Enhanced avoidance learning associated with elevated anxiety in the 3xTg-AD mouse model of Alzheimer's disease

Alzheimer's disease (AD) is the world's most prevalent degenerative neurological disease, characterized by extracellular accumulation of misfolded Aβ peptide and intracellular formation of neurofibrillary tangles. In addition to cognitive deficits, psychological and behavioral manifestations such as fear, anxiety, and depression are present in patients with AD. The relationship between these noncognitive symptoms and memory and learning deficits remains unknown. Using a genetic mouse model of the disease, we assessed fear-based learning and anxiety through the active avoidance test (AAT) and elevated plus maze (EPM) in middle-aged 3xTg-AD mice. Animals were tested in four consecutive daily sessions, and measures of avoidance rate, avoidance latency, escape rate, and escape latency were performed. After seven days, the mice were placed in the EPM, and the number of entries and time spent on the open arms were quantified. The AAT revealed that 3xTg-AD animals exhibited a higher avoidance rate in sessions 3 (p < 0.001) and 4 (p < 0.01), a shorter escape rate in sessions 3 (p < 0.01) and 4 (p < 0.05), and a shorter escape latency in session 3 (p < 0.05). Furthermore, 3xTg-AD mice had a lower percentage of entries (p < 0.001) and a shorter time spent (p < 0.001) in the open arms of the EPM compared to the control group. These results suggest that the high performance of transgenic animals in learning to avoid shocks may be related to an intrinsic state of alertness, making the 3xTg-AD mouse a reliable model for investigating the neurobiological and pathological mechanisms of anxiety and fear in AD.