的性别分化的组成部分。这 是令人兴奋的，因为AR与灵长类动物的性别分化有关， 包括人类我们将通过研究基因调控来推进这一发现， 性分化下游的AR，我们将发现重要的AR目标 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D28 k。 钙结合蛋白在内侧视前区定义了一个两性异形细胞簇。在 此外，这种钙结合蛋白在细胞凋亡中具有良好的抗凋亡作用。 大脑，由于这些原因，它很可能是性别分化的贡献者 通路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和钙结合蛋白之间的关系， mRNA和蛋白质水平。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衍生物。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， 神经保护途径的一部分，可能与性别分化有关。这 相同的策略可以再循环以鉴定其他AR靶基因。

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.