Environmental Regulation of Neurogenesis

描述(由申请人提供)：目前临床抑郁症的一种理论认为，海马区神经发生的兴衰与本病发作和康复有因果关系。因此，确定调节神经发生的因素可能对了解这种疾病和开发新的治疗方法至关重要。 我们对疾病机制的知识可以通过研究模型系统来扩展，在模型系统中，神经发生可以得到严格控制，定量分析可以在生理上可行的制剂中个别识别的神经元的水平上进行。甲壳动物的大脑为我们提供了这样一个模型系统。5-羟色胺水平、活动模式和生活条件影响着这个系统中神经元的增殖速度，就像在哺乳动物的大脑中一样。此外，甲壳动物大脑中对神经细胞周期的昼夜节律控制是任何系统中第一个光携带神经发生的例子，这增加了光可能为影响神经元增殖的许多因素提供主导协调信号的可能性。 这项建议的主要目标是了解光在神经发生控制中的作用。我们认为十足类甲壳动物脑中的调节通路之一是通过两个由内源振荡器驱动的5-羟色胺能巨型神经元进行操作。我们的假设是，这些神经元通过在发生神经元增殖的部位释放5-羟色胺来调节神经发生。这一假说将在完整的动物和分离的脑标本中使用细胞增殖标记方法、高压液相色谱、免疫细胞化学和电生理学相结合的方法进行验证，在这些标本中，可以对5-羟色胺能巨细胞进行生理学操作，以测试它们参与控制途径的情况。还将研究光周期、5-羟色胺水平和神经发生速率之间的关系，并定义在调节神经发生中重要的光感受系统(S)。

DESCRIPTION (provided by applicant): One current theory of clinical depression proposes that the waxing and waning of neurogenesis in the hippocampus are causally related to the onset of, and recovery from, episodes of this disease. Defining the factors that regulate neurogenesis may therefore be of critical importance in understanding this disease and developing novel therapies. Our knowledge of disease mechanisms can be extended by studying model systems where neurogenesis can be tightly controlled and where quantitative analyses can be conducted at the level of individual identified neurons in physiologically viable preparations. The crustacean brain provides us with such a model system. Serotonin levels, activity patterns, and living conditions influence the rate of neuronal proliferation in this system, just as in the mammalian brain. In addition, circadian control over the neuronal cell cycle in the crustacean brain is the first example of light entrainment of neurogenesis in any system, raising the possibility that light may provide a dominant coordinating signal for the many factors that influence neuronal proliferation. The primary goal of this proposal is to understand the role of light in the control of neurogenesis. We propose that one of the regulatory pathways in the decapod crustacean brain operates via two serotonergic giant neurons that are driven by the endogenous oscillator. Our hypothesis is that these neurons regulate neurogenesis by releasing serotonin at the site where neuronal proliferation occurs. This hypothesis will be tested using a combination of cell proliferation labeling methods, high pressure liquid chromatography, immunocytochemistry and electrophysiology in intact animals and in isolated brain preparations in which the serotonergic giant neurons can be manipulated physiologically to test their involvement in the control pathway. The relationship between photoperiod, serotonin levels and the rate of neurogenesis also will be examined, and the photoreceptive system(s) that are important in regulating neurogenesis will be defined.