Neuronal Integration of Newborn Granule Cells in Aged Brains

成年海马区新神经元的诞生(称为神经发生)对学习和记忆至关重要， 而衰老过程中这一过程的中断与神经精神疾病有关，这些疾病破坏了 老年人大脑中的认知。我们关于成人神经发生的大部分知识都与生存和 年轻成人大脑中新生神经元的分化。关于这些神经元是如何 整合到老化的海马体的现有神经回路中。海马体中的神经前体细胞给 升为颗粒细胞，当完全分化时，沿着苔藓纤维路径发送轴突，在那里形成轴突 与CA3锥体神经元的突触联系(称为突触)。在此之前，我们开发了一种系列免疫- 用电子显微镜研究成人新生苔藓纤维突起的发育 大脑。在这里，使用我们可以诱导的报告老鼠来标记在特定环境中出生的新神经元 研究老年大鼠海马区新生颗粒细胞的发育和整合情况。 这一小鼠品系使我们能够确定任何年龄的小鼠的出生日期和特征，包括18岁的小鼠。 几个月或更大。我们的初步研究表明，老年大鼠海马区的祖细胞池发生了变化； 与年轻人的大脑相比，存在着更多静止(不活跃)的祖细胞。我们还发现了 老年大脑中新生颗粒细胞形成新生突触的可能性显著降低；相反 当这些新生神经元形成突触时，现有的突触必须被替换。这些结果揭示了 衰老大脑中新生神经元及其前体细胞的未知变化。在这项提案中，我们 重点回答三个问题。(1)神经元的分子表型和发育来源是什么？ 老年海马体中的祖细胞？这些实验将揭示衰老大脑中的祖细胞是如何 与年轻人不同。(2)现存的北部湾的年龄和发育来源是什么？ 会被衰老大脑中新生的苔藓纤维突起所取代吗？为什么新生的颗粒细胞在 衰老的大脑失去了形成新生突触的能力？这种损失是由于神经元前体细胞的变化造成的吗？ 或者是对老化的海马体环境的改变？这些问题的答案将帮助我们 了解成人神经发生在老年大脑中的特定功能作用。(3)神经元的变化 活动会影响老年人大脑的神经发生吗？我们发现老化的海马体失去了一个电压- 调节神经元内在兴奋性的门控性钾通道，该通道具有显著的 对成人神经发生的影响。我们将会问，由于这一点的丧失，神经元活动的变化是如何产生的 经络影响老年海马区新生颗粒细胞的发育和整合。这些 实验将填补我们关于老年大脑中神经发生的知识的一个重要空白，这是我们所期望的 将有助于未来康复或治疗策略的发展，以改善 大脑老化。

The birth of new neurons (called neurogenesis) in the adult hippocampus is critical for learning and memory, and disruption of this process during aging is associated with neuropsychiatric illnesses that undermine cognition in the aged brain. Most of our knowledge about adult neurogenesis relates to the survival and differentiation of newborn neurons in the young adult brain. Much less is known about how these neurons integrate into existing neural circuits in the aged hippocampus. Neuronal progenitors in the hippocampus give rise to granule cells that, when fully differentiated, send axons along the mossy fiber pathway, where they form synaptic connections (called boutons) to CA3 pyramidal neurons. Previously we developed a serial immuno- electron microscopic approach to study the development of these newborn mossy fiber boutons in the adult brain. Here, using a reporter mouse that we can induce to label the new neurons that are born in a particular time period, we investigate the development and integration of newborn granule cells in the aged hippocampus. This mouse line allows us to birth-date and characterize neurogenesis at any age, including in aged mice 18 months or older. Our preliminary studies show that the progenitor pool changes in the aged hippocampus; more quiescent (inactive) progenitors are present compared to young-adult brain. We have also found the potential for newborn granule cells to form de novo synapses in aged brain is significantly reduced; instead existing boutons have to be replaced when these newborn neurons form synapses. These results reveal previously unknown changes in newborn neurons and their progenitors in the aged brain. In this proposal, we focus on three questions. (1) What are the molecular phenotype and developmental origin of the neuronal progenitors in aged hippocampus? These experiments will reveal how progenitors in the aged brain are different from those in young adults. (2) What is the age and developmental origin of the existing boutons that are replaced by the newborn mossy-fiber boutons in aged brain? Why do the newborn granular cells in the aged brain lose their ability to form de novo synapses? Is this loss due to changes in the neuronal progenitors or to changes to the environment in the aged hippocampus? The answers to these questions will help us understand the specific functional role of adult neurogenesis in the aged brain. (3) How do changes in neuronal activity affect neurogenesis in the aged brain? We have found that the aged hippocampus loses a voltage- gated potassium channel that regulates neuronal intrinsic excitability, and that this channel has a significant effect on adult neurogenesis. We will ask how the changes in neuronal activity resulting from the loss of this channel affect the development and integration of newborn granule cells in the aged hippocampus. These experiments will fill an important gap in our knowledge about neurogenesis in the aged brain, which we expect will contribute to the future development of rehabilitative or therapeutic strategies to improve the function of the aging brain.