Age-related cognitive deficits are observed in both humans and animals. Yet, the molecular mechanisms underlying these deficits are not yet fully elucidated. In aged animals, a decrease in intrinsic excitability of pyramidal neurons from the CA1 sub-region of hippocampus is believed to contribute to age-related cognitive impairments, but the molecular mechanism(s) that modulate both these factors has yet to be identified. Increasing activity of the transcription factor cAMP response element-binding protein (CREB) in young adult rodents has been shown to facilitate cognition, and increase intrinsic excitability of their neurons. However, how CREB changes with age, and how that impacts cognition in aged animals, is not clear. Therefore, we first systematically characterized age- and training-related changes in CREB levels in dorsal hippocampus. At a remote time point after undergoing behavioral training, levels of total CREB and activated CREB (phosphorylated at S133, pCREB) were measured in both young and aged rats. We found that pCREB, but not total CREB was significantly reduced in dorsal CA1 of aged rats. Importantly, levels of pCREB were found to be positively correlated with short-term spatial memory in both young and aged rats i.e. higher pCREB in dorsal CA1 was associated with better spatial memory. These findings indicate that an age-related deficit in CREB activity may contribute to the development of age-related cognitive deficits. However, it was still unclear if increasing CREB activity would be sufficient to ameliorate age-related cognitive, and biophysical deficits. To address this question, we virally overexpressed CREB in CA1, where we found the age-related deficit. Young and aged rats received control or CREB virus, and underwent water maze training. While control aged animals exhibited deficits in long-term spatial memory, aged animals with CREB overexpression performed at levels comparable to young animals. Concurrently, aged neurons overexpressing CREB had increased excitability. This indicates that overexpression of CREB was sufficient to rescue both the cognitive deficits, and the biophysical dysfunction normally seen in aged animals. Together, the results from this thesis identify CREB as a new mechanism underlying age-related cognitive deficits. This not only furthers our understanding of how cognitive processes change with age, but also suggests that increasing activity of CREB or its downstream transcription targets may be a novel therapeutic for the treatment of age-related cognitive decline.

Last modified

• 03/22/2018

Creator

• Xiao Wen Yu

DOI

• https://doi.org/10.21985/N29M41

Subject

• Interdepartmental Neuroscience Program (NUIN)

Keyword

• CREB
• Memory
• Hippocampus
• Aging

Date created

• 2016-01-01

Resource type

• Dissertation

Rights statement

• In Copyright