NEURAL STEROIDOGENIC ENZYMES AND BRAIN FUNCTION

说明(申请人摘要)：类固醇对心脏有很大影响 大脑的发育和功能。传统上，大脑被视为 性腺合成的性类固醇的作用靶点，或作用较小的 肾上腺的程度，因为每个器官都表达所有的酶 催化胆固醇转化为活性的性类固醇。在 在过去的二十年里，有证据表明，一些类固醇激素 在中枢神经系统中可以发现酶，这表明大脑 本身可以合成活性的类固醇信号分子。不过， 尽管在脑组织中发现了它们，但几乎没有证据表明 证实了这些酶在大脑中的功能作用。我们相信 脑中合成的类固醇可能有助于组织和激活 鸣禽的特定行为。行为和神经解剖学研究表明 在缺乏激素的情况下，鸣禽体内存在一些类固醇依赖的功能 可检测到来自外围的类固醇信号。这些功能可能是 由局部的非全身性类固醇信号激活。我们已经得到了支持 对于这一假设，我们已经发现了神经表达和/或活动 所有4种类固醇生成酶(Cyp11a1、3B-HSD、CyP17和CyP19)都是 成人胆固醇向孕激素、雄激素和雌激素的转化 斑马雀，包括所有酶在小脑浦肯野的表达 细胞。这些研究的目标是通过以下方式更全面地探索这一假说 确定1)脑中每种类固醇生成酶的mRNA是否被翻译 转化为功能蛋白，特别是在成年斑雀的浦肯野细胞中； 2)如果类固醇生成酶的神经表达与 中枢神经歌曲控制电路的组织与歌曲学习 发育斑马雀和鸣雀，以及3)如果神经表达 类固醇生成酶与性行为的激活有关 当循环中的类固醇是基础的时，类固醇依赖的行为功能 成年鸣叫的麻雀。我们相信这些研究将大大有助于 我们对大脑类固醇生成能力的了解，并扩展 类固醇作为神经信号分子的概念。

DESCRIPTION (applicant's abstract): Steroids have profound effects on the development and function of the brain. Traditionally, the brain is viewed as a target for action of sex steroids synthesized in the gonads, or to a lesser degree the adrenals, since each of these organs express all the enzymes that catalyze the conversion of cholesterol into the active sex steroids. In the last two decades, evidence has emerged indicating that some steroidogenic enzymes could be found in the central nervous system, suggesting that the brain itself could synthesize the active steroidal signaling molecules. Nevertheless, despite their identification in brain tissue, there is little evidence confirming a functional role for these enzymes in brain. We believe that steroids synthesized in brain may contribute to the organization and activation of specific behaviors in songbirds. Behavioral and neuroanatomical studies show that some steroid-dependent functions occur in songbirds in the absence of detectable steroid signaling from the periphery. These functions may be activated by a local, non-systemic steroidal signal. We have obtained support for this hypothesis in that we have found neural expression and/or activity of all 4 steroidogenic enzymes (CYP11A1, 3B-HSD, CYP17, and CYP19) required for the conversion of cholesterol to progestins, androgens, and estrogens in adult zebra finches, including expression of all enzymes in cerebellar Purkinje cells. The goal of these studies is to explore this hypothesis more fully by determining 1) if mRNA for each steroidogenic enzyme in brain is translated into functional protein, especially in Purkinje cells of adult zebra finches; 2) if neural expression of steroidogenic enzymes is associated with the organization of the neural song control circuit and with song learning in developing zebra finches and song sparrows, and 3) if neural expression of steroidogenic enzymes is associated with the activation of sex steroid-dependent behavioral functions when circulating steroids are basal in adult song sparrows. We believe these studies will contribute significantly to our understanding of the steroidogenic capability of the brain, and expand concepts of steroids as neural signaling molecules.