AGRP neurons modulate fasting-induced anxiolytic effects.

Recent studies indicate that activation of hypothalamic Agouti-related protein (Agrp) neurons can increase forage-related/repetitive behavior and decrease anxiety levels. However, the impact of physiological hunger states and food deprivation on anxiety-related behaviors have not been clarified. In the present study, we evaluated changes in anxiety levels induced by physiological hunger states and food deprivation, and identified the neuron population involved. Ad libitum fed and fasted mice were tested in the open field and elevated plus-maze behavioral tests. The DREADD approach was applied to selectively inhibit and stimulate neurons expressing Agrp in hypothalamic arcuate nucleus in Agrp-Cre transgenic mice. We found that anxiety levels were significantly reduced in the late light period when mice have increased need for food and increased Agrp neurons firing, in contrast to the levels in the early light period. Consistently, we also found that anxiety was potently reduced in 24-h fasted mice, relative to 12-h fasted mice or fed ad libitum. Mechanistically, we found that chemogenetic activation of Agrp neurons reduced anxiety in fed mice, and inactivation of Agrp neurons reduced fasting-induced anxiolytic effects. Our results suggest that anxiety levels may vary physiologically with the increasing need for food, and are influenced by acute fasting in a time-dependent manner. Agrp neurons contribute to fasting-induced anxiolytic effects, supporting the notion that Agrp neuron may serve as an entry point for the treatment of energy states-related anxiety disorders.