STEROID REGULATION OF ION CHANNELS

描述：（申请人摘要）本项目的长期目标是 为了确定各区域和性别之间的差异， 结构和功能不同的GABA-A受体的表达 有助于产生针对性别的行为。 公 确定性腺类固醇作用于诱导永久性（组织） 哺乳动物大脑中提供神经功能的区域中的两性异形 性行为产生的基础结构。 具体地说， 许多研究强烈暗示GABA能突触传递在 腹内侧核（VMN）的类固醇敏感区 下丘脑和视前区（POA）在介导 成人性行为 虽然这些动物的性别二态性 细胞核和GABA能传递的重要性， 控制成人性行为是无可争议的，目前还没有发表研究 日期的特征是GABAA受体功能或性别特异性 这些区域内GABAA受体表达的差异。 建立 GABA能药物改变性行为的能力是否存在于 VMN内结构不同的GABA-A受体的表达， POA，原位杂交和免疫细胞化学技术将是 分析GABA-A受体mRNA及其亚基的表达。 到 确定是否在结构上不同的表达差异 受体导致受体的性别和区域特异性差异 功能，GABA-A依赖性电流对变构调节剂的敏感性， 其作用取决于亚基组成，将通过 完整切片中VMN和POA神经元的全细胞膜片钳分析， 急性分离的细胞 最后，很明显， 动物产生适当的性行为取决于短暂的 神经传导的周期性变化引起的（激活）变化， 性腺类固醇 GABA-A受体已经被认为是 类固醇在性行为产生中的激活作用。 到 在雌性大鼠中建立行为感受性，其由 类固醇的激活变化，与 GABA-A受体表达和功能，原位杂交和补丁 将对来自VMN和POA的神经元进行钳夹分析，用于感受性 （发情前期）和非接受性（间情期）成年雌性大鼠， 行为测试 这些实验的数据将提供重要的 关于正常性行为背后的神经基质的信息， 并可能部分阐明复杂人类的生物学基础， 性取向和变性等属性。 此外，本发明还提供了一种方法， 这些实验的结果可以提供重要的信息， 了解认知状态中的性别差异，例如 产后抑郁症和疾病，如癫痫，其中GABA-A 受体起着关键作用。

DESCRIPTION: (Applicant's abstract) The long-term goal of this project is to establish that region-specific and gender-specific differences in the expression of structurally and functionally distinct GABA-A receptors contribute to the generation of gender-specific behaviors. It is well established that gonadal steroids act to induce permanent (organizational) sexual dimorphisms in regions of the mammalian brain that provide the neural architecture underlying the generation of sexual behaviors. Specifically, many studies have strongly implicated GABAergic synaptic transmission within steroid-sensitive areas of the ventromedial nucleus (VMN) of the hypothalamus and preoptic area (POA) as playing a key role in mediating adult sexual behavior. Although the sexually dimorphic nature of these nuclei and the importance of GABAergic transmission within them to the control of adult sexual behaviors is indisputable, no published study to date has characterized either GABAA receptor function or gender-specific differences in GABAA receptor expression within these regions. To establish whether the ability of GABAergic agents to modify sexual behavior resides in the expression of structurally distinct GABA-A receptors within the VMN and POA, in situ hybridization and immunocytochemical techniques will be employed to analyze GABA-A receptor mRNA and subunit expression. To determine if differences in the expression of structurally different receptors result in gender- and region-specific differences in receptor function, sensitivity of GABA-A-dependent currents to allosteric modulators, whose actions are dependent upon subunit composition, will be assessed by whole-cell patch clamp analysis of VMN and POA neurons in intact slices and acutely dissociated cells. Finally, it is clear that the ability of an animal to generate appropriate sexual behaviors depends upon transient (activational) changes in neural transmission evoked by cyclical changes in gonadal steroids. The GABA-A receptor has been implicated as a target for activational actions of steroids in the generation of sexual behaviors. To establish that behavioral receptivity in female rats, which is induced by activational changes in steroids, is correlated with transient changes in GABA-A receptor expression and function, in situ hybridization and patch clamp analysis of neurons from the VMN and POA will be made for receptive (proestrus) and nonreceptive (diestrus) adult female rats subsequent to behavioral testing. Data from these experiments will provide important information on the neural substrates that underlie normal sexual behaviors, and may elucidate, in part, the biological basis for complex human attributes such as sexual orientation and transsexuality. In addition, results from these experiments may provide important information relevant to understanding gender-dependent differences in cognitive states, such as postpartum depression, and diseases, such as epilepsy, in which GABA-A receptors play a pivotal role.