Aging to 24 months increased C57BL/6J mouse social sniffing and hippocampal Neto1 levels, and impaired female spatial learning

Understanding how natural aging impacts rodent performance in translational behavior tests is critical to teasing apart impairments due to age-related decline from neurodegenerative disorder modeling. Reduced neuropilin and tolloid-like 1 (NETO1), an accessory protein of ionotropic glutamate receptors involved in synaptic plasticity, was associated with Alzheimer's disease, yet aging effects on Neto1 remain unclear. For these reasons, our goal was to characterize how Neto1 expression corresponded with social, repetitive, and spatial learning behaviors and stress response across the C57BL/6J mouse lifespan. We measured social preferences in three-chamber tests, and motor stereotypies by marble burying. Cognitive flexibility is typically assessed in the Morris water maze (MWM), wherein C57BL/6J mice exhibit deficits with age. However, fatigue or locomotor impairment may confound interpretation of MWM performance. Therefore, we used a less arduous water T-maze (WTM) to compare spatial learning flexibility in 2, 9–15, and 24-month-old male and female mice to test the hypothesis that deficits would emerge with age. In both sexes, 9–15-month-olds made more chamber entries during social preference tests, while 2-month-olds did less social sniffing than aged mice. No age or sex differences emerged in marble burying or serum corticosterone measurements. In 24-month-olds hippocampal Neto1was increased relative to 2-month-olds, and male cognitive flexibility was strong, while spatial learning and reversal learning of 24-month-old females was impaired in WTM irrespective of Neto1 expression. The WTM is a useful alternative assessment for cognitive flexibility deficits in aged mice, and the role of hippocampal Neto1 in promoting social sniffing is of interest.