Neuronal Integration of Newborn Granule Cells in Aged Brains

成年海马体中新神经元的诞生（称为神经发生）对学习和记忆至关重要， 衰老过程中这一过程的中断与神经精神疾病有关， 老年大脑的认知能力我们对成体神经发生的大部分知识都与存活和 年轻成人脑中新生神经元的分化。关于这些神经元是如何 整合到老年海马体中现有的神经回路中。海马体中的神经元祖细胞 当完全分化时，这些颗粒细胞沿着苔藓纤维路径沿着发送轴突，在那里它们形成 突触连接（称为扣结）到CA 3锥体神经元。以前我们开发了一种系列免疫- 电镜下观察新生苔藓纤维终扣在成年后的发育过程 个脑袋在这里，使用一个报告小鼠，我们可以诱导标记新的神经元，出生在一个特定的 时间段，我们研究了新生颗粒细胞在老年海马的发育和整合。 这一小鼠系使我们能够确定出生日期并描述任何年龄的神经发生，包括老年小鼠18 几个月或更久。我们的初步研究表明，老年海马的祖细胞库发生了变化; 与未成年脑相比，存在更多的静止（非活动）祖细胞。我们还发现， 新生颗粒细胞在老年大脑中形成从头突触的潜力显著降低;相反， 当这些新生神经元形成突触时，现有的终扣必须被替换。这些结果揭示 老年大脑中新生神经元及其祖细胞的变化。在本提案中，我们 聚焦三个问题。(1)神经元的分子表型和发育起源是什么？ 老年海马体中的祖细胞这些实验将揭示老年大脑中的祖细胞是如何 与年轻人不同。(2)现存钮扣的年代和发展起源是什么， 被老年大脑中新生的苔藓纤维钮所取代？为什么新生的颗粒细胞 老年人的大脑会失去重新形成突触的能力吗这种损失是由于神经元祖细胞的变化造成的吗 还是老年海马体环境的变化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 活动影响老年大脑的神经发生？我们发现老化的海马体会失去一个电压- 门控钾通道调节神经元的内在兴奋性，并且该通道具有显著的 对成体神经发生的影响。我们会问，由于失去了这种功能，神经元活动的变化是如何发生的？ 通道影响老年海马新生颗粒细胞的发育和整合。这些 实验将填补我们对老年大脑神经发生的认识中的一个重要空白， 将有助于未来制定康复或治疗策略，以改善患者的功能， 老化的大脑

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.