Astringent flavanol fires the locus-noradrenergic system, regulating neurobehavior and autonomic nerves

Astringency is a characteristic exhibited by only a limited number of polyphenolic compounds which show high electrochemical activity and are susceptible to oxidation at neutral pH conditions like the oral cavity and small intestine. Large-scale intervention studies have demonstrated that the astringent flavanol (FLs) can restore hippocampal-dependent memory. However, due to the low bioavailability of FLs, the mechanism of action remains unclear. In this study, we aimed to elucidate the mechanism by which FLs acts on the nervous system through the gastrointestinal tract. Following a single gavage dose of FLs to mice, spontaneous motor activity in the open field and improved short-term memory in the novel object test were enhanced. Concurrently, activation of stress response systems, such as the sympathetic-adrenal-medullary axis (increased urinary catecholamines) and the hypothalamic-pituitary-adrenal axis (increased corticotropin-releasing hormone mRNA in paraventricular nucleus) was also observed. By the Mass imaging and in situ hybridization analyses, high-intensity noradrenaline (NA) originating from the locus coeruleus (LC) was revealed in the hypothalamus and brainstem immediately after FLs administration. These changes of NA have been suggested as the cause of enhanced memory, arousal and sympathetic activity. Furthermore, increased NA in the nucleus accumbens was observed as a response to visceral sensations induced by oral FLs administration. The present findings highlight how astringent stimulants FLs may activate brain function and the autonomic nervous system via gastrointestinal stimulation, causing physiological changes. These insights suggest that the sensory properties of food are important for maintaining homeostasis and promoting human health.