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The taste of sugar is one of the most basic sensory percepts for humans and other animals. Animals can develop a strong preference for sugar even if they lack sweet taste receptors, indicating a mechanism independent of taste(1-3). Here we examined the neural basis for sugar preference and demonstrate that a population of neurons in the vagal ganglia and brainstem are activated via the gut-brain axis to create preference for sugar. These neurons are stimulated in response to sugar but not artificial sweeteners, and are activated by direct delivery of sugar to the gut. Using functional imaging we monitored activity of the gut-brain axis, and identified the vagal neurons activated by intestinal delivery of glucose. Next, we engineered mice in which synaptic activity in this gut-to-brain circuit was genetically silenced, and prevented the development of behavioural preference for sugar. Moreover, we show that co-opting this circuit by chemogenetic activation can create preferences to otherwise less-preferred stimuli. Together, these findings reveal a gut-to-brain post-ingestive sugar-sensing pathway critical for the development of sugar preference. In addition, they explain the neural basis for differences in the behavioural effects of sweeteners versus sugar, and uncover an essential circuit underlying the highly appetitive effects of sugar.

Experiments in mice show that a population of neurons in the vagal ganglia respond to the presence of glucose in the gut and connect to neurons in the brainstem, revealing the circuit that underlies the neural basis for the behavioural preference for sugar.

An in vivo approach to identify proteins whose enrichment near cardiac Ca(V)1.2 channels changes upon beta-adrenergic stimulation finds the G protein Rad, which is phosphorylated by protein kinase A, thereby relieving channel inhibition by Rad and causing an increased Ca2+ current.

Increased cardiac contractility during the fight-or-flight response is caused by beta-adrenergic augmentation of Ca(V)1.2 voltage-gated calcium channels(1-4). However, this augmentation persists in transgenic murine hearts expressing mutant Ca(V)1.2 alpha(1C) and beta subunits that can no longer be phosphorylated by protein kinase A-an essential downstream mediator of beta-adrenergic signalling-suggesting that non-channel factors are also required. Here we identify the mechanism by which beta-adrenergic agonists stimulate voltage-gated calcium channels. We express alpha(1C) or beta(2B) subunits conjugated to ascorbate peroxidase(5) in mouse hearts, and use multiplexed quantitative proteomics(6,7) to track hundreds of proteins in the proximity of Ca(V)1.2. We observe that the calcium-channel inhibitor Rad(8,9), a monomeric G protein, is enriched in the Ca(V)1.2 microenvironment but is depleted during beta-adrenergic stimulation. Phosphorylation by protein kinase A of specific serine residues on Rad decreases its affinity for beta subunits and relieves constitutive inhibition of Ca(V)1.2, observed as an increase in channel open probability. Expression of Rad or its homologue Rem in HEK293T cells also imparts stimulation of Ca(V)1.3 and Ca(V)2.2 by protein kinase A, revealing an evolutionarily conserved mechanism that confers adrenergic modulation upon voltage-gated calcium channels.