The vagus nerve is a key communication pathway between the gut and the brain and has recently been implicated as having roles in cognition, reinforcement and affect, but the circuitry remains poorly understood. The prevailing view is that vagal activation reduces the reward value of food, but Han et al. now show that the vagus nerve can also transmit rewarding signals to the brain.
First, the authors used a combinatorial viral approach to selectively manipulate activity in vagal sensory neurons innervating the upper gut. The cell bodies of these vagal sensory afferents are located in the right and left nodose ganglia (R-NG and L-NG, respectively). Mice were transfected with a virally delivered construct that enabled channelrhodopsin 2 (ChR2) and a fluorescent marker to be selectively expressed in R-NG neurons. An optical fibre was then implanted just above the terminals of R-NG neurons in the medial nucleus of the solitary tract (NTS), which allowed stimulation of R-NG neurons in awake, behaving mice.
Next, the authors optically stimulated R-NG neurons while mice were exposed to a range of behavioural tests of reinforcement, including place preference and operant conditioning assays. They found that in a place preference test, mice preferred the chamber in which they received optical activation to the control chamber, and in an operant conditioning test in which nose pokes triggered R-NG neuronal activation, the mice showed an increasing tendency to self-stimulate, a hallmark of reward-neuron activation. Importantly, food intake was considerably reduced following optical stimulation of R-NG terminals, showing that the previously demonstrated satiety effects of vagal stimulation were intact in this model.
Behavioural reinforcement is known to involve dopamine (DA) release from the substantia nigra pars compacta (SNc) onto dorsal striatum (DS) neurons. The authors found that optically exciting R-NG neurons substantially increased DA release in the DS, consistent with a role of these neurons in reward signalling.
The authors then repeated these experiments following L-NG stimulation. Interestingly, and in contrast to R-NG neurons, L-NG neurons terminated mostly in the posterior part of the area postrema, and optical stimulation of these fibres, despite producing satiety, did not induce self-stimulation or alter striatal DA levels. Overall, these findings suggest that activation of R-NG, but not L-NG, neurons produces reward-like behaviour and DA release in the DS.
NG neurons do not project directly to the SNc, so the authors injected an anterograde trans-synaptic marker into the R-NG to map the central pathway linking vagal afferents to midbrain DA neurons. The marker was found in the dorsal vagal complex (including the NTS), the dorsolateral region of the parabrachial nucleus (PBNdl; an area with high expression of the glutamate transporter VGLUT2) and in neurons of the lateral aspect of the SNc, many of which were dopaminergic. The authors reasoned that excitatory PBNdl–SNc projections might mediate the relay of sensory information from R-NG neurons to the midbrain.
Injection of an anterograde tracer into the PBNdl revealed dense terminal fields in brain areas that included the SNc, and retrograde tracing from the DS showed that PBNdl and DS-projecting neurons coincide in the SNc, suggesting the existence of a PBNdl–SNc–DS pathway. To test this hypothesis, the authors optogenetically stimulated VGLUT2-expressing, SNc-projecting neurons and found that this produced reward-like effects in the operant conditioning and place preference tests, with response levels that were comparable to optogenetic stimulation of R-NG terminals. DA release was increased, suggesting that activating this pathway recapitulates activating R-NG terminals.
optically exciting R-NG neurons substantially increased DA release in the DS, consistent with a role of these neurons in reward signalling
Together, these data suggest that in contrast to previously held assumptions, gut-innervating sensory vagal afferents convey signals that enhance reward-related signalling in key nodes of the reward circuitry of the brain.
Han, W. et al. A neural circuit for gut-induced reward. Cell https://doi.org/10.1016/j.cell.2018.08.049 (2018)
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Lewis, S. Rewarding gut feeling. Nat Rev Neurosci 19, 639 (2018). https://doi.org/10.1038/s41583-018-0075-3