Post by Amanda McFarlan
What's the science?
Research studies have identified the gut as having a key role in the regulation of human motivational and emotional states. However, the mechanism by which emotion and motivation are regulated by the gut-brain axis is unknown. The vagus nerve, extending to the brain and to the gastrointestinal tract, has been the primary target for the study of the gut-brain axis. Initially thought to just be a negative-feedback mechanism for food intake, the vagal gut-brain axis is now known to be involved in emotional and motivational processes like anxiety, depression, and reinforcement learning. This week in Cell, Han and colleagues used virally delivered molecular tools to study the role of the vagal gut-brain axis in motivation and reward.
How did they do it?
In the first experiment, the authors transfected the upper gut (stomach and duodenum) of mice with a virus carrying Cre-recombinase. This virus moves up the neuron towards the cell body, thus, Cre-recombinase was bilaterally transported into the sensory ganglia (cell bodies) of the vagus nerve via sensory afferents innervating the upper gut. Then, they expressed light-sensitive Channelrhodopsin-2 (depolarizing ion channel activated by light via optogenetic techniques) in the left or right sensory ganglia of the vagus nerve. Confocal microscopy was used to determine where the sensory ganglia of the vagus nerve terminated in the brain. The right vagus nerve neurons terminated in the nucleus of the solitary tract and the left vagus nerve neurons terminated in the posterior part of area postrema. Next, they used optic fibers placed in these brain regions to stimulate the left and right vagal nerve terminals, respectively. Finally, they performed behavioural tests like self-stimulation, place preference and flavour conditioning assays. They also measured dopamine levels in the dorsal striatum to determine the reinforcing value of optically stimulating vagal nerve terminals. In the second experiment, the authors used chemogenetics to activate the right and left vagal nerve terminals at the same time. They repeated the place preference behavioural test, flavour conditioning assays and measured dopamine levels in the dorsal striatum to determine the reinforcing value of simultaneous stimulation. They then performed experiments to further characterize any asymmetry between right and left vagal nerve gut-brain pathways.
What did they find?
The authors found that optogenetic activation of the right vagus nerve ganglion (cell bodies) specifically, exhibited reward-type behaviours in mice. These mice had significantly more nose pokes compared to controls to obtain vagal nerve stimulation (self stimulation), and also spent more time in areas of the cage that were paired with optogenetic activation (of the vagal nerve terminals) in the place preference test. Flavour conditioning assays revealed that these mice displayed robust preferences for flavours that were paired with optogenetic stimulation of the right vagal nerve terminals. Additionally, dopamine release in the dorsal striatum, a key requirement in reward learning, was increased with optical activation of the right vagus nerve terminals. Mice that had optogenetic activation of the left vagal nerve ganglion did not display any self-stimulation, place preference or dopamine release in response to optical activation. Activation of the right and left vagus nerve ganglia simultaneously (using chemogenetics) led to reward behaviors: robust place preference and flavour preferences as well as an increase in dopamine release in the dorsal striatum. Thus, the rewarding effects associated with the activation of the right vagus nerve terminal does not appear to be disrupted by the simultaneous activation of the left.
The authors observed that the right and left vagus nerve ganglia project to the brain via asymmetric pathways. In a third experiment using transneuronal labeling, the authors found that glutamatergic neurons of the dorsolateral parabrachial region connect the right vagal sensory ganglion to the Substantia nigra (containing dopamine neurons). They also determined that optical activation of the dorsolateral parabrachial region had the same effects as optical activation of the right vagus nerve ganglion. Mice showed reward behaviors including self-stimulation, place preference for areas where they received optogenetic stimulation and preferences for flavours that were paired with optical stimulation. Mice also had increased levels of dopamine in the dorsal striatum.
What's the impact?
This study is the first to identify the critical role of the vagal gut-brain axis in motivation and reward. The authors show that the right, but not left vagal gut-brain pathway is crucial in mediating motivation and dopamine activity. These findings provide insight into a new direction to help improve treatments for disorders like depression by targeting vagal stimulation to the right side via the upper gut.
Han et al. A neural circuit for gut-induced reward. Cell (2018). Access the original scientific publication here.