Investigating how hippocampal place cell coding is affected by APOE4 homozygosity

About This Grant

Project Summary/Abstract. APOE4 homozygosity is a major genetic risk factor for late-onset Alzheimer’s disease (AD). The hippocampus is a brain region that is particularly affected by AD. The hippocampus exhibits different patterns of neuronal population activity that support different memory functions. Yet, the extent to which specific hippocampal neuronal population patterns are susceptible to disruption by APOE4 homozygosity remains unknown. Here, we propose to examine how APOE4 homozygosity affects hippocampal neuronal population dynamics that support different memory operations in the hippocampus. In healthy wildtype rats, memories are represented by coordinated populations of hippocampal “place cells”, neurons that fire in specific spatial locations and are thought to code the “where” component of episodic memories. During active behaviors, place cell populations represent successive locations across learned trajectories by firing in organized sequences within cycles of the ~8 Hz theta rhythm. Place cell sequences that fire during active exploratory behaviors later reactivate or “replay” in a temporally compressed manner during awake rest and slow-wave sleep. Replay is thought to play a key role in memory consolidation and retrieval by transferring a compressed memory format from the hippocampus to downstream cortical regions that store memories long-term and direct memory-guided behaviors. Theta-coordinated sequences of place cells and place cell sequence replay are widely believed to be key mechanisms underlying hippocampal memory encoding, consolidation, and retrieval. Yet, to our knowledge, no prior study has investigated how place cell sequence coding of memory representations is affected by APOE4 homozygosity. This project will address this critical gap in knowledge by recording large populations of place cells in the hippocampus in a rat model of APOE4 homozygosity, ApoE4 knockin (ApoE4-KI) rats. ApoE3 knockin (ApoE3-KI) rats will serve as a control group given that APOE3 in humans is not associated with an increased risk of AD. We will apply a state-of-the-art Bayesian decoding approach to place cell populations recorded during waking behaviors and sleep to determine how transmission of information related to specific memories and experiences is affected by APOE4 homozygosity. Specific Aim 1 will determine whether development of new memory representations coded by theta-coordinated sequences of place cells during active behaviors is impaired in ApoE4-KI rats. Specific Aim 2 will test the hypothesis that replay of place cell representations of new memories during rest and sleep is deficient in ApoE4-KI rats. Results from this project will reveal new insights about how APOE4 homozygosity affects hippocampal neuronal population coding of new spatial memory representations during memory formation, recall, and consolidation. We expect that this approach can be used in future studies to test whether proposed treatments for AD alleviate impairments in memory representations associated with APOE4 homozygosity.