Central nervous system SIRT1 expression is required for cued and contextual fear conditioning memory responses in aging mice

Abstract

BACKGROUND: Sirtuin 1 (SIRT1) is a NAD+-dependent enzyme that has important roles in many biological processes involved in aging, including cell growth and repair, inflammation, and energy regulation. SIRT1 activity is modulated in response to certain nutritional interventions that increase healthspan and longevity in rodents, including calorie restriction (CR) and intermittent fasting (IF). In addition to positively influencing cardiometabolic health, SIRT1 is important for brain health and may be critical in the preservation of memory processes that deteriorate during aging. OBJECTIVE: To investigate the role of brain-associated SIRT1 expression in the acquisition of fear memory in mice at 45 and 65 weeks of age. METHODS: Mice with brain-specific knock-out or overexpression of Sirt1 were assessed on a fear conditioning paradigm to determine the role of SIRT1 in fear memory acquisition. RESULTS: In the current study, mice lacking the expression of brain SIRT1 could not learn the fear conditioning paradigm during training, context, or cue phases. CONCLUSIONS: The results of the study indicate that SIRT1 expression in the brain is critical for the formation of fear memory in male mice at two distinct ages, highlighting the essential role of SIRT1 in fear memory acquisition during aging.