PROJECT SUMMARY
Aging is the most significant negative regulator of hippocampal neurogenesis, contributing to impairments in
synaptic plasticity and cognitive function. The main goal of this application is to identify juvenile protective
factors (JPFs) that are capable of maintaining neurogenesis and cognitive function in aged mice so that
effective therapeutic strategies for age-related cognitive disorders can be realized. Towards identifying novel
JPFs, we have recently provided first evidence that the mitotic checkpoint kinase BubR1 is required for
maintaining proper early brain development and hippocampal function later in life. Specifically, BubR1 level is
particularly high during early development and then declines to an adult level, followed by further decline
during the natural aging process. Given that neurogenesis is robust in childhood, but undergoes a progressive
decline with aging, such expression pattern of BubR1 correlates with age-dependent declines in neurogenesis.
However, whether sustained BubR1 levels have a protective role in the aged brain, and thus suggest a novel
JPF that maintains proper neurogenesis and related hippocampal function in aged mice, remains unknown.
Therefore, the main objective of this application is to resolve whether sustained high level of BubR1 in aged
brain prevents age-related hippocampal dysfunction. To support this idea, our preliminary data demonstrate
that BubR1 insufficiency accelerates age-dependent impairments in hippocampal neurogenesis. Importantly,
while a high level of BubR1 itself does not have any detrimental effects in young mice, it promotes
neurogenesis in aged mice. Based on these findings, our central hypothesis is that reduced BubR1 levels with
age contribute to age-dependent declines in hippocampal function, and that sustained high levels of BubR1
promote neurogenesis and improve synaptic plasticity and cognitive function in aged mice. Utilizing multiple
approaches including mouse genetics, confocal imaging, electrophysiology, and behavior analysis, Aim 1 will
determine a key downstream molecular pathway of BubR1 in regulating neurogenesis. Given the well-
established role of Wnt signaling in neurogenesis and aging, we will explore the involvement of the Wnt
signaling pathway in neurogenesis in both BubR1 insufficient and aged mice. Subsequently, Aim 2 will test
whether a sustained high level of BubR1 can restore hippocampal neurogenesis in aged mice. Lastly, Aim 3
will determine if a sustained high level of BubR1 improves synaptic plasticity and cognitive function in aged
mice in a neurogenesis-dependent manner. In summary, our findings will not only reveal the etiology of age-
related cognitive disorders, but also provide a framework by which therapeutic interventions may target
neurogenic declines during normal brain aging. Considering the prevalence of age-associated cognitive
deficits, determining the mechanistic elements improving hippocampal function will hold significant implications
for the fields of cognitive aging, neurogenesis, neural plasticity, regenerative medicine, and public health.