Intermittent fasting disrupts hippocampal-dependent memory and norepinephrine content in aged male and female mice.

Intermittent fasting (IMF) is associated with many health benefits in animals 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 and dopamine content in the hypothalamus and increases arcuate neuropeptide Y (NPY) gene expression more than in ad libitum control 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. Although, in humans, IMF during Ramadan may alleviate anxiety. Here, we address the impact of IMF on anxiety-like behavior using the open field test, hippocampal-dependent memory using the Y-maze and spatial object recognition, and hippocampal-independent memory using novel object recognition in middle-aged male and female (12 mo) and aged male and female (18 mo) mice. Using ELISA, we determined norepinephrine (NE) content in the dorsal hippocampus (DH) and prefrontal cortex (PFC). We also investigated gene expression in the arcuate nucleus (ARC), the lateral hypothalamus (LH), and the locus coeruleus (LC). In IMF-treated females at both ages, we observed an improvement in spatial navigation although an impairment in spatial object orientation. IMF-treated females (12 mo) had a reduction and IMF-treated males (12 mo) displayed an improvement in novel object recognition memory. IMF-treated females (18 mo) exhibited anxiolytic-like behavior and increased locomotion. In the DH, IMF-treated males (12 mo) had a greater amount of NE content and IMF-treated males (18 mo) had a reduction. In the ARC, IMF-treated males (12 mo) exhibited an increase in Agrp and Npy and a decrease in Adr1a. In the ARC, IMF-treated males (18 mo) exhibited an increase in Npy and a decrease in Adr1a; females had a trending decrease in Cart. In the LH at 12 months, IMF-treated males had a decrease in Npy5r, Adr1a, and Adr1b; both males and females had a reduction in Npy1r. In the LH, IMF-treated females (18 mo) had a decrease in Hcrt. In the LC at both ages, mice largely exhibited sex effects. Our findings indicate that IMF produces alterations in mood, cognition, DH NE content, and ARC, LH, and LC gene expression depending on sex and age.