Head direction cells in the TgF344‐AD rat model of Alzheimer's disease: Development of new models and analysis methods/validation of pre‐clinical methods

Background Spatial navigation is impaired in the early stages of Alzheimer’s disease (AD) and may be a defining behavioral marker of preclinical AD. Head direction (HD) cells are cortical‐limbic neurons that discharge action potentials as a function of an animal’s spatial orientation in an environment. HD cells can maintain their orientation across repeated test sessions, in reference to salient landmarks, and are thought to play a critical role in guiding accurate spatial behavior. Thus, we tested the hypothesis that impairments in HD cell stability would be apparent in AD. Methods To test this hypothesis, we used the TgF344‐AD rat model of AD which exhibits progressive pathology in cortical‐limbic regions. Previously, we found that 10 month old TgF344‐AD rats make progressively fewer spatially and directionally precise movements during navigation. Thus, HD cells were characterized in the posterior cortex (retrosplenial, postsubiculum, and visual association area 2) and the anterior thalamus of 10 ‐ 13 month TgF344‐AD rats and age matched F344 controls. Rats performed a pellet chasing task within a cylinder fitted with a white cue card during recordings. In some sessions, the cue card was rotated to assess landmark control. Results HD cells were identified and were found to exhibit similar directional firing characteristics between TgF344‐AD and F344 groups. Further, we found that HD cells in TgF344‐AD rats demonstrated intact responses to cue manipulations. In contrast, we observed that HD cells exhibited more variability and instability in their directional orientation across repeated test sessions. Conclusions These results support the hypothesis that deficits in the stability of HD cells may underlie spatial impairments in AD.