Neural Steroidogenic Enzymes and Brain Function

描述(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特性。在大脑中合成的类固醇(神经类固醇)具有许多已报道的功能，但对于神经类固醇生成的全部生物学意义仍存在疑问。对鸣禽的研究正在确定大脑类固醇合成的重要功能。我们有很好的证据表明，鸣禽大脑中合成的类固醇在歌唱控制回路的发展和一些成年行为的激活中发挥着关键作用。最近，我们创建了鸣禽特有的探针，并发现在发育过程中，类固醇生成酶集中在已知发生神经发生的脑室壁附近。我们假设鸣禽的脑室类固醇激素的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男性歌唱所需的大脑区域。一种相关的机制可能会在保持显著神经可塑性的成年人身上持续存在。神经损伤后，我们发现雌激素合成酶芳香化酶在放射状胶质细胞中有较强的表达，芳香酶阳性纤维引导新生的细胞。我们推测，必须在这些放射状胶质细胞中或其附近表达更多的类固醇生成酶，以提供雌激素合成的底物，以帮助神经修复。 最后，我们预测，在一些物种的非繁殖季节，这些酶被上调以激活类固醇依赖的攻击行为。在这里提出的研究中，我们将在斑马雀大脑发育中的切片培养准备中、成年斑雀神经损伤后的切片培养准备中以及季节性繁殖的鸣禽中验证这些假设。我们将抑制类固醇生成酶，并检测其对类固醇合成、细胞发生和分化、男性大脑发育和行为的影响。这些研究将揭示神经类固醇在神经生长、可塑性和修复中的重要作用，这将对基础发育神经生物学和神经退行性疾病的治疗具有重要意义。

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.