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.
Neurogenesis in the adult brain is often positively associated with cognitive function and therefore presents an important cellular target for therapies aimed at treating cognitive decline in aging. The studies described in this proposal will reveal new mechanisms regulating neurogenesis and the functional integration of these new neurons in adult brain. Understanding how adult neurogenesis works will create exciting new opportunities for boosting age related impairment in cognition.
