Delineating Creb Interactions with Per1 in Learning

open_access
Open Access
Author:
Marwaha, Cyrus
Area of Honors:
Biology
Degree:
Bachelor of Science
Document Type:
Thesis
Thesis Supervisors:
Janine Kwapis, Thesis Supervisor
Gabriele Brigitte Monshausen, Thesis Honors Advisor
Keywords:
Per1
CREB
Memory
Hippocampus
Maraviroc
OLM
OUL
Mice
Aging
Abstract:
As the global population ages, understanding the molecular mechanisms behind cognitive decline is essential for developing effective therapeutic interventions. This thesis investigates the role of the circadian clock gene Period1 (Per1) and its interaction with the transcription factor CREB in age-related memory impairment. We hypothesized that the disruption of this Per1-CREB signaling pathway is a primary driver of memory deficits in the aging brain and that restoring this interaction could mitigate cognitive decline. Using mice models, we explored how the dorsal hippocampus (DH) and the retrosplenial cortex (RSC) coordinate during spatial memory tasks, specifically the Object Location Memory (OLM) and Objects in Updated Locations (OUL) paradigms. Molecular analysis confirmed that Per1 is significantly upregulated in the hippocampus following learning. However, aging often disrupts this pattern, preventing the proper activation of CREB, which is required to turn short-term experiences into stable long-term memories. Our research demonstrated that memory function could be bolstered through targeted interventions. Viral overexpression of CREB in the DH of aging mice successfully modified the molecular landscape, while pharmacological treatment with Maraviroc restored the ability of aged mice to update existing spatial information. These results suggest that age-related memory impairments are driven by specific molecular gaps that can be addressed through therapeutic means. This material is based upon work supported by the NIH/NIA under grant R01AG074041 and the PSU Department of Biology under start-up funds all to Janine L. Kwapis. Any opinions, findings, and conclusions or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the views of the NIH, NIA, and PSU Department of Biology.