# Differential disruptions in population coding along the dorsal-ventral axis of CA1 in the APP/PS1 mouse model of Aβ pathology

## TL;DR

This study shows that amyloid beta disrupts brain activity differently in two parts of the hippocampus in a mouse model of Alzheimer's disease.

## Contribution

The study reveals region-specific disruptions in population coding in the hippocampus due to amyloid beta pathology.

## Key findings

- Dorsal CA1 showed decreased pairwise correlations and entropy in APP/PS1 mice.
- Ventral CA1 showed increased pairwise correlations and entropy in APP/PS1 mice.
- Maximum entropy models predicted dCA1 activity better but vCA1 activity worse in APP/PS1 mice.

## Abstract

Alzheimer’s Disease (AD) is characterized by a range of behavioral alterations, including memory loss and psychiatric symptoms. While there is evidence that molecular pathologies, such as amyloid beta (Aβ), contribute to AD, it remains unclear how this histopathology gives rise to such disparate behavioral deficits. One hypothesis is that Aβ exerts differential effects on neuronal circuits across brain regions, depending on the neurophysiology and connectivity of different areas. To test this, we recorded from large neuronal populations in dorsal CA1 (dCA1) and ventral CA1 (vCA1), two hippocampal areas known to be structurally and functionally diverse, in the APP/PS1 mouse model of amyloidosis. Despite similar levels of Aβ pathology, dCA1 and vCA1 showed distinct disruptions in neuronal population activity as animals navigated a virtual reality environment. In dCA1, pairwise correlations and entropy, a measure of the diversity of activity patterns, were decreased in APP/PS1 mice relative to age-matched C57BL/6 controls. However, in vCA1, APP/PS1 mice had increased pair-wise correlations and entropy as compared to age matched controls. Finally, using maximum entropy models, we connected the microscopic features of population activity (correlations) to the macroscopic features of the population code (entropy). We found that the models’ performance increased in predicting dCA1 activity, but decreased in predicting vCA1 activity, in APP/PS1 mice relative to the controls. Taken together, we found that Aβ exerts distinct effects across different hippocampal regions, suggesting that the various behavioral deficits of AD may reflect underlying heterogeneities in neuronal circuits and the different disruptions that Aβ pathology causes in those circuits.

Patients with Alzheimer’s disease (AD) experience an array of cognitive deficits, such as memory loss and executive dysfunction, as well as behavioral symptoms, such as agitation and anxiety. However, it is unclear how these myriad deficits arise from the molecular and cellular hallmarks of AD, such as amyloid beta (Aβ) plaques. In the current study, we sought to bridge this gap by studying how neural activity is disrupted in the context of Aβ pathology. We recorded the activity of large populations of neurons in two different brain regions, the dorsal and ventral CA1 subfields of the hippocampus, in a mouse model of Aβ pathology as animals navigated a virtual reality environment. Using statistical approaches to quantify the features of the population code, we showed that the disruptions to neuronal activity in the Aβ model were different across these two regions. These results suggest that Aβ exerts diverse effects across different brain regions that likely reflect underlying heterogeneities in the circuits of the brain.