Intermittent Fasting Alters Cognition, Anxiety‐like Behavior, and Hippocampal Norepinephrine Content in Aged Mice

Abstract

Intermittent fasting (IMF) is associated with many health benefits in animal models and humans. Yet, little is known if an IMF diet affects mood and cognitive processing. We have previously identified that IMF in diet-induced obese males increases norepinephrine content in the hypothalamus and increase arcuate neuropeptide Y (NPY) gene expression more than in ad libitum males. This suggests that IMF may improve cognition through activation of the hindbrain norepinephrine neuronal network and reverse the age-dependent decline in NPY expression. Less is known about the association between anxiety and IMF. In humans, IMF during Ramadan may alleviate anxiety. Here, we address the impact of IMF on hippocampal-dependent memory using the Y-maze and spatial object recognition (SOR), hippocampal-independent memory using novel object recognition (NOR), and anxiety-like behavior using the open field task (OFT) in middle-aged male (12 mo) and aged female (18 mo) mice. Y-maze data indicate that IMF males perform worse in the identification of the unknown arm than same-sex controls, suggesting an IMF-induced deficit in interpreting spatial navigation routes. Conversely, no difference was detected in females on this task. In the SOR task, which evaluates hippocampal-dependent object orientation, IMF males were not affected; however, IMF females exhibited a decrease in performance. This suggests that, in females, IMF impairs spatial information about the arrangement of objects. In the NOR, which detect differences in hippocampal-independent memory, IMF males performed better than their same-sex counterparts; however, we did not detect an effect in females. IMF treated males displayed and increase in hippocampal norepinephrine content, suggesting IMF may alter hindbrain norepinephrine signaling. Our overall cognitive results suggest that, in males, IMF results in deficits only in hippocampal-dependent tasks, yet an enhancement in performance when hippocampal-independent tasks are conducted. In females, only the hippocampal-dependent task of SOR was affected by IMF, suggesting IMF disrupts spatial object configuration. In the OFT, IMF male and female mice spent more time in the center zone, indicative of an anxiolytic phenotype. Collectively our research suggests that IMF is enough to produce both an impairment and enhancement in memory dependent upon age, sex, and hippocampal involvement, as well as an anxiolytic phenotype in both male and female aged mice.