Exploring the role of dopamine neurons in salt intake

Abstract

Sodium is an essential element, but in the modern world average salt intake is too high and this is associated with a significant disease burden. In most mammals, depletion of salt leads to a profound behavioural change. This is termed salt appetite. The components of salt appetite are motivation for, ingestion of and enjoyment for hypertonic saline (which is aversive in the salt replete state). Deciphering the neuronal circuits that drive salt seeking behaviour may enable possible future manipulation of pathological salt appetite. Ventral tegmental area (VTA) dopamine neurons play key roles in motivated behaviours. I therefore hypothesise that the mesolimbic dopamine system is an essential component of the circuits driving salt seeking behaviour. To test this idea I studied the effect that manipulation of dopamine neuron activity has on salt appetite. My first step required the establishment of a reliable salt appetite in mice. To achieve this I used a combination of low salt feed and furosemide-induced natriuresis. I quantified the appetite for salt by measuring the intake of salt jellies of varying concentrations in a canteen setup. To control the firing rate of the dopamine neurons I have used optogenetics and chemogenetics. Strikingly, optogenetic excitation of dopamine neurons decreased salt intake in a rapid and reversible manner, despite a strong salt appetite. Importantly, optogenetic stimulation was not aversive, did not induce hyperactivity, and did not interfere with salt concentration preferences when there was no appetite. Optogenetic inhibition, chemogenetic excitation, and chemogenetic inhibition experiments suggested that a ‘burst-like’ pattern of excitation was important to the reduction in salt intake. In addition, optogenetic excitation of dopamine neurons reduced consumption of sucrose following an overnight fast, indicating a more general role of VTA dopamine neuron excitation in suppressing appetite.