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

海马体的齿状回是大脑中两个在一生中保持产生新神经元能力的区域之一。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调控。最近的研究表明，成年期海马体中神经元的持续生成可能与抑郁症的发展以及抗抑郁药的治疗有关。例如，在抑郁症的动物模型中，新的海马神经元的产生对于改善抗抑郁药引起的应激性行为改变是必要的。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）开发了一个小鼠模型，允许有条件地消融成人神经祖细胞。在该模型中，在人GFAP启动子的控制下，单纯疱疹病毒胸苷激酶（HSV-tk）的表达实现了成人神经祖细胞增殖的条件消融。使用抗病毒药物缬更昔洛韦（VGCV）可防止表达HSV-tk的细胞重新进入细胞周期。该小鼠模型的基线生理和病理观察显示，治疗或治疗和植入转基因的组合没有表明不良副作用的差异。此外，行为观察并没有显示在没有神经发生的动物中焦虑或抑郁样行为的基线增加。我们发现缺乏成年神经发生的动物在暴露于轻度应激时表现出增加的下丘脑-垂体-肾上腺（HPA）轴反应。这些结果表明，海马体中新生的神经元对海马体对HPA轴的负调控很重要。我们现在已经开始研究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下丘脑室旁核轻度应激后c-fos的激活。我们还扩展了我们的研究，以观察新生神经元在调节对慢性压力的反应中的作用。在与细胞和分子调控实验室合作进行的一项研究中，我们表明，通过将动物饲养在丰富的环境中，可以实现从心理社会压力中恢复，这依赖于完整的成年神经发生。基于这些结果，我们认为海马体中这些新生神经元可能是应激恢复和弹性程序的关键组成部分，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介导的。为了更好地了解这些新生神经元对主要目标区域（如下丘脑和内侧前额叶皮层）的影响，我们已经开始在缺乏成年神经发生的动物中与野生型动物相比，使用途径特异性PCR阵列组合研究途径特异性基因调控。我们预计这些研究的结果将进一步深入了解受成人神经发生丧失影响的基因靶点，并可能在促进应激恢复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.