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.

Public Health Relevance

Cognitive impairments are a common feature in aging and aging-related disorders, yet the underlying molecular mechanisms remain unknown. The results of this study are essential towards delineating how hippocampal dysfunction correlates with an aging-implicated component to affect cognitive function. This understanding will help guide a rational approach to designing and developing interventions targeting age- related cognitive deficits.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG058560-01
Application #
9495459
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Wise, Bradley C
Project Start
2018-03-15
Project End
2022-12-31
Budget Start
2018-03-15
Budget End
2018-12-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Hussaini, Syed M Q; Jang, Mi Hyeon (2018) New Roles for Old Glue: Astrocyte Function in Synaptic Plasticity and Neurological Disorders. Int Neurourol J 22:S106-114
Cho, Chang Hoon; Yang, Zhongxi; Yoo, Ki Hyun et al. (2018) BubR1 Insufficiency Impairs Affective Behavior and Memory Function in Mice. Int Neurourol J 22:S122-130