Anxiety, a common mental disorder, is epidemiologically linked to high dietary sugar intake. However, the underlying neural mechanisms remain poorly understood. Here, using male C57BL/6 mice (n ≥ 10 per group), we show that two-week consumption of sugar-sweetened drinks reliably induced anxiety-like behavior, characterized by reduced center time in the open field test and less open arm exploration in the elevated plus maze. Notably, consumption of sucrose, glucose, or the non-metabolizable glucose analog methyl-α-D-glucopyranoside induced anxiety-like behavior, whereas intake of the artificial sweetener acesulfame potassium (Ace-K) did not. Moreover, after two weeks of exposure to sucrose or glucose but not to Ace-K, c-Fos expression was elevated in glutamatergic neurons of the nucleus of the solitary tract (NTS). Mechanistically, high glucose activated intrinsic excitability and the amplitude of spontaneous excitatory postsynaptic currents in NTS glutamatergic neurons; congruently, selective activation of NTS glutamatergic neurons mimicked anxiety-like behavior in mice, while chemogenetic silencing of these neurons abolished glucose-induced anxiety. Together, our findings demonstrate that NTS glutamatergic neurons activation mediates sugar-induced anxiety. These results suggest that this anxiogenic effect is driven by glucose-related signaling rather than artificial sweet taste perception alone, shedding light on a novel clinical therapy against anxiety.
Wang et al. (Sun,) studied this question.