REGULATION OF ADULT NEUROGENESIS--STRESS /ANTIDEPRESSANT

最近的临床研究表明，抑郁症以及其他精神疾病可导致海马体积和功能的减少，在啮齿动物和非人类灵长类动物中进行的临床前研究表明，压力可导致海马神经元的形态改变，包括萎缩和细胞增殖减少。尽管海马体只是与抑郁症有关的几个大脑区域之一，但海马体的结构改变可能与抑郁症患者的某些认知和营养异常有关。这些发现也提高了抗抑郁药的治疗作用的可能性，部分是通过逆转或阻断这些改变来实现的。我们最近的研究表明，抗抑郁治疗增加了成年啮齿动物海马的神经发生，这一假设得到了支持。这种作用依赖于慢性给药，并在不同类型的抗抑郁药中观察到，这表明增加神经发生是这类药物的共同作用。初步研究还表明，抗抑郁药的施用阻断了由压力引起的神经发生的下调。当前应用的重点是确定介导抗抑郁药对成人神经发生影响的分子机制。我们之前的研究（由该基金支持）表明，抗抑郁药上调cAMP反应元件结合蛋白（CREB），这是一种涉及细胞可塑性的转录因子，以及脑源性神经营养因子。我们将使用药理学和突变小鼠模型相结合的方法来研究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，阻断cAMP代谢的药物（罗利普兰）的使用增加，而CREB显性阴性突变体的过表达减少，成人海马神经发生。我们还将研究CREB的其他可能影响成人海马新生细胞分化和存活的基因靶点。最后，研究将进行检查成人神经发生和抗抑郁治疗的行为反应之间的关系。这些研究将为控制成人海马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.