REGULATION OF ADULT NEUROGENESIS--STRESS /ANTIDEPRESSANT

最近的临床研究表明，抑郁以及其他精神疾病可以导致海马体体积和功能的减少。啮齿类动物和非人类灵长类动物的临床前研究表明，应激可以导致海马神经元的形态变化，包括萎缩和细胞增殖减少。据报道，应激还会降低脑源性神经营养因子的表达，虽然海马区只是抑郁症的几个脑区之一，但海马区的结构变化可能与抑郁症患者的某些认知和植物功能异常有关。这些发现还提出了这样一种可能性，即抗抑郁剂的治疗作用可能部分通过逆转或阻断这些改变而发生。这一假设得到了我们最近的研究的支持，该研究表明抗抑郁药物治疗增加了成年啮齿动物海马区的神经发生。这种效果依赖于慢性给药，并在不同类别的抗抑郁药中观察到，这表明增加神经再生是这种类型药物的常见作用。初步研究还表明，抗抑郁药物的使用可以阻止由压力引起的神经发生的下调。目前的应用重点是确定抗抑郁剂对成人神经发生影响的分子机制我们之前的研究在这项拨款的支持下证明了抗抑郁剂上调cAMP反应元件结合蛋白(CREB)和脑源性神经营养因子(CREB)，CREB是一种与细胞可塑性有关的转录因子。我们将使用药理学和突变小鼠模型的组合来研究CREB和BDNF在成人神经发生和抗抑郁治疗反应中的作用。初步研究表明，给予一种阻断cAMP代谢的药物(罗利普兰)会增加，而CREB的显性负突变的过度表达减少，成年海马区的神经发生。我们还将检查CREB的其他基因靶点，这些基因靶点可能会影响成年海马区新生细胞的分化和存活。最后，将进行研究，以检验成人神经发生与抗抑郁治疗的行为反应之间的关系。这些研究将为控制成年海马区神经发生的分子机制以及这些通路在抗抑郁治疗中的作用提供新的见解。

Recent clinical studies demonstrate that depression, as well as other psychiatric illnesses can result in a reduce in the volume and function of the hippocampus Pre-clinical studies in rodents in rodents and non- human primates demonstrate that stress can result in morphological alterations of hippocampal neurons, including atrophy and reduced cell proliferation. Stress is also reported to decrease the expression of brain derived neurotrophic factor Although hippocampus is only one of several brain regions implicated in depression, the structural alterations of hippocampus could be related to certain cognitive and vegetative abnormalities in depressed patients. These findings also raise the possibility that the therapeutic action of anti-depressants could occur, in part, via reversal or blockade of these alterations. This hypothesis is supported by our recent studies demonstrated that anti- depressant treatment increases neurogenesis in adult rodent hippocampus. This effect is dependent on chronic administration and is observed with different classes of antidepressants , suggesting that increased neurogenesis is a common action of this type of medication. Preliminary studies also demonstrate that anti-depressant administration blocks the down-regulation of neurogenesis that is caused by stress. The focus of the current application is to determine the molecular mechanisms that mediate the effect of anti-depressants on adult neurogenesis Our previous studies, supported by this grant, demonstrated that anti-depressants up-regulate the cAMP response element binding protein (CREB), a transcription factor implicated in cellular plasticity, and brain derived neurotrophic factor. We will use a combination of pharmacological and mutant mouse models to study the role of CREB and BDNF in adult neurogenesis and in the response to antidepressant treatment. Preliminary studies demonstrate that administration of a drug which blocks cAMP metabolism (rolipram) increases, while over- expression of a dominant negative mutant of CREB decreases, neurogenesis in adult hippocampus. We will also examine additional gene targets of CREB that could influence the differentiation and survival of newborn cells in the adult hippocampus. Finally, studies will be conducted to examine the relationship between adult neurogenesis and behavior responses to anti-depressant treatment. These studies will provide new insight on the molecular mechanisms that control neurogenesis in adult hippocampus and of the role of these pathways in the action of anti-depressant treatment.