Role of adult neurogenesis in regulation of the HPA axis and stress resiliency

海马齿状回是大脑中的两个区域之一，在整个生命周期中保持着生成新神经元的能力。这些新生神经元的存活受到应激暴露和糖皮质激素增加的负面调节。最近的研究表明，成年后海马区神经元的持续产生可能与抑郁障碍的发展以及抗抑郁药物的治疗有关。例如，已经证明，在抑郁症动物模型中，新海马神经元的产生对于改善抗抑郁药物应激诱导的行为变化是必要的。为了进一步了解成人神经发生对情绪和焦虑相关行为的影响，我们(与神经可塑性单位Heather Cameron博士合作)开发了一种小鼠模型，允许有条件地消融成人神经前体细胞。在这个模型中，成人神经前体细胞的增殖是通过在人GFAP启动子的控制下表达单纯疱疹病毒胸苷激酶(HSV-tk)来实现的。使用抗病毒药物valganciclovir(VGCV)可以阻止表达HSV-tk的细胞重新进入细胞周期。对这种小鼠模型的基线生理和病理观察没有发现差异，表明转基因治疗或治疗和植入的组合会产生不良副作用。此外，行为学观察没有显示出在没有神经发生的动物中基线焦虑或抑郁样行为的增加。我们发现，缺乏成年神经发生的动物在暴露于轻度应激时，下丘脑-垂体-肾上腺(HPA)轴反应增加。这些结果表明，海马区新生的神经元对于海马区对HPA轴的负性调节很重要。我们现在已经开始研究，以了解这些新生神经元在提供这种抑制控制方面的生理作用。这些研究包括研究缺乏神经发生的动物在轻度应激后下丘脑室旁核c-fos的激活。我们还扩大了我们的研究范围，以观察新生神经元在调节对慢性压力的反应中所起的作用。在与细胞和分子调节实验室合作进行的一项研究中，我们表明，通过将动物安置在丰富的环境中可以实现从心理社会应激中恢复，这依赖于完整的成年神经发生。根据这些结果，我们认为海马区的这些新生神经元可能是应激恢复和恢复计划的关键组成部分，这至少部分是通过这些新生神经元对HPA轴的抑制控制的影响来调节的。为了更好地了解这些新生神经元对主要靶区的影响，例如下丘脑和内侧前额叶皮质，我们已经开始使用与野生型动物相比缺乏成年神经发生的动物的路径特异性PCR阵列来研究路径特异性基因调控。我们预计，这些研究的结果将进一步深入了解成年神经发生丧失所影响的基因靶点，这些基因靶点可能在促进应激适应能力方面发挥重要作用。

The dentate gyrus of the hippocampus is one of two regions in the brain that retains the capacity to generate new neurons throughout the lifespan. The survival of these newly born neurons is negatively regulated by stress exposure and increased glucocorticoids. Recent studies have proposed that the ongoing production of neurons during adulthood in the hippocampus may be linked to the development of depressive disorders as well as their treatment with antidepressants. For example, it has been shown that production of new hippocampal neurons is necessary for amelioration of stress-induced behavioral changes by antidepressants in an animal model of depression. To further understand the impact of adult neurogenesis on mood and anxiety-related behaviors , we (in collaboration with the Unit on Neural Plasticity, Dr. Heather Cameron) developed a mouse model that allows for the conditional ablation of adult neural progenitors. Conditional ablation of adult neural progenitor cell proliferation in this model is achieved by expression of herpes simplex virus thymidine kinase (HSV-tk) under the control of the human GFAP promoter. Administration of the antiviral drug valganciclovir (VGCV) causes prevention of cells expressing HSV-tk from re-entering the cell cycle. Baseline physiological and pathological observations of this mouse model revealed no differences indicating adverse side effects by the treatment or a combination of treatment and insertion of the transgene. Further, behavioral observations did not show increases in baseline anxiety or depressive-like behavior in animals without neurogenesis. We discovered that animals lacking adult neurogenesis show an increased hypothalamic pituitary adrenal (HPA) axis response when exposed to mild stress. These results suggest that newly born neurons in the hippocampus are important for the negative regulation that the hippocampus has over the HPA axis. We have now initiated studies to understand the physiological role of these newly born neurons in providing this inhibitory control. These studies include studying c-fos activation following mild stress in the paraventricular nucleus of the hypothalamus in animals lacking neurogenesis. We have also extended our studies to look at the role of newly born neurons in regulating the response to chronic stress. In a study conducted in collaboration with the Laboratory of Cellular and Molecular Regulation we showed that recovery from psychosocial stress, which can be achieved by housing animals in an enriched environment, is dependent on intact adult neurogenesis. Based on these results we believe that these newly born neurons in the hippocampus may be a critical component of the stress recovery and resiliency program, which is at least partially mediated through the impact of these newly born neurons on inhibitory control of the HPA axis. To better understand the impact of these newly born neurons on primary target regions, e.g. the hypothalamus and the medial prefrontal cortex, we have begun to study pathway specific gene regulation using a combination of pathway-specific PCR arrays in animals lacking adult neurogenesis compared to wild type animals. We anticipate that the results of these studies will provide further insight into the gene targets that are affected by loss of adult neurogenesis and which may be important in promoting stress resiliency.