BEHAVIORAL STUDY OF DENDRITIC AND SYNAPTIC CORRELATES IN RETROSPLENIAL CORTEX NEURONS IN ALZHEIMER’S DISEASE

Strategy updating is crucial for survival, allowing species to adapt to environmental changes. The retrosplenial cortex (RSC) plays a key role in this process, with lesions or inactivation impairing the ability to explore and learn alternative strategies—highlighting its importance in set-shifting behavior¹. Building on reports of reversal learning deficits in 6-month-old 5xFAD mice², this study investigates the synaptic correlates of reversal learning in the RSC in the context of Alzheimer’s disease (AD). We used a set-shifting task that required mice to adapt to a new stimulus-reward³ rule after learning an initial association. Mice were first trained to move a floating platform toward a dark (unstimulated) port for water rewards. Once learned, the rule was reversed: the reward was now at the lit port⁴,⁵. Surprisingly, 6-month-old 5xFAD mice did not show deficits in this reversal task. To further characterize their cognitive phenotype, the same cohort was tested in a hippocampus-dependent task and specifically the Object Location (OL)—previously shown to be impaired in 12-month-old 5xFAD mice⁶. Notably, the 6-month-old 5xFAD mice showed impairments in these tasks but enhanced reversal learning. To investigate cellular mechanisms behind these behaviors, we are currently using confocal microscopy and plan to employ in vivo two-photon microscopy to assess dendritic spine dynamics. We will also perform RNA sequencing (RNA-seq) to uncover gene expression differences between 5xFAD and control mice following behavioral testing. This project aims to reveal early synaptic changes in RSC and their role in adaptive behavior in AD.