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。服用抗病毒药物valganciclovir可阻止表达HSV-tk的细胞重新进入细胞周期。对这一小鼠模型的基线生理和病理观察显示没有差异，表明转基因治疗或治疗和植入的组合没有不良副作用。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轻度应激下表现出下丘脑-垂体-肾上腺(HPA)轴反应增加。这些结果表明，海马区新生神经元在海马区对HPA轴的负性调节中起重要作用。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即刻早期基因的激活。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，通过将动物安置在一个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，这至少部分是通过新生神经元对HPA轴的抑制控制的影响而介导的。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，我们研究了与野生型动物相比，缺乏成体神经发生的动物的CA3、齿状回和下丘脑的基因调控。这些研究已经开始为我们提供进一步的洞察力，以了解成年神经发生丧失影响的基因靶点，这些基因靶标可能在促进压力弹性方面发挥重要作用。 此外，我们还对新生齿状回颗粒细胞在其海马区CA3区神经支配靶点上的作用进行了研究。这些研究结果表明，抑制成年海马神经发生导致CA3锥体细胞树突状重塑。Messenger RNA和Micro RNA表达研究表明，参与树突重塑的几个基因发生了变化，很可能是所观察到的重塑的潜在分子原因。此外，我们已经开始研究成年海马区神经发生对女性行为的作用，特别是产前和产后情绪和焦虑的行为适应。这些研究是与Hen博士(哥伦比亚大学)合作完成的，他为我们提供了经海马区照射的雌性动物，以验证我们在hGFAPtk转基因动物中的发现。 长期以来，海马体一直被认为是各种精神障碍的结构和功能病理部位。例如，抑郁症、精神分裂症和创伤后应激障碍与海马体体积减少、学习和记忆障碍以及情绪紊乱相关。与这些疾病相关的一些行为症状的改善与海马可塑性和功能缺陷的逆转有关。特别是，相关和直接的证据都将成人海马顶神经发生的神经再生过程与精神障碍的病因和治疗联系在一起。我们的研究揭示了应激相关障碍中海马神经发生和HPA轴调节失调的神经生物学机制，有可能极大地帮助我们理解海马神经发生失调如何参与情绪障碍和抗抑郁反应。

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.