40 Hz sensory stimulation enhances CA3-CA1 coordination and prospective coding during navigation in a mouse model of Alzheimer's disease

Abstract

40 Hz sensory stimulation ("flicker") has emerged as a new technique to potentially mitigate pathology and improve cognition in mouse models of Alzheimers disease (AD) pathology. However, it remains unknown how 40 Hz flicker affects neural codes essential for memory. Accordingly, we investigate the effects of 40 Hz flicker on neural representations of experience in the hippocampus of the 5XFAD mouse model of AD by recording 1000s of neurons during a goal-directed spatial navigation task. We find that an hour of daily exposure to 40 Hz audio-visual stimulation over 8 days leads to higher coordination between hippocampal subregions CA3 and CA1 during navigation. Consistent with CA3s role in generating sequential activity that represents future positions, 40 Hz flicker exposure increased prospective coding of future positions. In turn, prospective coding was more prominent during efficient navigation behavior. Our findings show how 40 Hz flicker enhances key hippocampal activity during behavior that is important for memory. Significance StatementBrain stimulation has emerged as a new potential therapeutic approach to potentially correct or improve altered neural activity in Alzheimers disease. One such approach, 40 Hz sensory stimulation, or flicker, has been shown to improve cognition in disease models. However, it is not clear how 40 Hz flicker affects neural activity underlying memory processes. Here, we investigate how 40 Hz flicker exposure affects neural activity patterns that are crucial for memory. We find 40Hz flicker increases neural coordination in memory circuits, indicating better communication. Furthermore, 40Hz flicker increased neural representations of future positions, patterns theorized to support memory-based planning. These results indicate that 40 Hz flicker increases key neural activity that is important for memory.