The Role of Afferent Hippocampal to Prefrontal Cortex Projections in a Mouse Model of Alzheimer's Disease

Abstract

Alzheimer's disease is the most common cause of dementia and is marked by progressive cognitive decline. Early dysfunction appears in the hippocampus and later involves the prefrontal cortex. These two brain regions are strongly interconnected and support critical functions such as spatial navigation, working memory, and memory consolidation. Healthy animals show strong synchronization between hippocampal and prefrontal activity, especially in the theta (4–12 Hz) and gamma (40–80 Hz) ranges, which supports memory performance. <br/> While hippocampal pathology in Alzheimer's disease has been studied extensively, the specific role of disrupted hippocampal-prefrontal circuitry in driving memory deficits remains unclear. In particular, it is not well understood how excitatory and inhibitory hippocampal projections to the prefrontal cortex are altered in Alzheimer's disease, and how such changes impair local network activity and cognitive function. <br/> The first aim of this project is to describe and characterize hippocampal projections to the prefrontal cortex in a transgenic mouse model of Alzheimer's disease such as the APP/PS1 mouse model. This will involve the use of cell type-specific viral tracers in Cre-driver mouse lines, such as Somatostatin-Cre, combined with immunohistochemical techniques to distinguish excitatory from inhibitory pathways. This anatomical mapping will provide insights into whether certain neuronal subtypes are particularly vulnerable to Alzheimer's disease-related degeneration. <br/> The second objective is to determine the functional consequences of any structural alterations. Using calcium imaging in awake, behaving mice engaged in a spatial working memory paradigm, I monitored how hippocampal inputs recruit local prefrontal circuits during encoding and retrieval phases. Disruptions in synchronous oscillatory activity will be directly related to cognitive impairments characteristic of Alzheimer's disease. To establish causal links, chemogenetic manipulations were employed in healthy control animals to selectively silence hippocampal projections to the prefrontal cortex at defined stages of the memory task, thereby experimentally simulating the connectivity deficits observed in Alzheimer's disease. Finally, by reactivating or enhancing specific prefrontal neuronal ensembles, I tested whether memory performance can be restored. Together, these experiments aim to advance our mechanistic understanding of how abnormal hippocampal-prefrontal interactions drive cognitive decline in Alzheimer's disease and to highlight potential circuit-level targets for therapeutic intervention.