Neural Steroidogenic Enzymes and Brain Function

描述（由申请人提供）：类固醇激素是中枢神经系统中强大的信号分子，有大量证据表明类固醇合成是大脑的一种特性。脑内合成的类固醇（神经类固醇）有许多已报道的功能，但对神经类固醇形成的全部生物学重要性仍有疑问。对鸣禽的研究正在确定脑类固醇合成的重要功能。我们有充分的证据表明，在鸣禽大脑中合成的类固醇在鸣禽控制回路的发育和一些成年行为的激活中起着关键作用。最近，我们创造了鸣禽特异性探针，发现在发育过程中，类固醇生成酶集中在脑室壁附近，那里已知发生神经发生。我们假设鸣禽的心室甾体生成影响了神经元的正常出生、分化或迁移，这些神经元注定要进入雄性鸣声表达所需的大脑区域。一个相关的机制可能持续存在于保持突出的神经可塑性的成人。神经损伤后，我们发现雌激素合成酶芳香酶在放射状胶质细胞中强烈表达，芳香酶阳性纤维引导新生细胞。我们假设，在这些放射状胶质细胞内或附近一定有额外的类固醇生成酶表达，为雌激素合成提供底物，以协助神经修复。

DESCRIPTION (provided by applicant): Steroid hormones are powerful signaling molecules in the CNS and there is substantial evidence that steroid synthesis is a property of the brain. Steroids synthesized in brain (neurosteroids) have many reported functions, but there is still doubt about the full biological importance of neurosteroidogenesis. Studies of songbirds are identifying important functions of brain steroid synthesis. We have excellent evidence that steroids synthesized in the songbird brain play a key role in the development of song control circuits and in the activation of some adult behaviors. Recently, we created songbird specific probes and found that developmentally, steroidogenic enzymes are concentrated near the walls of the ventricles where neurogenesis is known to occur. We hypothesize that ventricular steroidogenesis in songbirds impacts the proper birth, differentiation or migration of neurons destined to enter brain regions required for masculine song expression. A related mechanism may persist in adults that retain prominent neural plasticity. After neural injury, we find the estrogen synthetic enzyme aromatase is strongly expressed in radial glia with aromatase-positive fibers guiding newly generated cells. We hypothesize that additional steroidogenic enzymes must be expressed in or near these radial glia to provide substrates for estrogen synthesis to assist in neural repair. Lastly, we predict that these enzymes are up-regulated during non-breeding seasons in some species to activate steroid-dependent aggressive behaviors. In studies proposed here, we will test these hypotheses in slice-culture preparations of developing zebra finch brain, after neural injury to adult zebra finches and in a seasonal breeding songbird. We will inhibit steroidogenic enzymes and examine the effects on steroid synthesis, cytogenesis and differentiation, masculine brain development and behavior. These studies will reveal important actions of neurosteroids in neural growth, plasticity and repair that will have important implications in basic developmental neurobiology and in treatments of neurodegenerative disease.