Iso-α-acids, the bitter components of beer, improve hippocampus-dependent memory through vagus nerve activation

Abstract

Iso-α-acids (IAAs) are hop-derived bitter acids of beer. Epidemiologic studies suggest that moderate alcohol consumption is beneficial for cognitive function, but they do not show the ingredients in alcoholic beverages. Previously, we reported that long-term consumption of IAAs prevents inflammation and Alzheimer pathologies in mice, but their effects on cognitive function have not been evaluated. In the present study, we demonstrated that the consumption of IAAs improves spatial and object recognition memory functions not only in normal Crl:CD1(ICR) male mice but also in mice with pharmacologically induced amnesia. IAA consumption increased the total and extracellular levels of dopamine in the hippocampus of mice and Sprague-Dawley male rats, respectively. Dopamine D₁ receptor antagonist treatment and knockdown of dopamine D₁ receptor expression in the hippocampus attenuated IAA-induced spatial memory improvement. Furthermore, vagotomy attenuated the effects of IAAs in improving spatial and object recognition memory functions and increasing the total level of dopamine in the hippocampus. These results suggest that the consumption of IAAs activates dopamine D₁ receptor-signaling in the hippocampus in a vagus nerve-dependent manner and, consequently, improves spatial and object recognition memory functions. Vagal activation with food components including IAAs may be an easy and safe approach to improve cognitive functions.-Ano, Y., Hoshi, A., Ayabe, T., Ohya, R., Uchida, S., Yamada, K., Kondo, K., Kitaoka, S., Furuyashiki, T. Iso-α-acids, the bitter components of beer, improve hippocampus-dependent memory through vagus nerve activation.

Keywords: amnesia; beer; dopamine; hop.

Figure 1

Effects of IAAs on memory function. A, B) Effects of IAAs on spatial memory. Mice were administered 0, 0.02, 0.2, or 2 mg/kg IAA intragastrically, followed by intraperitoneal injection with 0.85 mg/kg of SCP at 40 min after IAA administration. At 1 h after IAA administration, each mouse was allowed to explore the Y maze for 8 min. Spontaneous alternations and arm entries were recorded. The effects of IAAs on spontaneous alternations (A) and arm entries (B), respectively, are shown. C, D) Effects of IAAs on episodic memory (NORT). The time spent exploring novel and familiar objects during 5 min of reexploration (C) was measured and DI [(time spent with object A− time spent with object B)/(total time exploring both objects)] (D) was calculated. E, F) Effects of IAAs on Aβ-induced memory impairment. Mice were injected intracerebroventricularly with oligomer Aβ, administered donepezil or trans-isohumulone intragastrically, and subjected to the Y-maze test or NORT. Spontaneous alternation (E) and DI (F) are shown. Data represent the means ± sem of 10 mice/group. *P < 0.05, **P < 0.01.

Figure 2

Effects of IAAs on the levels of monoamines and metabolites in the hippocampus. The levels of dopamine (DA) (A), DOPAC (B), 3-MT (C), HVA (D), 5-HT (E), and 5-hydroxyindole acetic acid (HIAA) (F) in the hippocampus of mice at 1 h after intragastric administration of 0, 0.2, or 0.6 mg/kg IAA. The levels of monoamines and metabolites were measured using an HPLC-ECD system. Data represent the means ± sem of 5 mice/group. *P < 0.05.

Figure 3

Effects of IAAs on the levels of monoamines and metabolites in ISF of the hippocampus. SD rats were administered 0 or 0.5 mg/kg IAA intragastrically (0 min indicated by arrow), and ISF from the hippocampus was collected using the probe between −20 and 120 min relative to the intragastric administration. The levels of dopamine (DA) (A), DOPAC (B), 3-MT (C), HVA (D), and 5-HT (E) were measured using the respective HPLC-ECD system. Data represent the means ± sem of 9–12 rats/group. **P < 0.01 (baseline vs. time point).

Figure 4

Involvement of dopamine D₁ receptor with memory improvement induced by IAAs. A, B) Effects of IAAs on spatial memory. Mice were administered 0 or 1 mg/kg IAA intragastrically and then injected intraperitoneally with 0.85 mg/kg of SCP and 0.05 mg/kg SCH23390 at 40 min after IAA consumption. At 1 h after IAA consumption, each mouse was allowed to explore the Y maze for 8 min. Spontaneous alternations and arm entries were measured. Effects of IAAs on spontaneous alternations (A) and arm entries (B), respectively, are shown. Data represent the means ± sem of 10 mice/group. *P < 0.05, **P < 0.01. C, D) Effects of dopamine D₁ receptor knockdown (D1-KD) in the hippocampus on memory improvement by IAAs. Mice were administered control miRNA or dopamine D₁ receptor miRNA containing AAV to the hippocampus to suppress the expression of dopamine D₁ receptor. One hour after the intragastric administration of 1 mg/kg IAAs, mice were tested in the Y maze for 8 min. Spontaneous alternations (C) and arm entries (D) are shown. Data analyzed using 2-way ANOVA and Bonferroni test. Data represent the means ± sem of 9 mice/group. *P < 0.05.

Figure 5

Involvement of the vagus nerve on memory improvement induced by IAAs. A, B) Vagotomized or sham-treated mice were administered IAAs intragastrically and subjected to the Y-maze test and NORT. At 1 h after intragastric administration, each mouse was subjected to the Y-maze test and NORT. Spontaneous alternations (A) and DI (B) are shown. C) The levels of dopamine (DA) in the hippocampus treated with IAAs as assessed using HPLC-ECD. Data represent the means ± sem of 7–12 mice/group. *P < 0.05.