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（与神经可塑性单位合作）开发了一个小鼠模型，该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可以防止表达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无差异，表明治疗或治疗与植入转基因的组合没有不良副作用。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。我们发现缺乏成体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，海马新生神经元在海马对HPA轴的负调控中起重要作用。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即刻早期基因激活。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，我们认为这些新生的海马神经元可能是应激恢复和弹性程序的关键组成部分，至少部分是通过新生神经元对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靶区（如下丘脑和内侧前额叶皮质）的影响，我们研究了缺乏成年神经发生动物的CA3、齿状回和下丘脑的基因调控。这些研究已经开始为我们进一步了解受成人神经发生丧失影响的基因靶点，并可能在促进压力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) 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 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 that there were no 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 of the HPA axis by the hippocampus. 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 immediate-early gene 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 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 studied gene regulation in the CA3, dentate gyrus and hypothalamus of animals lacking adult neurogenesis compared to wild-type animals. These studies have begun to provide us with further insight into the gene targets that are affected by loss of adult neurogenesis and which may be important in promoting stress resiliency. In addition we have conducted studies examining the role of newborn dentate gyrus granule cells on their innervation targets in the CA3 region of the hippocampus. Results of these studies show that suppression of adult hippocampal neurogenesis leads to dendritic remodeling of CA3 pyramidal cells. Messenger RNA and micro RNA expression studies showed changes in several genes that are involved in dendritic remodeling and are likely to be the underlying molecular causes for the observed remodeling. Furthermore, we have started examining the role of adult hippocampal neurogenesis on female behavior, especially pre- and postpartum behavioral adaptations of mood and anxiety. These studies are done in collaboration with Dr. Hen (Columbia University) who is supplying us with hippocampally irradiated females to validate our findings in the hGFAPtk transgenic animals. The hippocampus has long been noted as a site of structural and functional pathology in a variety of mental disorders. For example, depression, schizophrenia and post-traumatic stress disorder have been correlated with decreased hippocampal volume, deficits in learning and memory as well as mood perturbations. Improvement in some of the behavioral symptoms associated with these disorders has been linked to reversal of deficits in hippocampal plasticity and function. In particular, both correlative and direct evidence has linked the neuroplastic process of adult hippocamapal neurogenesis with the etiology and treatment of mental disorders. Our research, which is uncovering the neurobiological mechanisms linking hippocampal neurogenesis and dysregulation of the HPA-axis in stress-related disorders, has the potential to greatly aid our understanding of how dysregulation of hippocampal neurogenesis may be involved in mood disorders and in the antidepressant response.